Composition for treatment and / or prevention of type 2 diabetes, pre-diabetes and / or symptoms thereof

Abstract

The present invention provides methods for treating and / or preventing type 2 diabetes mellitus, pre-diabetes mellitus and / or symptoms thereof in a subject using a composition comprising one or more strains of Bacillus genus, rice bran, L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate. Other uses of the composition are also provided herein.

Description

[0001] The present invention provides methods for treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject using a composition comprising one or more bacterial species of the genus Bacillus, rice bran, L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate. Other uses of the composition are also provided herein. Background Art

[0002] There is increasing evidence that the intestinal microbiome is involved in the development of human diseases, including but not limited to disorders of the immune system, energy metabolism, lipid metabolism, and glucose metabolism [1, 2]. The proper development of metabolic functions in the human body is largely driven by this symbiosis between the intestinal microbiome and the host organism. The amount of microorganisms in the human body is estimated to be approximately 3.8×10 13 , with a total mass ranging from 200 g to 1 kg of total human body weight [3-5]. A wide range of biological processes are influenced by the gut microbiome, such as energy balance homeostasis and nutrient digestion. The trigger for this function is the production of short-chain fatty acids (butyrate, propionate, and acetate), which are considered signaling molecules in the intestinal and extraintestinal tissues [6]. Other functions involve the transport and metabolism of carbohydrates and amino acids, the production of fat-soluble and water-soluble vitamins [7], the elimination of xenobiotics and drugs, and bile acid metabolism [8]. Disturbances in the composition and subsequent function of host-microbiome interactions can lead to chronic systemic inflammation caused by bacterial fragments that appear in the circulation due to intestinal barrier dysfunction. Therefore, intestinal barrier dysfunction has a considerable triggering effect on host obesity and insulin resistance [9].

[0003] Recent evidence suggests that certain bacterial species may interact with host metabolism, for example through metabolite-mediated stimulation of gut hormones. Modulating the gut microbiome with the help of exogenous bacterial supplementation and probiotics may provide a beneficial opportunity for adjunctive therapy in several diseases

[10] . By definition, probiotics are substances contained in certain foods that can modulate the composition of the gut microbiome, thereby affecting short-chain fatty acid production, satiety, weight control, energy homeostasis, as well as inhibiting pathogen growth and immunomodulatory effects [11, 12]. In fact, probiotics have been shown to be effective in a variety of clinical conditions - ranging from infantile diarrhea, necrotizing enterocolitis, antibiotic-associated diarrhea, inflammatory bowel disease to cancer, female urogenital tract infections, surgical infections, insulin resistance and oxidative stress [13-15].

[0004] Diabetes mellitus is a chronic systemic disease associated with complications in most organs of the body. It is an epidemic disease affecting ~9% of the world's population

[21] . Changes in pancreatic β-cell function and insulin resistance lead to relative insulin deficiency and impaired cellular response to insulin. The most prominent symptom of the disease is hyperglycemia, which can cause several serious secondary complications [22, 23]. Antidiabetic drugs are usually used according to national and international treatment guidelines [24, 25], and the most commonly used drug, metformin, has limited efficacy and may adversely affect the composition of the intestinal bacterial microbiota.

[0005] Therefore, there is a need for new compositions, supplements and / or therapeutics for the treatment and / or prevention of type 2 diabetes and / or its symptoms. Summary of the Invention

[0006] Recently, it has been found that patients with diabetes have altered intestinal microbiota, such as an increased ratio of Bacteroides species to Clostridium species in the intestine and an increase in the number of various opportunistic pathogens [26-29]. Circulating Gram-positive intestinal bacteria have been detected in blood samples from patients with diabetes

[28] . Changes in the intestinal microbiota may lead to metabolic endotoxemia by releasing lipopolysaccharides, thereby stimulating inflammation and insulin resistance

[30] . Epithelial enteroendocrine L cells play a role in generating inflammation, and their number is positively or negatively correlated with the abundance of 25 bacterial taxa in the intestine [31, 32].

[0007] In light of these findings, the effects of probiotic supplementation on diabetes and diabetes-related complications have been investigated.

[0008] The inventors have previously developed a (fermented) rice bran-based composition (e.g., a nutritional supplement) with Bacillus subtilis and Bacillus coagulans that provides prebiotic and probiotic properties. The inventors have now surprisingly shown that this composition (referred to herein as AB001) can be advantageously used to safely improve cardiometabolic profiles in subjects, particularly those with type 2 diabetes and / or prediabetes. For example, this composition can advantageously provide a valuable supplement to existing treatment regimens for subjects with type 2 diabetes and / or prediabetes.

[0009] The inventors have unexpectedly shown that AB001 has a beneficial effect on glycemic control and biomarkers of inflammation (e.g., chronic systemic inflammation), insulin resistance, and beta cell dysfunction in patients with type 2 diabetes compared to placebo. Thus, the inventors have advantageously demonstrated that the compositions described herein (AB001) can be used to stabilize blood glucose levels and / or improve glycemic control, particularly for subjects with type 2 diabetes and / or prediabetes. Advantageously, the compositions described herein can also be used to reduce insulin resistance, beta cell dysfunction, and / or inflammation (e.g., chronic systemic inflammation and / or intestinal inflammation) in subjects with type 2 diabetes and / or prediabetes. In some instances, the inflammation can be intestinal and / or pancreatic inflammation.

[0010] Furthermore, the inventors unexpectedly observed that AB001 was more effective than placebo in patients with type 2 diabetes in terms of lipid profile and other parameters of metabolic syndrome. Advantageously, the compositions described herein can be used to treat and / or prevent symptoms of metabolic syndrome in subjects with type 2 diabetes and / or prediabetes.

[0011] AB001 includes specially selected bacterial strains that preferably metabolize glucose and other carbohydrates, thus providing a strong impact on blood sugar levels and insulin resistance. Sugars metabolized in the intestine, such as glucose in food and beverages, are nutrients for microbial community cells (e.g., intestinal microbial community cells) to some extent and are then reabsorbed into the blood as an energy reservoir. Without wishing to be bound by theory, this suggests that AB001 has four glucose control effects: 1) the bacillus strains of AB001 and their secreted enzymes act as additional glucose digesters (in other words, in addition to the microbial community (e.g., intestinal microbial community) of the subject existing before taking AB001, there are also the bacillus strains of AB001 and their secreted enzymes to act) to further reduce glucose absorption by the blood, 2) AB001 reduces low-grade pancreatic inflammation, causing the beta cells of the pancreas to produce more insulin and less proinsulin, 3) AB001 increases the sensitivity of cells to insulin, normalizing the glucose-insulin mechanism, and 4) AB001 changes the ratio of low-density lipids (LDL) to high-density lipids (HDL), making HDL concentrations higher. The latter means that excess glucose is converted to a higher degree into blood fats, such as triglycerides, which are then transported from the blood by HDL to the liver for degradation. In contrast, LDL does the opposite, transporting fat from the liver to the blood. Thus, in some cases, the effects of AB001 are driven by the secretion of bioactive substances (such as enzymes) that break down complex organic molecules into nutrients, reactants, and energy. In some cases, (elevated) glucose levels normalize due to the presence of more insulin.

[0012] This suggests that after resuscitation in the intestine, the Bacillus spp. (and their endospores) in the composition for use according to the present invention scan the biochemical conditions of their microenvironment and begin to secrete uniquely selected bioactive substances to optimize the conditions for their survival and reproduction, such as pH, conductivity, and electrolytes. Nutrients and substrates are crucial for survival and subsequent reproduction. When carbohydrates (particularly glucose) are present in the microenvironment, enzymes targeting carbohydrates (e.g., glucose) are secreted to break down the substrate.

[0013] Advantageously, the composition according to the present invention can be formulated into acid-resistant tablets or capsules. Such preparations are known to be resistant to gastric acid and only dissolve when they reach the duodenum. The Bacillus species of the composition can then be released to colonize the upper part of the intestine, where they can stay for about a day and then be eliminated from the body through feces. The strains of the composition described herein are selected to preferably and effectively metabolize carbohydrates (particularly glucose). This shows that the result of supplementing AB001 is that the intestinal absorption of glucose is lower. Similar effects and corresponding biochemical findings can also be seen when drugs belonging to the SGLT-1 inhibitor class (α-glucosidase inhibitors, such as acarbose or voglibiose) are used in conventional diabetes treatment. SGLT-1 inhibitors actively retain glucose molecules in the intestine, and ultimately they are metabolized by bacteria in the large intestine, with the final product being methane gas. Therefore, the main problems complained by patients treated with SGLT-1 inhibitors are flatulence and bloating [39, 40]. This shows that supplementing with AB001 means less glucose reaches the blood.

[0014] Provided herein is a composition comprising one or more species of Bacillus and rice bran for treating and / or preventing type 2 diabetes, prediabetes and / or symptoms thereof in a subject.

[0015] Also provided herein is a composition comprising one or more species of Bacillus, rice bran, L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate for treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject.

[0016] Also provided herein is a method of treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject, comprising administering to the subject a composition comprising one or more species of Bacillus and rice bran.

[0017] Also provided herein is a method for treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject, comprising administering to the subject a composition comprising one or more species of Bacillus, rice bran, L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate.

[0018] Suitably, the composition may be used to treat and / or prevent type 2 diabetes and / or its symptoms.

[0019] Suitably, administration of the composition to a subject may:

[0020] (a) reducing the level of one or more of HbA1c, glucose, insulin, intact proinsulin, and / or hsCRP in the blood;

[0021] (b) reduction in HOMA-IR score; and / or

[0022] (c) Increase the level of adiponectin in the blood.

[0023] Suitably, administration of the composition to a subject can control blood sugar.

[0024] Suitably, administration of the composition to a subject degrades glucose.

[0025] Suitably, administration of the composition to a subject metabolizes glucose in the subject's gut, optionally, administration of the composition to a subject metabolizes glucose in the subject's intestine, more optionally, administration of the composition to a subject metabolizes glucose in the subject's small intestine.

[0026] Suitably, administration of the composition to a subject reduces the absorption of glucose into the subject's blood.

[0027] Suitably, administration of the composition to a subject reduces the subject's blood glucose concentration.

[0028] Provided herein is a use of a composition comprising one or more species of Bacillus and rice bran for degrading glucose.

[0029] The present invention also provides a composition comprising one or more species of Bacillus and rice bran for the following uses:

[0030] (a) reducing the level of one or more of the following in the subject's blood: HbA1c, glucose (e.g., fasting blood glucose), insulin, intact proinsulin, and / or hsCRP;

[0031] (b) reducing the subject's HOMA-IR score; and / or

[0032] (c) increasing the level of adiponectin in the blood of a subject.

[0033] Provided herein is a use of a composition comprising one or more species of Bacillus and rice bran for controlling blood sugar in a subject.

[0034] The present invention also provides a use of a composition comprising one or more species of Bacillus, rice bran, L-cysteine ​​and a high molecular weight, low osmotic pressure carbohydrate for degrading glucose.

[0035] A composition comprising one or more species of Bacillus, rice bran, L-cysteine ​​and a high molecular weight, low osmotic pressure carbohydrate is used for the following purposes:

[0036] (a) reducing the level of one or more of the following in the subject's blood: HbA1c, glucose, insulin, intact proinsulin, and / or hsCRP;

[0037] (b) reducing the subject's HOMA-IR score; and / or

[0038] (c) increasing the level of adiponectin in the blood of a subject.

[0039] Further provided herein is a use of a composition comprising one or more species of Bacillus, rice bran, L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate for controlling blood sugar in a subject.

[0040] Suitably, the one or more species of the genus Bacillus may be selected from B. subtilis and B. coagulans.

[0041] Suitably, the composition may include Bacillus subtilis and Bacillus coagulans.

[0042] Appropriately,

[0043] a) the Bacillus subtilis species may be selected from the group consisting of: Bacillus subtilis strain DFM 0326 (LMGP-32899) and Bacillus subtilis strain DFM 1015 (LMG P-32900); and / or

[0044] c) The Bacillus coagulans species may be Bacillus coagulans strain DFM 0705 (LMG P-32921).

[0045] Suitably, the high molecular weight low osmotic pressure carbohydrate may be dextrin.

[0046] Suitably, the composition may further comprise one or more species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus velezensis, Bacillus sp MT 03, Bacillus atrophaeus and Pediococcus pentosaceus. Suitably, the composition may further comprise one or more species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus Velezii, Bacillus MT 03, Bacillus atrophaeus, Pediococcus pentosaceus and a genus from the Saccharomycetes (e.g. Brettanomyces bruxellensis (Dekkera bruxellensis according to the old classification), and / or Millerozoma farinosa (Pichia farinosa according to the old classification)).

[0047] Suitably, the composition may comprise at least about 20% w / w L-cysteine.

[0048] Suitably, the composition may comprise at least about 1×10 5 Bacillus bacteria.

[0049] Suitably, the composition may comprise at least about 73% w / w rice bran.

[0050] Suitably, the composition may comprise at least about 0.5% w / w high molecular weight low osmolarity carbohydrate.

[0051] Suitably, the composition may further comprise one or more of the following: vitamin B12, magnesium salt of fatty acid, calcium phosphate, potassium phosphate, silicon dioxide and cellulose, optionally wherein the magnesium salt of fatty acid is magnesium stearate.

[0052] Suitably, the composition may be formulated as acid-resistant tablets or capsules.

[0053] Suitably, the acid resistant tablet or capsule may comprise a film coating, wherein the film coating comprises hydroxypropyl methylcellulose (HPMC).

[0054] Suitably, the one or more species of the genus Bacillus may not be genetically modified.

[0055] Suitably, the composition is intended for daily administration.

[0056] Compositions for use according to the present invention (e.g., compositions for treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject, and / or compositions for use in methods of treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject) include one or more species of Bacillus, rice bran, L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate. Methods of using the compositions are also provided herein.

[0057] In each aspect and each embodiment of the invention described herein, unless the context dictates otherwise, rice bran can be replaced with any suitable cereal (e.g., cereal grain). In these aspects and embodiments, the suitable cereal can be any suitable cereal bran. Suitable cereals and suitable cereal brans are discussed elsewhere herein.

[0058] Throughout the description and claims of this specification, the words "comprise" and "contain" and their variations mean "including but not limited to", and they are not intended to (and do not) exclude other parts, additives, components, integers or steps.

[0059] Throughout the specification and claims of this application, the singular encompasses the plural unless the context requires otherwise. In particular, where the indefinite article is used, the application is to be understood as contemplating plurality as well as singularity unless the context requires otherwise.

[0060] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

[0061] Various aspects of the invention are described in further detail below.

[0062] Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure

[0063] Several Bacillus strains described in this application have been deposited in the Belgian Coordinating Collection of Microorganisms (BCCM) - Bacterial Collection (LMG), an international depository located at Universiteit Gent, KLLedeganckstraat 35, 9000 Gent, Belgium. These deposits were made under the terms of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] The embodiments of the present invention will be further described below with reference to the accompanying drawings, in which:

[0065] Figure 1 Shown are changes in the Freestyle Libre assay between the first two weeks (weeks 0 to 2) and the last two weeks (weeks 5 to 6) of the study observation period.

[0066] Figure 2 Shown are changes from baseline in biomarkers of glycemic control and potential diabetes exacerbation (n=40) measured after 6 weeks of treatment.

[0067] The patents, scientific, and technical literature cited herein establish the knowledge available to those skilled in the art at the time of filing. The entire disclosures of the issued patents, published and pending patent applications, and other publications cited herein are hereby incorporated by reference to the same extent as if each individual disclosure was specifically and individually indicated to be incorporated by reference. In the event of any inconsistency, the present disclosure controls.

[0068] Various aspects of the invention are described in further detail below. DETAILED DESCRIPTION

[0069] The present invention is based on the surprising discovery that a composition (e.g. a nutritional supplement) based on (fermented) rice bran with Bacillus subtilis and Bacillus coagulans can be advantageously used to safely improve the cardiometabolic profile of a subject, in particular a subject with type 2 diabetes and / or prediabetes.

[0070] The inventors have unexpectedly shown that, compared to placebo, AB001 has a beneficial effect on glycemic control and biomarkers of inflammation (e.g., chronic systemic inflammation), insulin resistance, and beta cell dysfunction in patients with type 2 diabetes. Therefore, the inventors have advantageously demonstrated that the compositions described herein (AB001) can be used to stabilize blood sugar levels and / or improve glycemic control, particularly for subjects with type 2 diabetes and / or prediabetes. Advantageously, the compositions described herein can also be used to reduce insulin resistance, beta cell dysfunction, and / or inflammation (e.g., chronic systemic inflammation and / or intestinal inflammation) in subjects with type 2 diabetes and / or prediabetes. In some instances, inflammation can be intestinal and / or pancreatic inflammation. In addition, the inventors unexpectedly observed that, in patients with type 2 diabetes, AB001 was more beneficial than placebo for changes in lipid profiles and other parameters of metabolic syndrome. Advantageously, the compositions described herein can therefore be used to treat and / or prevent the symptoms of metabolic syndrome in subjects with type 2 diabetes and / or prediabetes.

[0071] Thus, provided herein is a composition comprising one or more species of Bacillus, rice bran, L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate for treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject.

[0072] In addition, a method for treating and / or preventing type 2 diabetes, prediabetes and / or symptoms thereof in a subject is provided, comprising administering to the subject a composition comprising one or more species of Bacillus, rice bran, L-cysteine ​​and a high molecular weight, low osmotic pressure carbohydrate.

[0073] Compositions for use according to the invention

[0074] The compositions for treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject, and / or the compositions for use in methods of treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject may be referred to as “MYRKL-S,” “MYRKLS,” “SB001,” and / or “AB001.”

[0075] AB001 includes specially selected bacterial strains that preferentially degrade (e.g., metabolize) glucose and other carbohydrates and also reduce (intestinal and / or pancreatic) inflammation. Without wishing to be bound by theory, this suggests that AB001 has four glucose-controlling effects, as discussed elsewhere herein.

[0076] In vivo, complex carbohydrates that reach the small intestine must be hydrolyzed into monosaccharides (such as glucose or galactose) before they can be transported across the intestinal mucosa. The term "carbohydrate" is particularly used in biochemistry as a synonym for "saccharide." Carbohydrates (saccharides) can be divided into four chemical groups: monosaccharides, disaccharides, oligosaccharides, and polysaccharides. In general, monosaccharides and disaccharides are smaller (lower molecular weight) carbohydrates, commonly referred to as sugars. Those skilled in the art will be able to readily identify carbohydrates using conventional methods in the art. A non-limiting example of a carbohydrate is glucose. The classical pathway for glucose absorption is across the intestinal brush border membrane (BBM) and is believed to be primarily mediated by SGLT1, a sodium-dependent glucose transporter located on the apical side of the enterocytes. This symporter (SGLT1) uses the electrochemical gradient of two sodium ions to transport one glucose molecule. Intracellular glucose is released into the interstitial space near the capillaries via a mechanism believed to occur through facilitated diffusion via the glucose transporter GLUT2, located in the basolateral membrane of the enterocytes.

[0077] Glucose is a 6-carbon structure with the chemical formula C6H12O6. It is a universal source of energy for every organism in the world and is essential for both aerobic and anaerobic cellular respiration.

[0078] In some examples, the composition for use according to the present invention may be a glucose degrading composition.

[0079] As will be clear to those skilled in the art, " glucose degradation compositions " as used herein is a composition for degrading glucose. In other words, " glucose degradation compositions " as used herein is a composition for decomposing (for example, biochemical decomposition) glucose. In the context of the present invention, the degradation (for example decomposition) of a substance (such as a carbohydrate, for example glucose) relates to converting the substance into one or more other different substances. In addition, as will be understood by those skilled in the art, " glucose degradation (glucose degrading) " as used herein refers to decomposing glucose, and " glucose degradation (glucose degradation) " as used herein refers to the decomposition of glucose. As will be clear to those skilled in the art, compositions as described herein can be used in vitro or in vivo.

[0080] Glucose can be degraded (e.g., decomposed) in several different ways. Particularly relevant in the context of the present invention is biochemical degradation. Therefore, in an example, glucose can be biochemically degraded (e.g., decomposed). As known to those skilled in the art, the biochemical decomposition of a substance can involve an enzyme-catalyzed reaction. Therefore, in an example, glucose can be enzymatically degraded.

[0081] Advantageously, compositions as described herein can promote the degradation (e.g., decomposition) of glucose in the digestive tract, thereby reducing the absorption of glucose by the intestinal tract. When using drugs belonging to the SGLT-1 inhibitor class (α-glucosidase inhibitors, such as acarbose or voglibose) in conventional diabetes treatment, similar effects and corresponding biochemical findings can also be seen. SGLT-1 inhibitors actively retain glucose molecules in the intestinal tract, where they are eventually metabolized by the bacteria in the large intestine, and the final product is methane gas. Advantageously, this shows that AB001 has the four glucose control effects discussed above. This shows that being supplemented with AB001 means that less glucose arrives in the blood.

[0082] As used herein, "metabolism" is a term used to describe all biochemical reactions involved in maintaining the vital state of cells and organisms. For example, metabolism includes all biochemical reactions involved in converting one molecule into another (to essentially maintain the viability of the cell or organism). Metabolism includes processes such as cell growth, reproduction, response to the environment, survival mechanisms, nutritional support, and maintenance of cell structure and integrity. The biochemical reactions involved in metabolism utilize various enzymes.

[0083] In one example, glucose can be metabolized (i.e., glucose can be degraded via metabolism). Therefore, in one example, there is provided a glucose metabolism composition according to the present invention's purposes (e.g., for treating and / or preventing type 2 diabetes, prediabetes, and / or its symptoms of a subject, and / or for treating and / or preventing type 2 diabetes, prediabetes, and / or its symptoms in a method), comprising one or more strains of Bacillus, rice bran, L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate (e.g., dextrin). As known to those skilled in the art, metabolism can be enzymatic, and therefore, in some instances, glucose can be metabolized enzymatically.

[0084] Metabolism can be divided into two categories: catabolism and anabolism. Catabolism includes a series of degradative biochemical reactions that break down complex molecules into smaller units, usually releasing energy in the process. For example, catabolism can be used to refer to all biochemical or enzymatic reactions involved in the breakdown of organic or inorganic materials (such as proteins, sugars, fatty acids, etc.). Anabolism includes a series of biochemical reactions that build or synthesize molecules from smaller units, which usually requires the input of energy (ATP) in the process. Therefore, catabolism refers to the destructive biochemical reactions that occur in an organism, while metabolism refers to the entire set of biochemical reactions in an organism, which can be either constructive or destructive.

[0085] In some instances, glucose can be considered as catabolism via the degradation of metabolism. Therefore, in some instances, glucose can be catabolized (i.e., glucose can be degraded via catabolism). In other instances, glucose can be enzymatically catabolized.

[0086] Generally, in the context of the present invention, glucose is degraded in the subject. As non-limiting examples, glucose can be enzymatically decomposed, metabolized or catabolized in the subject. When glucose is degraded in the subject (for example, particularly in the duodenum and / or small intestine), this can be referred to as digestion. In some instances, glucose can be degraded by biochemical digestion.

[0087] Thus, in one example, provided herein is a glucose degrading composition for use according to the present invention, comprising one or more species of Bacillus, rice bran, L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate (eg, dextrin).

[0088] In another embodiment, provided herein is a glucose metabolism composition for use according to the present invention, comprising one or more species of Bacillus, rice bran, L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate (eg, dextrin).

[0089] As discussed elsewhere herein, the compositions for use according to the present invention (e.g., compositions for treating and / or preventing type 2 diabetes, prediabetes, and / or its symptoms in a subject, and / or compositions in methods for treating and / or preventing type 2 diabetes, prediabetes, and / or its symptoms in a subject) include one or more species of the genus Bacillus. For example, the compositions for use according to the present invention may include two or more species of the genus Bacillus. In another example, the compositions for use according to the present invention may include three or more species of the genus Bacillus. In other examples, the compositions for use according to the present invention may include four or more species of the genus Bacillus. In another example, the compositions for use according to the present invention may include five or more species of the genus Bacillus. In another example, the compositions for use according to the present invention may include six or more species of the genus Bacillus. In another example, the compositions for use according to the present invention may include seven or more species of the genus Bacillus.

[0090] As is known in the art, a genus consists of several species. Thus, the genus "Bacillus" includes all species within the genus "Bacillus" known to those skilled in the art, including, but not limited to, Bacillus alkalophilus, Bacillus amyloliquefaciens, Bacillus brevis, Bacillus circulans, Bacillus clausii, Bacillus coagulans, Bacillus firmus, Bacillus lautus, Bacillus lentus, Bacillus licheniformis, Bacillus megaterium, Bacillus pumilus, Bacillus stearothermophilus, Bacillus subtilis, Bacillus velez, Bacillus MT 03, Bacillus atrophaeus, and Bacillus thuringiensis. It is recognized that the genus Bacillus continues to undergo taxonomic reorganization. Thus, this genus is intended to include species that have been reclassified, including but not limited to organisms such as B. stearothermophilus (now designated "Geobacillus stearothermophilus"). The production of resistant endospores in the presence of oxygen is considered the defining characteristic of the genus Bacillus, although this property also applies to the more recently named Alicyclobacillus, Amphibacillus, Aneurinibacillus, Anoxybacillus, Brevibacillus, Filobacillus, Gracilibacillus, Halobacillus, Paenibacillus, Salibacillus, Thermobacillus, Ureibacillus, and Virgibacillus.

[0091] Species in the genus Bacillus are Gram-positive bacteria classified as members of the family Bacillaceae, order Bacilales, class Bacilli. As used herein, "Bacillus species" ("Bacillus sp.") refers to species within the genus "Bacillus."

[0092] Bacillus species found to be particularly important in the context of the present invention include Bacillus subtilis and Bacillus coagulans. As described in the examples below, these bacteria are abundant in the compositions for use according to the present invention and are particularly effective in degrading (e.g., metabolizing) glucose, especially in the digestive tract.

[0093] Thus, in one embodiment, the one or more species of the genus Bacillus are selected from Bacillus subtilis and Bacillus coagulans.

[0094] In another example, the composition for use of the present invention includes Bacillus subtilis and Bacillus coagulans.

[0095] According to the present invention, any suitable strain of Bacillus subtilis and / or Bacillus coagulans may be used. Those skilled in the art will readily be able to identify suitable strains. Bacillus subtilis strain DFM 0326 (LMG P-32899), Bacillus subtilis strain DFM 1015 (LMG P-32900), and Bacillus coagulans strain DFM 0705 (LMG P-32921) have been found to be particularly important in the context of the present invention.

[0096] The Bacillus subtilis strain deposited under LMG-P accession number 32899 may be referred to herein as "DFM 0326" or "strain DFM 0326." Bacillus subtilis strain DFM 0326 (deposited under LMG-P accession number 32899) was deposited on November 22, 2022, under the Budapest Treaty of 1977 with the Belgian Coordinating Collection of Microorganisms (BCCM), Laboratory of Microbiology - Bacterial Collection (LMG), University of Ghent, Roedergonck 35, 9000 Ghent, Belgium.

[0097] The Bacillus subtilis strain deposited under LMG-P accession number 32900 may be referred to herein as "DFM 1015" or "strain DFM 1015." Bacillus subtilis strain DFM 1015 (deposited under LMG-P accession number 32900) was deposited on November 22, 2022, under the Budapest Treaty of 1977 at the Belgian Coordinating Collection of Microorganisms (BCCM) - Laboratory of Microbiology - Bacterial Collection (LMG), University of Ghent, Roedergankstrasse 35, 9000 Ghent, Belgium.

[0098] The Bacillus coagulans strain deposited under LMG-P accession number 32921 may be referred to herein as "DFM 0705" or "strain DFM 0705." Bacillus coagulans strain DFM 0705 (deposited under LMG-P accession number 32921) was deposited on December 14, 2022, under the Budapest Treaty of 1977 at the Belgian Coordinating Collection of Microorganisms (BCCM) - Laboratories of Microbiology - Bacterial Collection (LMG), University of Ghent, Roedergonck 35, 9000 Ghent, Belgium.

[0099] Thus, in some examples, the Bacillus subtilis species can be selected from the group consisting of: Bacillus subtilis strain DFM 0326 (LMG P-32899) and Bacillus subtilis strain DFM 1015 (LMG P-32900); and / or the Bacillus coagulans species can be Bacillus coagulans strain DFM 0705 (LMG P-32921).

[0100] Thus, in examples where the composition includes Bacillus subtilis and Bacillus coagulans, the Bacillus subtilis species can be Bacillus subtilis strain DFM 0326 (LMG P-32899) and the Bacillus coagulans species can be Bacillus coagulans strain DFM 0705 (LMG P-32921).

[0101] In another example where the composition includes Bacillus subtilis and Bacillus coagulans, the Bacillus subtilis species can be Bacillus subtilis strain DFM 1015 (LMG P-32900) and the Bacillus coagulans species can be Bacillus coagulans strain DFM 0705 (LMG P-32921).

[0102] In some examples, a composition according to the present invention may include a combination of Bacillus subtilis strain DFM 0326 (LMG P-32899) and Bacillus subtilis strain DFM 1015 (LMG P-32900).

[0103] In another example where the composition includes Bacillus subtilis and Bacillus coagulans, the composition can include Bacillus subtilis strain DFM 0326 (LMG P-32899) and Bacillus subtilis strain DFM 1015 (LMG P-32900) and Bacillus coagulans species strain DFM 0705 (LMG P-32921). Of note, the compositions used in the Examples provided herein include Bacillus subtilis strain DFM 0326 (LMG P-32899) and Bacillus subtilis strain DFM 1015 (LMGP-32900) and Bacillus coagulans strain DFM 0705 (LMG P-32921).

[0104] Thus, the composition for use according to the present invention may comprise Bacillus subtilis strain DFM 0326 (LMG P-32899), Bacillus subtilis strain DFM 1015 (LMG P-32900) and Bacillus coagulans strain DFM 0705 (LMG P-32921).

[0105] The inventors have also identified several other bacterial species that are particularly relevant in the context of the present invention. Thus, in one example, the composition for use according to the present invention may further include one or more bacterial species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus Velez-Bacillus, Bacillus MT 03, Bacillus atrophaeus, and Pediococcus pentosaceus. In one example, the composition for use according to the present invention may further include one or more bacterial species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus Velez-Bacillus, Bacillus MT 03, Bacillus atrophaeus, Pediococcus pentosaceus, and a genus from the yeast family (e.g., Dekkera bruxellensis and / or Thauma milleri powdery). In another example, the composition for use according to the present invention may further include two or more, three or more, or four or more bacterial species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus Velez-Bacillus, Bacillus MT 03, Bacillus atrophaeus, and Pediococcus pentosaceus. In another example, the composition for use according to the present invention can further include two or more, three or more, or four or more species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus velezensis, Bacillus sp. MT 03, Bacillus atrophaeus, Pediococcus pentosaceus, and a genus from Saccharomyces (e.g., Dekkera bruxellensis and / or Thaumatella milleri).

[0106] In another example, the composition for use according to the present invention may further include Bacillus amyloliquefaciens, Bacillus Velezii, Bacillus MT 03, Bacillus atrophaeus and Pediococcus pentosaceus. In another example, the composition for use according to the present invention may further include Bacillus amyloliquefaciens, Bacillus Velezii, Bacillus MT 03, Bacillus atrophaeus, Pediococcus pentosaceus and a genus from the yeast species (e.g., Dekkera bruxellensis and / or Thaumatella milleri).

[0107] The bacterial strains included in the compositions described herein were identified as preferentially and efficiently metabolizing glucose. Advantageously, this showed that supplementation with AB001 resulted in lower glucose absorption through the intestine. Therefore, this suggests that supplementation with AB001 means less glucose enters the bloodstream.

[0108] The composition of purposes according to the present invention includes one or more strains of the described Bacillus of appropriate amount or concentration.Therefore, the amount or concentration of one or more strains of Bacillus can be described by the number (cfu / g) of colony forming units (cfu) of reference per gram of composition or the total number (in other words, the cfu of every effective dose) of colony forming units (cfu) of every dosage composition.As should be clear to those skilled in the art, and as described in more detail elsewhere herein, dosage can include one or more dosage units (for example, 2 dosage units).In the example that wherein using multiple dosage units to provide effective dose, cfu / dosage corresponds to the total cfu of multiple dosage units.

[0109] In one example, the composition described herein includes about 10,000 cfu / g of Bacillus bacteria to about 1×10 8 cfu / g of Bacillus bacteria.

[0110] In one embodiment, the compositions described herein include at least about 1×10 8 cfu / g of Bacillus bacteria. In another example, the composition described herein includes at least about 1×10 7 cfu / g of Bacillus bacteria. In another example, the composition described herein includes at least about 1×10 6 cfu / g of Bacillus bacteria. In other examples, the compositions described herein include at least about 1×10 5 cfu / g of Bacillus bacteria.

[0111] In one example, the compositions described herein include at least about 10,000 cfu / g (i.e., at least about 1.0×10 4 cfu / g) of Bacillus bacteria.

[0112] In another example, the compositions described herein include at least about 11,000 cfu / g (i.e., at least about 1.1×10 4 cfu / g) of Bacillus bacteria. In other examples, the compositions described herein include at least about 12,000 cfu / g (i.e., at least about 1.2×10 4 cfu / g) of Bacillus bacteria.

[0113] In another example, the compositions described herein include at least about 13,000 cfu / g (i.e., at least about 1.3×10 4 cfu / g) of Bacillus bacteria.

[0114] In another example, the compositions described herein include at least about 14,000 cfu / g (i.e., at least about 1.4×10 4 cfu / g) of Bacillus bacteria. In another example, the composition described herein includes at least about 15,000 cfu / g (i.e., at least about 1.5×10 4 cfu / g) of Bacillus bacteria.

[0115] In one embodiment, the composition described herein comprises about 1×10 8 cfu / g of Bacillus bacteria. In another example, the composition described herein includes about 1×10 7 cfu / g of Bacillus bacteria. In another example, the composition described herein includes about 1×10 6 cfu / g of Bacillus bacteria. In other examples, the compositions described herein include about 1×10 5 cfu / g of Bacillus bacteria.

[0116] In one example, the compositions described herein include about 10,000 cfu / g (ie, about 1.0×10 4 cfu / g) of Bacillus bacteria.

[0117] In another example, the composition described herein comprises about 11,000 cfu / g (ie, about 1.1×10 4 cfu / g) of Bacillus bacteria. In other examples, the compositions described herein include about 12,000 cfu / g (ie, about 1.2×10 4 cfu / g) of Bacillus bacteria.

[0118] In another example, the composition described herein comprises about 13,000 cfu / g (ie, about 1.3×10 4 cfu / g) of Bacillus bacteria.

[0119] In another example, the composition described herein comprises about 14,000 cfu / g (ie, about 1.4×10 4 cfu / g) of Bacillus bacteria. In other examples, the compositions described herein include about 15,000 cfu / g (ie, about 1.5×10 4 cfu / g) of Bacillus bacteria.

[0120] Those skilled in the art will be able to readily determine the amount or concentration of bacteria present in a composition using conventional methods known in the art. For example, the total viable count (TVC) of Bacillus viable cells can be determined, for example, by established culture methods based on specific Bacillus culture media (such as Chrome Select agar). Alternative methods are known in the art.

[0121] In one example, the compositions described herein include about 5,000 cfu of Bacillus bacteria per dose to about 1×10 8 cfu of Bacillus bacteria / dose.

[0122] In one embodiment, the compositions described herein include at least about 1×10 8 cfu of Bacillus bacteria / dose. In another example, the compositions described herein include at least about 1×10 7 cfu of Bacillus bacteria / dose. In another example, the compositions described herein include at least about 1×10 6 cfu of Bacillus bacteria / dose.

[0123] In other examples, the compositions described herein include at least about 1×10 5 cfu of Bacillus bacteria / dose.

[0124] In one example, the compositions described herein include at least about 5,000 cfu (ie, at least about 0.5×10 4 cfu) of Bacillus bacteria / dose.

[0125] In another example, the compositions described herein include at least about 10,000 cfu (i.e., at least about 1.0×10 4 cfu) of Bacillus bacteria per dose. In another example, the compositions described herein include at least about 11,000 cfu (i.e., at least about 1.1×10 4 cfu) of Bacillus bacteria per dose. In other examples, the compositions described herein include at least about 12,000 cfu (i.e., at least about 1.2×10 4cfu) of Bacillus bacteria per dose. In another example, the compositions described herein include at least about 13,000 cfu (i.e., at least about 1.3×10 4 cfu) of Bacillus bacteria per dose. In another example, the compositions described herein include at least about 14,000 cfu (i.e., at least about 1.4×10 4 cfu) of Bacillus bacteria per dose. In another example, the compositions described herein include at least about 15,000 cfu (i.e., at least about 1.5×10 4 cfu) of Bacillus bacteria / dose.

[0126] In one embodiment, the composition described herein comprises about 1×10 8 cfu of Bacillus bacteria / dose. In another example, the composition described herein includes about 1×10 7 cfu of Bacillus bacteria / dose. In another example, the composition described herein includes about 1×10 6 cfu of Bacillus bacteria / dose.

[0127] In other examples, the compositions described herein include about 1×10 5 cfu of Bacillus bacteria / dose.

[0128] In one example, the compositions described herein include about 5,000 cfu (ie, about 0.5×10 4 cfu) of Bacillus bacteria per dose. In one example, the compositions described herein include about 10,000 cfu (ie, about 1.0×10 4 cfu) of Bacillus bacteria per dose. In another example, the composition described herein includes about 11,000 cfu (ie, about 1.1×10 4 cfu) of Bacillus bacteria per dose. In other examples, the compositions described herein include about 12,000 cfu (ie, about 1.2×10 4 cfu) of Bacillus bacteria per dose. In another example, the composition described herein includes about 13,000 cfu (ie, about 1.3×10 4 cfu) of Bacillus bacteria per dose. In another example, the composition described herein includes about 14,000 cfu (ie, about 1.4×10 4 cfu) of Bacillus bacteria per dose. In other examples, the compositions described herein include about 15,000 cfu (ie, about 1.5×10 4 cfu) of Bacillus bacteria / dose.

[0129] As will be apparent to those skilled in the art, the amount or concentration of one or more species of the genus Bacillus in the composition can consist of any single species of the genus Bacillus or any combination of species of the genus Bacillus. For example, the amount or concentration of one or more species of the genus Bacillus in the composition can consist entirely of one species of Bacillus (e.g., the concentration can consist entirely of Bacillus subtilis or entirely of Bacillus coagulans). Alternatively, the amount or concentration of one or more species of the genus Bacillus in the composition can consist of two or more species of the genus Bacillus, three or more species of the genus Bacillus, four or more species of the genus Bacillus, or five or more species of the genus Bacillus (e.g., the concentration can consist of Bacillus subtilis and Bacillus coagulans). Thus, in one example, the amount or concentration of one or more species of the genus Bacillus in the composition refers to the amount or concentration of the combination of species of Bacillus present.

[0130] In some examples, the compositions provided herein include an appropriate concentration of bacteria, wherein the concentration ratio is composed of one or more species of the genus Bacillus (e.g., Bacillus subtilis and / or Bacillus coagulans). In one example, the composition described herein includes about 10,000 cfu / g (i.e., about 1.0×10 4 cfu / g) of bacteria is about 1×10 8 cfu / g of bacteria. In one embodiment, the composition described herein comprises at least about 1×10 8 In another example, the composition described herein comprises at least about 1×10 7 In another example, the composition described herein comprises at least about 1×10 6 cfu / g of bacteria. In other examples, the compositions described herein include at least about 1×10 5 cfu / g of bacteria. In one example, the compositions described herein include at least about 10,000 cfu / g (i.e., at least about 1.0×10 4 cfu / g) of bacteria. In another example, the compositions described herein include at least about 11,000 cfu / g (i.e., at least about 1.1×10 4 cfu / g) of bacteria. In other examples, the compositions described herein include at least about 12,000 cfu / g (i.e., at least about 1.2×10 4 cfu / g) of bacteria. In another example, the compositions described herein include at least about 13,000 cfu / g (i.e., at least about 1.3×10 4 cfu / g) of bacteria. In another example, the compositions described herein include at least about 14,000 cfu / g (i.e., at least about 1.4×10 4In another example, the composition described herein comprises at least about 15,000 cfu / g (i.e., at least about 1.5×10 4 cfu / g) of bacteria. In one example, the composition described herein includes about 1×10 8 cfu / g of bacteria. In another example, the composition described herein comprises about 1×10 7 cfu / g of bacteria. In another example, the composition described herein comprises about 1×10 6 cfu / g of bacteria. In other examples, the compositions described herein include about 1×10 5 cfu / g of bacteria. In one example, the composition described herein includes about 10,000 cfu / g (ie, about 1.0×10 4 cfu / g) of bacteria. In another example, the composition described herein includes about 11,000 cfu / g (ie, about 1.1×10 4 cfu / g) of bacteria. In other examples, the compositions described herein include about 12,000 cfu / g (ie, about 1.2×10 4 cfu / g) of bacteria. In another example, the composition described herein includes about 13,000 cfu / g (ie, about 1.3×10 4 cfu / g) of bacteria. In another example, the composition described herein includes about 14,000 cfu / g (ie, about 1.4×10 4 cfu / g) of bacteria. In other examples, the compositions described herein include about 15,000 cfu / g (ie, about 1.5×10 4 cfu / g) of bacteria.

[0131] In some examples, the compositions described herein include an appropriate amount of bacteria, wherein the ratio of the amount is composed of one or more species of the genus Bacillus (e.g., Bacillus subtilis and / or Bacillus coagulans). In one example, the compositions described herein include about 5,000 cfu of bacteria / dose to about 1×10 8 cfu of bacteria / dose. In one embodiment, the compositions described herein include at least about 1×10 8 cfu of bacteria / dose. In another example, the compositions described herein include at least about 1×10 7 cfu of bacteria / dose. In another example, the compositions described herein include at least about 1×10 6 cfu of bacteria / dose. In other examples, the compositions described herein include at least about 1×10 5 cfu of bacteria / dose. In one example, the compositions described herein include at least about 5,000 cfu (i.e., at least about 0.5×104 cfu) of bacteria per dose. In another example, the compositions described herein include at least about 10,000 cfu (i.e., at least about 1.0×10 4 cfu) of bacteria per dose. In another example, the compositions described herein include at least about 11,000 cfu (i.e., at least about 1.1×10 4 cfu) of bacteria per dose. In other examples, the compositions described herein include at least about 12,000 cfu (i.e., at least about 1.2×10 4 cfu) of bacteria per dose. In another example, the compositions described herein include at least about 13,000 cfu (i.e., at least about 1.3×10 4 cfu) of bacteria per dose. In another example, the compositions described herein include at least about 14,000 cfu (i.e., at least about 1.4×10 4 cfu) of bacteria per dose. In another example, the compositions described herein include at least about 15,000 cfu (i.e., at least about 1.5×10 4 cfu) of bacteria / dose. In one example, the composition described herein includes about 1×10 8 cfu of bacteria / dose. In another example, the composition described herein comprises about 1×10 7 cfu of bacteria / dose. In another example, the composition described herein comprises about 1×10 6 cfu of bacteria / dose. In other examples, the compositions described herein include about 1×10 5 cfu of bacteria / dose. In one example, the compositions described herein include about 5,000 cfu (ie, about 0.5×10 4 cfu) of bacteria per dose. In one example, the compositions described herein include about 10,000 cfu (ie, about 1.0×10 4 cfu) of bacteria per dose. In another example, the composition described herein includes about 11,000 cfu (ie, about 1.1×10 4 cfu) of bacteria per dose. In other examples, the compositions described herein include about 12,000 cfu (ie, about 1.2×10 4 cfu) of bacteria per dose. In another example, the composition described herein includes about 13,000 cfu (ie, about 1.3×10 4 cfu) of bacteria per dose. In another example, the compositions described herein include about 14,000 cfu (ie, about 1.4×10 4 cfu) of bacteria per dose. In other examples, the compositions described herein include about 15,000 cfu (ie, about 1.5×10 4cfu) of bacteria / dose.

[0132] As will be clear to those skilled in the art, the amount or concentration of bacteria, wherein the proportion consists of one or more species of the genus Bacillus (e.g., Bacillus subtilis and / or Bacillus coagulans), may further include any suitable individual species or any combination of species. For example, the amount or concentration of bacteria, wherein the proportion consists of one or more species of the genus Bacillus (e.g., Bacillus subtilis and / or Bacillus coagulans), may further include a proportion of one or more species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus velezensis, Bacillus MT 03, Bacillus atrophaeus, and Pediococcus pentosaceus. For example, the amount or concentration of bacteria, wherein the proportion consists of one or more species of the genus Bacillus (e.g., Bacillus subtilis and / or Bacillus coagulans), may further include a proportion of one or more species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus velezensis, Bacillus MT 03, Bacillus atrophaeus, Pediococcus pentosaceus, and a genus from the yeast family (e.g., Dekkera bruxellensis and / or Thaumatella milleri).

[0133] In one example, one or more species of the genus Bacillus are genetically modified.

[0134] As used herein, "genetic modification" and "genetic engineering" refer to the direct manipulation (e.g., modification) of one or more genes, for example, using recombinant DNA technology. Traditionally, humans have indirectly manipulated genomes by controlling breeding and selecting offspring with desired characteristics, however, genetic engineering involves the direct manipulation (e.g., modification) of one or more genes. For example, a gene from another species can be added to the genome of an organism to give it a desired phenotype.

[0135] In other examples, the one or more species of Bacillus are not genetically modified. In other words, the one or more species of Bacillus can be naturally occurring.

[0136] One or more species of the genus Bacillus can be present in a microbial consortium. As used herein, a "microbial consortium" refers to a group of microorganisms (e.g., bacteria) wherein the group includes two or more different microorganisms (e.g., two or more bacteria, which can be from the same species (e.g., two or more different strains) or different species (e.g., two or more different species).

[0137] The microbial consortium can be a naturally occurring microbial consortium (e.g., a consortium naturally produced during the fermentation of a cereal grain (such as rice bran). In other words, the one or more species of Bacillus can become part of the composition due to the presence of the fermented cereal grain (such as rice bran) (and its associated naturally occurring microbial consortium) in the composition. Thus, the one or more species of Bacillus can be a natural component of the fermented cereal grain (such as rice bran).

[0138] The present inventors have discovered that Bacillus subtilis strain DFM 0326 (LMG P-32899), Bacillus subtilis strain DFM 1015 (LMG P-32900), and Bacillus coagulans strain DFM 0705 (LMG P-32921) can be isolated from the compositions used in the examples provided herein, particularly fermented rice bran. Thus, Bacillus subtilis strain DFM 0326 (LMG P-32899), Bacillus subtilis strain DFM 1015 (LMG P-32900), and Bacillus coagulans strain DFM 0705 (LMGP-32921) can be part of the compositions described herein because fermented grains, such as rice bran (and their associated naturally occurring microbial consortia) are present in the compositions.

[0139] In one example, the one or more species of Bacillus selected from Bacillus subtilis and Bacillus coagulans can be a naturally occurring microbial consortium (e.g., a consortium naturally produced during the fermentation of a grain, such as rice bran). In other words, due to the presence of a fermented grain, such as rice bran (and its associated naturally occurring microbial consortium), in the composition, the one or more species of Bacillus selected from Bacillus subtilis and Bacillus coagulans can be part of the composition. Thus, the one or more species of Bacillus selected from Bacillus subtilis and Bacillus coagulans can be a natural component of the fermented grain, such as rice bran.

[0140] In another example, one or more species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus Velezius, Bacillus MT 03, Bacillus atrophaeus, and Pediococcus pentosaceus can be (part of) a naturally occurring microbial consortium (e.g., a consortium naturally produced during the fermentation of a grain, such as rice bran). In other words, due to the presence of a fermented grain, such as rice bran (and its associated naturally occurring microbial consortium) in the composition, one or more species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus Velezius, Bacillus MT 03, Bacillus atrophaeus, and Pediococcus pentosaceus can be part of the composition. Thus, one or more species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus Velezius, Bacillus MT 03, Bacillus atrophaeus, and Pediococcus pentosaceus can be a natural component of a fermented grain, such as rice bran.

[0141] In another example, one or more species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus velezensis, Bacillus sp. MT 03, Bacillus atrophaeus, Pediococcus pentosaceus, and a genus from the yeast family (e.g., Dekkera bruxellensis and / or Thaumatella milleri) can be (part of) a naturally occurring microbial consortium (e.g., a consortium naturally produced during fermentation of a grain (such as rice bran)). In other words, due to the presence of a fermented grain, such as rice bran (and its associated naturally occurring microbial consortium) in the composition, one or more species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus velezensis, Bacillus sp. MT 03, Bacillus atrophaeus, Pediococcus pentosaceus, and a genus from the yeast family (e.g., Dekkera bruxellensis and / or Thaumatella milleri) can be part of the composition. Thus, one or more species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus velezensis, Bacillus sp. MT 03, Bacillus atrophaeus, Pediococcus pentosaceus and from the genus Saccharomyces (e.g. Dekkera bruxellensis and / or Thaumatella milleri) may be natural components of fermented cereals such as rice bran.

[0142] In another example, one or more species of Bacillus (e.g., Bacillus subtilis and / or Bacillus coagulans) and one or more species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus Velezii, Bacillus MT 03, Bacillus atrophaeus, and Pediococcus pentosaceus can be (part of) a naturally occurring microbial consortium (e.g., a consortium naturally produced during the fermentation of a grain (such as rice bran)). In other words, due to the presence of a fermented grain, such as rice bran (and its associated naturally occurring microbial consortium) in the composition, one or more species of Bacillus (e.g., Bacillus subtilis and / or Bacillus coagulans) and one or more species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus Velezii, Bacillus MT 03, Bacillus atrophaeus, and Pediococcus pentosaceus can be part of the composition. Thus, one or more species of Bacillus (e.g., Bacillus subtilis and / or Bacillus coagulans) and one or more species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus velezensis, Bacillus MT 03, Bacillus atrophaeus, and Pediococcus pentosaceus can be natural components of fermented grains, such as rice bran.

[0143] In another example, one or more species of Bacillus (e.g., Bacillus subtilis and / or Bacillus coagulans) and one or more species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus velezensis, Bacillus MT 03, Bacillus atrophaeus, Pediococcus pentosaceus, and a genus from Saccharomyces (e.g., Dekkera bruxellensis and / or Thaumatella milleri) can be (part of) a naturally occurring microbial consortium (e.g., a consortium naturally produced during fermentation of a grain (such as rice bran)). In other words, one or more species of Bacillus (e.g., Bacillus subtilis and / or Bacillus coagulans) and one or more species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus velezensis, Bacillus MT 03, Bacillus atrophaeus, Pediococcus pentosaceus, and a genus from Saccharomyces (e.g., Dekkera bruxellensis and / or Thaumatella milleri) can be part of the composition due to the presence of a fermented grain, such as rice bran (and its associated naturally occurring microbial consortium) in the composition. Thus, one or more species of the genus Bacillus (e.g., Bacillus subtilis and / or Bacillus coagulans) and one or more species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus velezensis, Bacillus MT 03, Bacillus atrophaeus, Pediococcus pentosaceus, and from the genus Saccharomyces (e.g., Dekkera bruxellensis and / or Thaumatella milleri). can be natural components of fermented grains (such as rice bran).

[0144] As will be apparent to those skilled in the art, the compositions for use according to the present invention are not limited to naturally occurring microbial consortia. Thus, the microbial consortia discussed above may also be artificially generated, for example by combining one or more bacterial isolates. In one example, one or more species of the genus Bacillus (e.g., Bacillus subtilis and / or Bacillus coagulans) may be added to the composition alone.

[0145] Thus, the compositions for use according to the present invention (e.g., compositions for treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject, and / or compositions for use in methods of treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject) may also include a cereal, such as rice bran (e.g., fermented rice bran), as discussed in more detail elsewhere herein. For example, fermented rice bran may be the natural source of one or more species of Bacillus (e.g., Bacillus subtilis and / or Bacillus coagulans) present in the composition.

[0146] As described elsewhere herein, compositions for use according to the present invention (e.g., compositions for treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject, and / or compositions for use in methods of treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject) comprise L-cysteine ​​in combination with one or more species of the genus Bacillus (e.g., wherein the bacteria are added to the composition as a bacterial supplement or natural product (e.g., as part of fermented rice bran)).

[0147] L-cysteine ​​(L-cys) is a non-essential amino acid and is therefore one of the building blocks required for protein synthesis. It contains sulfur in the form of a thiol group (-SH) at the end of its side chain. The -SH group is responsible for the high reactivity of amino acids and, therefore, for many of their biological functions in humans. L-cysteine ​​plays a key role in the sulfur metabolism of all organisms and is used to synthesize proteins, glutathione, biotin, lipoic acid, methionine, and other sulfur-containing metabolites. In addition, L-cysteine ​​is a precursor for the biosynthesis of coenzyme A. The biosynthesis of L-cysteine ​​has been studied in detail in bacteria, especially in Enterobacteriaceae. The amino acid L-cysteine ​​is not only of biological importance, but also of economic importance. For example, it is used as a food additive (particularly in the baking industry), as a starting material in cosmetics, and as a starting material for the preparation of active pharmaceutical ingredients (particularly N-acetylcysteine ​​and S-carboxymethylcysteine).

[0148] As will be clear to the skilled person, L-cysteine ​​referred to herein refers to the amino acid L-cysteine ​​in any suitable form. Thus, the term "L-cysteine" encompasses both free form L-cysteine ​​as well as L-cysteine ​​salts.

[0149] In the context of the present invention, in one embodiment, L-cysteine ​​can be in free form, a salt thereof, or a mixture thereof. Examples of salts include, for example, sulfates, hydrochlorides, carbonates, ammonium salts, sodium salts, and potassium salts. In one embodiment, the crystal fraction of L-cysteine ​​is >0.1 mm.

[0150] L-cysteine ​​is available from several suppliers and can be readily obtained by the skilled person. In addition, the skilled person can readily detect the presence of L-cysteine ​​in a substance (e.g., in the compositions described herein) using methods known in the art. For example, L-cysteine ​​crystals can be macroscopically detected in the compositions described herein as white particles. HPLC (high performance liquid chromatography) on an Inertsil ODs-3 column is an established method for detecting L-cysteine.

[0151] L-cysteine ​​can be obtained industrially by hydrolyzing animal materials such as poultry feathers or pig hair. In contrast, synthetic L-cysteine ​​can be obtained from the fermentation of genetically modified Escherichia coli (E. coli) or Pseudomonas thiazolinophilum. Therefore, in some instances, L-cysteine ​​is derived from animals. In other instances, L-cysteine ​​is derived from synthesis.

[0152] Thus, in some examples, the L-cysteine ​​is derived from a plant source.

[0153] In some examples, the compositions described herein can include an L-cysteine ​​derivative in place of or in addition to L-cysteine.

[0154] L-cysteine ​​derivatives are well known to those skilled in the art. N-acetylcysteine ​​(NAC) is the N-acetylated form of the amino acid L-cysteine ​​and is therefore an example of an L-cysteine ​​derivative. Thus, in some examples, the compositions described herein may include N-acetylcysteine ​​(NAC). NAC is readily available in the art.

[0155] L-cysteine ​​is present in the compositions described herein at an appropriate concentration or amount. Therefore, the amount or concentration of L-cysteine ​​can be described with reference to the % w / w of the composition or the gross weight (e.g., mg) of each dose of the composition (in other words, the weight of each effective dose). As will be apparent to those skilled in the art, and as described in more detail elsewhere herein, a dosage can include one or more dosage units (e.g., 2 dosage units). In instances where an effective dose is provided using multiple dosage units, the weight of each dosage corresponds to the gross weight of the L-cysteine ​​in the multiple dosage units.

[0156] In one example, the composition includes about 10% w / w L-cysteine ​​to about 40% w / w L-cysteine.

[0157] In another example, the composition includes about 15% w / w L-cysteine ​​to about 35% w / w L-cysteine. In another example, the composition includes about 20% w / w L-cysteine ​​to about 30% w / w L-cysteine.

[0158] In one example, the composition includes at least about 10% w / w L-cysteine.

[0159] In another example, the composition includes at least about 15% w / w L-cysteine.

[0160] In other examples, the composition includes at least about 20% w / w L-cysteine.

[0161] In another example, the composition includes at least about 25% w / w L-cysteine. In another example, the composition includes at least about 30% w / w L-cysteine. In other examples, the composition includes at least about 35% w / w L-cysteine. In other examples, the composition includes at least about 40% w / w L-cysteine.

[0162] In some examples, the composition includes about 10% w / w L-cysteine.

[0163] In another example, the composition includes about 15% w / w L-cysteine.

[0164] In another example, the composition includes about 20% w / w L-cysteine.

[0165] In other examples, the composition includes about 25% w / w L-cysteine. In another example, the composition includes about 30% w / w L-cysteine. In another example, the composition includes about 35% w / w L-cysteine. In other examples, the composition includes about 40% w / w L-cysteine.

[0166] In one example, the composition includes about 38 mg of L-cysteine ​​per dose to about 200 mg of L-cysteine ​​per dose.

[0167] In one example, the composition includes at least about 38 mg of L-cysteine ​​per dose.

[0168] In one example, the composition includes at least about 50 mg of L-cysteine ​​per dose. In one example, the composition includes at least about 75 mg of L-cysteine ​​per dose. In one example, the composition includes at least about 100 mg of L-cysteine ​​per dose.

[0169] In one example, the composition includes at least about 150 mg of L-cysteine ​​per dose.

[0170] In one example, the composition includes at least about 160 mg of L-cysteine ​​per dose. In one example, the composition includes at least about 180 mg of L-cysteine ​​per dose.

[0171] In one example, the composition includes about 38 mg of L-cysteine ​​per dose.

[0172] In one example, the composition includes about 50 mg of L-cysteine ​​per dose. In one example, the composition includes about 75 mg of L-cysteine ​​per dose. In one example, the composition includes about 100 mg of L-cysteine ​​per dose.

[0173] In one example, the composition includes about 150 mg of L-cysteine ​​per dose.

[0174] In one example, the composition includes about 160 mg of L-cysteine ​​per dose. In one example, the composition includes about 180 mg of L-cysteine ​​per dose.

[0175] As described elsewhere herein, compositions for use according to the present invention (e.g., compositions for treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject, and / or compositions for use in methods of treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject) comprise L-cysteine ​​in combination with one or more species of Bacillus and a high molecular weight, low osmotic pressure carbohydrate (e.g., dextrin).

[0176] As used herein, "high molecular weight low osmotic pressure carbohydrate" refers to a carbohydrate having a molecular weight of about 500,000 g / mol to about 700,000 g / mol, wherein the osmotic pressure of the carbohydrate is low. One skilled in the art will be able to readily identify suitable carbohydrates having low osmotic pressure using routine tests known in the art. For the avoidance of doubt, as used herein, a low osmotic pressure carbohydrate is a carbohydrate that has a glycogen recovery rate that is about 50% higher than that of maltodextrin.

[0177] High molecular weight low osmotic pressure carbohydrate is present in the compositions described herein with appropriate concentration or amount.Therefore, the amount or concentration of high molecular weight low osmotic pressure carbohydrate can be described with reference to the % w / w of composition or the gross weight (such as mg) of each dosage composition (in other words, the weight of each effective dose).As should be clear to those skilled in the art, and as described in more detail elsewhere herein, dosage can include one or more dosage units (such as 2 dosage units).In the example that wherein multiple dosage units are used to provide effective dose, the weight of each dosage corresponds to the gross weight of high molecular weight low osmotic pressure carbohydrate in multiple dosage units.

[0178] In one example, the composition includes from about 0.5% w / w to about 5% w / w of a high molecular weight low osmotic pressure carbohydrate.

[0179] In another example, the composition includes about 0.5% w / w to about 3% w / w of a high molecular weight, low osmotic pressure carbohydrate. In one example, the composition includes about 0.5% w / w to about 2% w / w of a high molecular weight, low osmotic pressure carbohydrate.

[0180] In one example, the composition includes at least about 0.5% w / w high molecular weight low osmotic pressure carbohydrate.

[0181] In another example, the composition includes at least about 1% w / w of a high molecular weight, low osmotic pressure carbohydrate. In another example, the composition includes at least about 1.5% w / w of a high molecular weight, low osmotic pressure carbohydrate. In other examples, the composition includes at least about 2% w / w of a high molecular weight, low osmotic pressure carbohydrate. In another example, the composition includes at least about 2.5% w / w of a high molecular weight, low osmotic pressure carbohydrate. In another example, the composition includes at least about 3% w / w of a high molecular weight, low osmotic pressure carbohydrate. In another example, the composition includes at least about 3.5% w / w of a high molecular weight, low osmotic pressure carbohydrate. In other examples, the composition includes at least about 4% w / w of a high molecular weight, low osmotic pressure carbohydrate. In another example, the composition includes at least about 4.5% w / w of a high molecular weight, low osmotic pressure carbohydrate. In other examples, the composition includes at least about 5% w / w of a high molecular weight, low osmotic pressure carbohydrate.

[0182] In one example, the composition includes about 0.5% w / w high molecular weight low osmotic pressure carbohydrate.

[0183] In another example, the composition includes about 1% w / w of high molecular weight low osmotic pressure carbohydrates. In another example, the composition includes about 1.5% w / w of high molecular weight low osmotic pressure carbohydrates. In other examples, the composition includes about 2% w / w of high molecular weight low osmotic pressure carbohydrates. In another example, the composition includes about 2.5% w / w of high molecular weight low osmotic pressure carbohydrates. In another example, the composition includes about 3% w / w of high molecular weight low osmotic pressure carbohydrates. In another example, the composition includes about 3.5% w / w of high molecular weight low osmotic pressure carbohydrates. In other examples, the composition includes about 4% w / w of high molecular weight low osmotic pressure carbohydrates. In another example, the composition includes about 4.5% w / w of high molecular weight low osmotic pressure carbohydrates. In other examples, the composition includes about 5% w / w of high molecular weight low osmotic pressure carbohydrates.

[0184] In one example, the composition includes from about 2 mg to about 50 mg of the high molecular weight low osmotic pressure carbohydrate per dose.

[0185] In one example, the composition includes at least about 2 mg of the high molecular weight low osmotic pressure carbohydrate per dose.

[0186] In one example, the composition includes at least about 4 mg of the high molecular weight low osmotic pressure carbohydrate per dose.

[0187] In one example, the composition comprises at least about 10 mg of high molecular weight low osmotic pressure carbohydrates per dose. In one example, the composition comprises at least about 15 mg of high molecular weight low osmotic pressure carbohydrates per dose. In one example, the composition comprises at least about 20 mg of high molecular weight low osmotic pressure carbohydrates per dose. In one example, the composition comprises at least about 25 mg of high molecular weight low osmotic pressure carbohydrates per dose. In one example, the composition comprises at least about 30 mg of high molecular weight low osmotic pressure carbohydrates per dose. In one example, the composition comprises at least about 35 mg of high molecular weight low osmotic pressure carbohydrates per dose. In one example, the composition comprises at least about 40 mg of high molecular weight low osmotic pressure carbohydrates per dose. In one example, the composition comprises at least about 45 mg of high molecular weight low osmotic pressure carbohydrates per dose.

[0188] In one example, the composition includes about 2 mg of the high molecular weight low osmotic pressure carbohydrate per dose.

[0189] In one example, the composition includes about 4 mg of the high molecular weight low osmotic pressure carbohydrate per dose.

[0190] In one example, the composition includes about 10 mg of high molecular weight low osmotic pressure carbohydrate / dose. In one example, the composition includes about 15 mg of high molecular weight low osmotic pressure carbohydrate / dose. In one example, the composition includes about 20 mg of high molecular weight low osmotic pressure carbohydrate / dose. In one example, the composition includes about 25 mg of high molecular weight low osmotic pressure carbohydrate / dose. In one example, the composition includes about 30 mg of high molecular weight low osmotic pressure carbohydrate / dose. In one example, the composition includes about 35 mg of high molecular weight low osmotic pressure carbohydrate / dose. In one example, the composition includes about 40 mg of high molecular weight low osmotic pressure carbohydrate / dose. In one example, the composition includes about 45 mg of high molecular weight low osmotic pressure carbohydrate / dose.

[0191] In one example, the high molecular weight low osmotic pressure carbohydrate is dextrin.

[0192] Dextrin is a general term applied to a variety of products obtained by heating starch in the presence of small amounts of water and acid. Dextrins are a group of low-molecular-weight carbohydrates produced by the hydrolysis of starch or glycogen. "Dextrin" refers to glucose polymers produced by the hydrolysis of starch (or glycogen) that consist of glucose units linked together primarily by α-1,4 bonds. In addition to α-1,4 bonds, a certain proportion of α-1,6 bonds may be present in a particular dextrin, the amount of which depends on the starch starting material. Because the biodegradability of α-1,6 bonds is generally lower than that of α-1,4 bonds, it is preferred for many applications that the percentage of α-1,6 bonds is less than 10%, and more preferably less than 5%. In some instances, therefore, dextrins are mixtures of polymers of D-glucose units linked by α-(1->4) or α-(1->6) glycosidic bonds.

[0193] Dextrins can be produced from starch by using enzymes such as amylases, as in human digestion and in malting and saccharification processes, or by applying dry heat (pyrolysis or baking) under acidic conditions. The latter process is used in industry. Dextrins produced by heating are also referred to as pyrodextrins. Typically, dextrins are produced by hydrolyzing starch obtained from various natural products such as wheat, rice, corn, maize, and cassava.

[0194] Dextrins are typically white, yellow, or brown powders that are partially or completely soluble in water to produce optically active solutions of low viscosity. Dextrins are available from several suppliers and are readily available to the skilled person. The skilled person will be able to readily identify suitable dextrins for use in the context of the present invention. The skilled person will be able to readily detect the presence of dextrins in a substance (e.g., in the compositions described herein) using methods known in the art. For example, most dextrins can be detected using an iodine solution.

[0195] The term "dextrin" encompasses pyrodextrin, digestible dextrin, and hydrogenated products thereof, including derivatives thereof. The term "dextrin derivative" herein means those obtained by chemically or enzymatically treating dextrin, and encompasses, in addition to the above-mentioned polydextrose, for example, branched dextrins obtained by allowing glycosyltransferase to act on dextrin, and cyclodextrins obtained by allowing cyclodextrin-producing enzymes to act on starch.

[0196] In some examples, the dextrin is enzymatically treated.

[0197] In one example, therefore, a dextrin, a high molecular weight, low osmotic pressure carbohydrate, is a cluster dextrin (also known as a highly branched cyclic dextrin). A cluster dextrin is a maltodextrin, which has a high molecular weight but a narrow weight distribution, is soluble, and its osmotic pressure is close to zero. Typical large molecular weight carbohydrates have lower solubility than cluster dextrins. On the other hand, low molecular weight carbohydrates exhibit higher osmotic pressures, as do pure glucose solutions. Along with other digestible ingredients commonly found in sports drinks, this slows their entry into the small intestine. Cluster dextrins enter the small intestine faster, and endurance is boosted faster. Solubility is central to the function of cluster dextrins. High molecular weight cluster dextrins also degrade slowly, balancing insulin secretion and lipid breakdown. Cluster dextrins are manufactured by Glico Nutrition.

[0198] In some examples, the dextrin, and therefore the high molecular weight low osmotic pressure carbohydrate, is derived from wheat or corn (eg, in some examples, the dextrin is wheat dextrin or corn dextrin).

[0199] In some examples, the dextrin is enzymatically treated wheat or corn.

[0200] In one example, the dextrin is derived from wheat (eg, wheat dextrin). For example, the dextrin can be wheat dextrin powder (such as Surbex Nutri-Fiber wheat dextrin powder, which is a soluble, non-viscous fiber).

[0201] In another example, the dextrin is derived from corn (eg, corn dextrin).

[0202] In a particular example, the dextrin is hydrolyzed corn dextrin (eg, Vitargo).

[0203] In some examples, dextrin is present in the compositions described herein at a suitable concentration or amount.

[0204] In one example, the composition includes about 0.5% w / w to about 5% w / w dextrin.

[0205] In another example, the composition includes about 0.5% w / w to about 3% w / w dextrin. In another example, the composition includes about 0.5% w / w to about 2% w / w dextrin.

[0206] In one example, the composition includes at least about 0.5% w / w dextrin.

[0207] In another example, the composition includes at least about 1% w / w dextrin. In another example, the composition includes at least about 1.5% w / w dextrin. In other examples, the composition includes at least about 2% w / w dextrin. In another example, the composition includes at least about 2.5% w / w dextrin. In another example, the composition includes at least about 3% w / w dextrin. In another example, the composition includes at least about 3.5% w / w dextrin. In other examples, the composition includes at least about 4% w / w dextrin. In another example, the composition includes at least about 4.5% w / w dextrin. In other examples, the composition includes at least about 5% w / w dextrin.

[0208] In one example, the composition includes about 0.5% w / w dextrin.

[0209] In another example, the composition includes about 1% w / w dextrin. In another example, the composition includes about 1.5% w / w dextrin. In other examples, the composition includes about 2% w / w dextrin. In another example, the composition includes about 2.5% w / w dextrin. In another example, the composition includes about 3% w / w dextrin. In another example, the composition includes about 3.5% w / w dextrin. In other examples, the composition includes about 4% w / w dextrin. In another example, the composition includes about 4.5% w / w dextrin. In other examples, the composition includes about 5% w / w dextrin.

[0210] In one example, the composition includes about 2 mg to about 50 mg of dextrin per dose.

[0211] In one example, the composition includes at least about 2 mg of dextrin per dose.

[0212] In one example, the composition includes at least about 4 mg of dextrin per dose.

[0213] In one example, the composition includes at least about 5 mg of dextrin per dose. In one example, the composition includes at least about 10 mg of dextrin per dose. In one example, the composition includes at least about 15 mg of dextrin per dose. In one example, the composition includes at least about 20 mg of dextrin per dose. In one example, the composition includes at least about 25 mg of dextrin per dose. In one example, the composition includes at least about 30 mg of dextrin per dose. In one example, the composition includes at least about 35 mg of dextrin per dose. In one example, the composition includes at least about 40 mg of dextrin per dose. In one example, the composition includes at least about 45 mg of dextrin per dose.

[0214] In one example, the composition includes about 2 mg of dextrin per dose.

[0215] In one example, the composition includes about 4 mg of dextrin per dose.

[0216] In one example, the composition includes about 10 mg of dextrin per dose. In one example, the composition includes about 15 mg of dextrin per dose. In one example, the composition includes about 20 mg of dextrin per dose. In one example, the composition includes about 25 mg of dextrin per dose. In one example, the composition includes about 30 mg of dextrin per dose. In one example, the composition includes about 35 mg of dextrin per dose. In one example, the composition includes about 40 mg of dextrin per dose. In one example, the composition includes about 45 mg of dextrin per dose.

[0217] In one example, a composition according to the present invention's purposes (e.g., a composition for treating and / or preventing type 2 diabetes, prediabetes, and / or its symptoms in a subject, and / or a composition in a method for treating and / or preventing type 2 diabetes, prediabetes, and / or its symptoms in a subject) includes L-cysteine ​​and dextrin. L-cysteine ​​and dextrin can be present in the compositions described herein at any appropriate concentration. Suitable concentrations or amounts of L-cysteine ​​and dextrin are described elsewhere herein and are also applicable to compositions comprising L-cysteine ​​and dextrin as described herein. Illustrative examples of suitable concentrations or amounts are provided below.

[0218] In one example, the composition includes about 0.5% w / w to 5% w / w dextrin and about 10% w / w to about 40% w / w L-cysteine. In each of these examples, the composition may further include about 50% w / w to about 90% w / w rice bran (e.g., fermented rice bran) and / or about 10,000 cfu / g to about 15,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans).

[0219] In one example, the compositions described herein include at least about 0.5% w / w dextrin and at least about 10% w / w L-cysteine. For example, the compositions described herein may include about 0.5% w / w dextrin and about 10% w / w L-cysteine. In each of these examples, the composition may also include at least about 67% w / w rice bran (e.g., at least about 67% w / w fermented rice bran) and / or at least 10,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans). For example, in each of these examples, the composition may include about 67% w / w rice bran (e.g., about 67% w / w fermented rice bran) and / or 10,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans).

[0220] In one example, the compositions described herein include at least about 0.5% w / w dextrin and at least about 20% w / w L-cysteine. For example, the compositions described herein may include about 0.5% w / w dextrin and about 20% w / w L-cysteine. In each of these examples, the composition may also include at least about 67% w / w rice bran (e.g., at least about 67% w / w fermented rice bran) and / or at least 10,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans). For example, in each of these examples, the composition may include about 67% w / w rice bran (e.g., about 67% w / w fermented rice bran) and / or 10,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans).

[0221] In one example, the compositions described herein include at least about 0.5% w / w dextrin and at least about 20% w / w L-cysteine. For example, the compositions described herein may include about 0.5% w / w dextrin and about 20% w / w L-cysteine. In each of these examples, the composition may also include at least about 73% w / w rice bran (e.g., at least about 73% w / w fermented rice bran) and / or at least 100,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans). For example, in each of these examples, the composition may include about 73% w / w rice bran (e.g., about 73% w / w fermented rice bran) and / or 100,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans).

[0222] In one example, the compositions described herein include at least about 0.5% w / w dextrin and at least about 30% w / w L-cysteine. For example, the compositions described herein may include about 0.5% w / w dextrin and about 30% w / w L-cysteine. In each of these examples, the composition may also include at least about 67% w / w rice bran (e.g., at least about 67% w / w fermented rice bran) and / or at least 10,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans). For example, in each of these examples, the composition may include about 67% w / w rice bran (e.g., about 67% w / w fermented rice bran) and / or 10,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans).

[0223] In one example, the compositions described herein include at least about 5% w / w dextrin and at least about 20% w / w L-cysteine. For example, the compositions described herein may include about 5% w / w dextrin and about 20% w / w L-cysteine. In each of these examples, the composition may also include at least about 67% w / w rice bran (e.g., at least about 67% w / w fermented rice bran) and / or at least 10,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans). For example, in each of these examples, the composition may include about 67% w / w rice bran (e.g., about 67% w / w fermented rice bran) and / or 10,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans).

[0224] In one example, the compositions described herein include at least about 3% w / w dextrin and at least about 30% w / w L-cysteine. For example, the compositions described herein may include about 3% w / w dextrin and about 30% w / w L-cysteine. In each of these examples, the composition may also include at least about 67% w / w rice bran (e.g., at least about 67% w / w fermented rice bran) and / or at least 10,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans). For example, in each of these examples, the composition may include about 67% w / w rice bran (e.g., about 67% w / w fermented rice bran) and / or 10,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans).

[0225] In one example, the composition includes about 2 mg to about 50 mg of dextrin per dose and about 38 mg to about 200 mg of L-cysteine ​​per dose. In each of these examples, the composition may further include about 300 mg to about 600 mg of rice bran per dose (e.g., fermented rice bran per dose) and / or about 5,000 cfu of Bacillus bacteria per dose to about 1×10 8 cfu of Bacillus bacteria / dose (e.g. Bacillus subtilis and / or Bacillus coagulans).

[0226] In one example, compositions as described herein include at least about 2 mg of dextrin / dose and at least about 38 mg of L-cysteine / dose. For example, compositions as described herein may include about 2 mg of dextrin / dose and about 38 mg of L-cysteine / dose. In each of these examples, the composition may also include at least about 300 mg of rice bran / dose (e.g., at least about 300 mg of fermented rice bran / dose) and / or at least 5,000 cfu of Bacillus bacteria / dose (e.g., Bacillus subtilis and / or Bacillus coagulans). For example, in each of these examples, the composition may include about 300 mg of rice bran / dose (e.g., about 300 mg of fermented rice bran / dose) and / or 5,000 cfu of Bacillus bacteria / dose (e.g., Bacillus subtilis and / or Bacillus coagulans).

[0227] In one example, compositions as described herein include at least about 2 mg of dextrin and at least about 76 mg of L-cysteine / dose. For example, compositions as described herein may include about 2 mg of dextrin / dose and about 76 mg of L-cysteine / dose. In each of these examples, the composition may also include at least about 300 mg of rice bran / dose (e.g., at least about 300 mg of fermented rice bran / dose) and / or at least 5,000 cfu of Bacillus bacteria / dose (e.g., bacillus subtilis and / or bacillus coagulans). For example, in each of these examples, the composition may include about 300 mg of rice bran / dose (e.g., about 300 mg of fermented rice bran / dose) and / or 5,000 cfu of Bacillus bacteria / dose (e.g., bacillus subtilis and / or bacillus coagulans).

[0228] In one example, compositions as described herein include at least about 2 mg of dextrin / dose and at least about 114 mg of L-cysteine / dose. For example, compositions as described herein may include about 2 mg of dextrin / dose and about 114 mg of L-cysteine / dose. In each of these examples, the composition may also include at least about 300 mg of rice bran / dose (e.g., at least about 300 mg of fermented rice bran / dose) and / or at least 5,000 cfu of Bacillus bacteria / dose (e.g., bacillus subtilis and / or bacillus coagulans). For example, in each of these examples, the composition may include about 300 mg of rice bran / dose (e.g., about 300 mg of fermented rice bran / dose) and / or 5,000 cfu of Bacillus bacteria / dose (e.g., bacillus subtilis and / or bacillus coagulans).

[0229] In one example, compositions as described herein include at least about 20 mg of dextrin / dose and at least about 76 mg of L-cysteine / dose. For example, compositions as described herein may include about 20 mg of dextrin / dose and about 76 mg of L-cysteine / dose. In each of these examples, the composition may also include at least about 300 mg of rice bran / dose (e.g., at least about 300 mg of fermented rice bran / dose) and / or at least 5,000 cfu of Bacillus bacteria / dose (e.g., bacillus subtilis and / or bacillus coagulans). For example, in each of these examples, the composition may include about 300 mg of rice bran / dose (e.g., about 300 mg of fermented rice bran / dose) and / or 5,000 cfu of Bacillus bacteria / dose (e.g., bacillus subtilis and / or bacillus coagulans).

[0230] In one example, the compositions described herein include at least about 4 mg of dextrin per dose and at least about 150 mg of L-cysteine ​​per dose. For example, the compositions described herein may include about 4 mg of dextrin per dose and about 150 mg of L-cysteine ​​per dose. In each of these examples, the composition may further include at least about 552 mg of rice bran per dose (e.g., at least about 552 mg of fermented rice bran per dose) and / or at least 1×10 5 cfu of Bacillus bacteria / dose (e.g., Bacillus subtilis and / or Bacillus coagulans). For example, in each of these examples, the composition can include about 552 mg of rice bran / dose (e.g., about 552 mg of fermented rice bran / dose) and / or 1×10 5 cfu of Bacillus bacteria / dose (e.g. Bacillus subtilis and / or Bacillus coagulans).

[0231] As discussed elsewhere herein, this indicates that AB001 has four glucose control effects. In one example, without wishing to be bound by theory, this indicates that when the bacillus cells and endospores thereof in the duodenum and small intestine are revived, the cells scan the biochemical conditions of their microenvironment and begin to secrete uniquely selected bioactive substances to optimize the conditions for their survival and reproduction, such as pH, conductivity, electrolytes. Nutrients and substrates are essential for survival and subsequent reproduction. When glucose and other carbohydrates are present in the microenvironment, enzymes targeting carbohydrates (e.g., glucose) are secreted to advantageously decompose glucose, as described elsewhere herein.

[0232] As described elsewhere herein, the compositions for use according to the invention as described herein (e.g., compositions for treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject, and / or compositions for use in methods of treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject) may include cereals (e.g., cereal kernel components, such as rice bran). A cereal is any grass plant that is grown (botanically, a fruit called a caryopsis) for the edible component of its grain, which consists of the endosperm, germ, and bran. The term cereal may also refer to the resulting grain itself (particularly "cereal kernel"). Cereal kernels are seeds from grass plants such as wheat, millet, rice, barley, oats, rye, triticale, sorghum, and maize (corn).

[0233] In some examples, the composition for use according to the present invention may include a cereal (e.g., cereal grain) selected from the group consisting of wheat, millet, rice, barley, oats, rye, triticale, sorghum, and maize (corn). Those skilled in the art will readily be able to identify cereals (e.g., cereal grains) suitable for use in the compositions described herein.

[0234] Bran, also known as mill bran, is the hard outer layer of cereal kernels. It includes aleurone and pericarp. Corn (maize) bran also includes pedicel (tip cap). Bran is an integral part of whole grains together with the germ, and is typically produced as a by-product of milling in the refined grain production process. Bran is present in cereal kernels (including rice, corn (maize), wheat, oats, barley, rye and millet). Therefore, in some instances, the composition for use according to the present invention may include cereal bran. In some instances, the composition for use according to the present invention may include a cereal bran selected from the group consisting of rice bran, corn (maize) bran, wheat bran, oat bran, barley bran, rye bran and millet bran.

[0235] In some examples, the composition for use according to the present invention may include oat bran.

[0236] In some examples, the composition for use according to the present invention may include rice bran.

[0237] Rice bran is a by-product of the rice milling process. Typically, rice milling produces about 15% w / w broken rice kernels, about 10% w / w rice bran, about 20% rice husks, and about 55% w / w whole rice kernels. The composition of rice bran (by weight percentage) is typically 11-13% water, 18-21% crude fats and oils, 14-16% crude protein, 8-10% crude fiber, 9-12% ash, and 33-36% carbohydrates. Rice bran contains naturally occurring lipases that hydrolyze the oil into glycerol and free fatty acids, giving the product a rancid odor and taste. As used herein, "rice bran" refers to the hard outer layer of rice, including the aleurone and pericarp. It, along with the germ, is a component of whole rice and, as mentioned above, is typically produced as a by-product of milling during the refined rice production process.

[0238] The compositions described herein for use according to the present invention can include rice bran in any suitable form. Suitable forms include raw rice bran, recently ground (unhydrolyzed) full-fat rice bran, low-fat rice bran, defatted rice bran, fermented rice bran, stabilized rice bran, and the like. Raw rice bran is the rice bran obtained after grinding. Low-fat rice bran and defatted rice bran are obtained from full-fat rice bran by methods such as solvent extraction. Full-fat rice bran has a fat content of about 14-18% by weight, and low-fat and defatted rice bran have fat contents of about 3-14% and less than 3% by weight, respectively.

[0239] In one example, the rice bran is formulated as raw rice bran, recently ground (unhydrolyzed) full-fat rice bran, low-fat rice bran, defatted rice bran, fermented rice bran, and / or stabilized rice bran.

[0240] In another more preferred embodiment, the rice bran is formulated as fermented rice bran and / or stabilized rice bran.

[0241] In other examples, the rice bran is fermented rice bran. The rice bran undergoes a natural / spontaneous fermentation process by naturally occurring microbial strains, typically soil-bound strains such as Bacillus and Pediococcus.

[0242] As used herein, "fermented rice bran" refers to rice bran that has undergone a fermentation process. Fermented rice bran contains probiotics that stabilize the microbial flora of the small intestine.

[0243] Often, the terms "microflora" and "microbiome" are used to describe a collection of microbial populations.

[0244] As used herein, "stabilized rice bran" refers to rice bran that has been heated for a short period of time, for example, by passing it through a high-temperature, high-pressure extruder. Heating stabilizes the rice bran. In other words, therefore, "stabilized rice bran" is heat-treated rice bran. For example, after milling, the rice bran can be stabilized by heating at 130 degrees Celsius for less than 10 seconds. In some instances, stabilized rice bran is a dietary fiber. Typically, stabilized rice bran is a dietary fiber that can be broken down in the colon. As a dietary fiber, stabilized rice bran acts as a prebiotic that interacts with the colon's microbiome.

[0245] The microbial content of fermented rice bran may have a prebiotic and stabilizing effect on the small intestinal microbiome, while rice bran, as a dietary fiber, may stabilize colonic conditions. Another mechanism of action may be the reduction of intestinal oxidative stress, which normalizes the barrier function of the intestinal mucosa.

[0246] Rice bran (e.g., fermented rice bran) is present in the compositions described herein in an appropriate amount or concentration as described below. Thus, the amount or concentration of rice bran can be described with reference to the % w / w of the composition or the total weight (e.g., mg) of the composition per dose (in other words, the weight per effective dose). As will be apparent to those skilled in the art, and as described in more detail elsewhere herein, a dosage can include one or more dosage units (e.g., 2 dosage units). In instances where multiple dosage units are used to provide an effective dose, the weight per dosage corresponds to the total weight of the rice bran in the multiple dosage units.

[0247] In one example, the composition includes about 50% w / w to about 90% w / w rice bran.

[0248] In another example, the composition comprises about 60% w / w to about 80% w / w rice bran. In another example, the composition comprises about 73% w / w to about 79% w / w rice bran.

[0249] In one example, the composition comprises at least about 50% w / w rice bran. In another example, the composition comprises at least about 55% w / w rice bran. In one example, the composition comprises at least about 60% w / w rice bran. In other examples, the composition comprises at least about 65% w / w rice bran. In one example, the composition comprises at least about 73% w / w rice bran. In one example, the composition comprises at least about 75% w / w rice bran. In one example, the composition comprises at least about 79% w / w rice bran. In other examples, the composition comprises at least about 85% w / w rice bran. In one example, the composition comprises at least about 90% w / w rice bran.

[0250] In one example, the composition comprises about 50% w / w rice bran. In another example, the composition comprises about 55% w / w rice bran. In one example, the composition comprises about 60% w / w rice bran. In other examples, the composition comprises about 65% w / w rice bran. In one example, the composition comprises about 73% w / w rice bran. In one example, the composition comprises about 75% w / w rice bran. In one example, the composition comprises about 79% w / w rice bran. In other examples, the composition comprises about 85% w / w rice bran. In one example, the composition comprises about 90% w / w rice bran.

[0251] In certain examples, the composition comprises at least about 67% w / w rice bran (eg, fermented rice bran).For example, the composition can comprise about 67% w / w rice bran (eg, fermented rice).

[0252] In certain examples, the composition comprises at least about 73% w / w rice bran (eg, fermented rice).For example, the composition can comprise about 73% w / w rice bran (eg, fermented rice).

[0253] In another example, the composition includes at least about 79% w / w rice bran (eg, fermented rice).For example, the composition can include about 79% w / w rice bran (eg, fermented rice).

[0254] In certain examples, the composition comprises at least about 79.5% w / w rice bran (eg, fermented rice).For example, the composition can comprise about 79.5% w / w rice bran (eg, fermented rice).

[0255] In one example, the composition includes at least about 300 mg of rice bran (eg, fermented rice bran) per dose. As described elsewhere herein, a dose can be formulated as two capsules.

[0256] In one example, said composition comprises the rice bran (for example fermented rice bran) of at least about 300mg per dose. In one example, said composition comprises the rice bran (for example fermented rice bran) of at least about 350mg per dose. In one example, said composition comprises the rice bran (for example fermented rice bran) of at least about 400mg per dose. In one example, said composition comprises the rice bran (for example fermented rice bran) of at least about 450mg per dose. In one example, said composition comprises the rice bran (for example fermented rice bran) of at least about 500mg per dose. In one example, said composition comprises the rice bran (for example fermented rice bran) of at least about 550mg (for example at least about 552mg) per dose.

[0257] In one example, said composition comprises the rice bran (for example fermented rice bran) of about 300mg per dose. In one example, said composition comprises the rice bran (for example fermented rice bran) of about 350mg per dose. In one example, said composition comprises the rice bran (for example fermented rice bran) of about 400mg per dose. In one example, said composition comprises the rice bran (for example fermented rice bran) of about 450mg per dose. In one example, said composition comprises the rice bran (for example fermented rice bran) of about 500mg per dose. In one example, said composition comprises the rice bran (for example fermented rice bran) of about 550mg (for example about 552mg) per dose.

[0258] As discussed elsewhere herein, compositions for use according to the present invention (e.g., for treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject, and / or for use in a method of treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject) are provided, comprising one or more species of Bacillus (e.g., Bacillus subtilis and / or Bacillus coagulans), rice bran (e.g., fermented rice bran), L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate (e.g., dextrin). The one or more species of Bacillus (e.g., Bacillus subtilis and / or Bacillus coagulans), rice bran (e.g., fermented rice bran), L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate (e.g., dextrin) can be present in the composition for use according to the present invention in any suitable amount or concentration. Suitable amounts and concentrations of the one or more species of Bacillus (e.g., Bacillus subtilis and / or Bacillus coagulans), rice bran (e.g., fermented rice bran), L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate (e.g., dextrin) are described elsewhere herein. Illustrative examples of appropriate concentrations are provided below.

[0259] In one example, the composition includes about 0.5% w / w to 5% w / w dextrin, about 10% w / w to about 40% w / w L-cysteine, about 50% w / w to about 90% w / w rice bran (e.g., fermented rice bran), and about 10,000 cfu / g to about 15,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans).

[0260] In one example, the compositions described herein include at least about 0.5% w / w dextrin, at least about 10% w / w L-cysteine, at least about 67% w / w rice bran (e.g., at least about 67% w / w fermented rice bran), and at least 10,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans).

[0261] In one example, the compositions described herein include at least about 0.5% w / w dextrin, at least about 20% w / w L-cysteine, at least about 67% w / w rice bran (e.g., at least about 67% w / w fermented rice bran), and at least 10,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans).

[0262] In one example, the compositions described herein include at least about 0.5% w / w dextrin, at least about 20% w / w L-cysteine, at least about 73% w / w rice bran (e.g., at least about 73% w / w fermented rice bran), and at least 100,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans).

[0263] In one example, the compositions described herein include at least about 0.5% w / w dextrin, at least about 30% w / w L-cysteine, at least about 67% w / w rice bran (e.g., at least about 67% w / w fermented rice bran), and at least 10,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans).

[0264] In one example, the compositions described herein include at least about 5% w / w dextrin, at least about 20% w / w L-cysteine, at least about 67% w / w rice bran (e.g., at least about 67% w / w fermented rice bran), and at least 10,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans).

[0265] In one example, the compositions described herein include at least about 3% w / w dextrin, at least about 30% w / w L-cysteine, at least about 67% w / w rice bran (e.g., at least about 67% w / w fermented rice bran), and at least 10,000 cfu / g of Bacillus bacteria (e.g., Bacillus subtilis and / or Bacillus coagulans).

[0266] In one example, the composition includes about 2 mg to about 50 mg of dextrin per dose, about 38 mg to about 200 mg of L-cysteine ​​per dose, about 300 mg to about 600 mg of rice bran per dose (e.g., fermented rice bran per dose), and about 5,000 cfu of Bacillus bacteria per dose to about 1×10 8 cfu of Bacillus bacteria / dose (e.g. Bacillus subtilis and / or Bacillus coagulans).

[0267] In one example, the compositions described herein include at least about 2 mg of dextrin per dose, at least about 38 mg of L-cysteine ​​per dose, at least about 300 mg of rice bran per dose (e.g., at least about 300 mg of fermented rice bran per dose), and at least 5,000 cfu of Bacillus bacteria per dose (e.g., Bacillus subtilis and / or Bacillus coagulans).

[0268] In one example, the compositions described herein include at least about 2 mg of dextrin, at least about 76 mg of L-cysteine ​​per dose, at least about 300 mg of rice bran per dose (e.g., at least about 300 mg of fermented rice bran per dose), and at least 5,000 cfu of Bacillus bacteria per dose (e.g., Bacillus subtilis and / or Bacillus coagulans).

[0269] In one example, the compositions described herein include at least about 2 mg of dextrin per dose, at least about 114 mg of L-cysteine ​​per dose, at least about 300 mg of rice bran per dose (e.g., at least about 300 mg of fermented rice bran per dose), and at least 5,000 cfu of Bacillus bacteria per dose (e.g., Bacillus subtilis and / or Bacillus coagulans).

[0270] In one example, the compositions described herein include at least about 20 mg of dextrin per dose, at least about 76 mg of L-cysteine ​​per dose, at least about 300 mg of rice bran per dose (e.g., at least about 300 mg of fermented rice bran per dose), and at least 5,000 cfu of Bacillus bacteria per dose (e.g., Bacillus subtilis and / or Bacillus coagulans).

[0271] In one example, the compositions described herein include at least about 4 mg of dextrin per dose, at least about 150 mg of L-cysteine ​​per dose, at least about 552 mg of rice bran per dose (e.g., at least about 552 mg of fermented rice bran per dose), and at least 1×10 5 cfu of Bacillus bacteria / dose (e.g. Bacillus subtilis and / or Bacillus coagulans).

[0272] In certain examples, the compositions described herein include at least about 0.5% w / w dextrin, at least about 20% w / w L-cysteine, and at least about 73% w / w rice bran (e.g., at least about 73% w / w fermented rice bran). For example, the compositions described herein may include about 0.5% w / w dextrin, about 20% w / w L-cysteine, and about 73% w / w rice bran (e.g., about 73% w / w fermented rice bran). In these examples, the fermented rice bran may include one or more species of Bacillus.

[0273] In a specific example, the composition described herein includes about 79.5% w / w fermented rice bran (including one or more species of Bacillus), about 0.5% w / w dextrin, and about 20.0% w / w L-cysteine.

[0274] The compositions described herein for use according to the present invention (e.g., for use in treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject, and / or for use in methods of treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject) may include one or more additional components, such as one or more additional ingredients. For example, the compositions described herein may further include emulsifiers, fillers, excipients, and / or inactive ingredients. Those skilled in the art will readily understand the meaning of "emulsifiers," "fillers," "excipients," and "inactive ingredients" in the context of the compositions for use according to the present invention provided herein. Non-limiting examples of additional components include vitamin B12, magnesium salts of fatty acids (e.g., magnesium stearate), calcium phosphate, potassium phosphate, silicon dioxide, and cellulose (e.g., microcrystalline cellulose).

[0275] The additional components described herein may be in any suitable form. Suitable forms will be readily recognized by those skilled in the art.

[0276] Thus, in one example, the compositions described herein may further include one or more of the following: vitamin B12, magnesium salts of fatty acids (e.g., magnesium stearate), calcium phosphate, potassium phosphate, silicon dioxide, and cellulose (e.g., microcrystalline cellulose). In another example, the compositions described herein may further include two or more of the following: vitamin B12, magnesium salts of fatty acids (e.g., magnesium stearate), calcium phosphate, potassium phosphate, silicon dioxide, and cellulose (e.g., microcrystalline cellulose). In another example, the compositions described herein may further include three or more of the following: vitamin B12, magnesium salts of fatty acids (e.g., magnesium stearate), calcium phosphate, potassium phosphate, silicon dioxide, and cellulose (e.g., microcrystalline cellulose). In another example, the compositions described herein may further include four or more of the following: vitamin B12, magnesium salts of fatty acids (e.g., magnesium stearate), calcium phosphate, potassium phosphate, silicon dioxide, and cellulose (e.g., microcrystalline cellulose).

[0277] In one example, the composition further includes vitamin B12, magnesium salts of fatty acids (eg, magnesium stearate), calcium phosphate, potassium phosphate, silicon dioxide, and cellulose (eg, microcrystalline cellulose).

[0278] Examples of magnesium salts of fatty acids include magnesium stearate. Thus, in one example, the compositions described herein may further include magnesium stearate. Magnesium stearate is the magnesium salt of the fatty acid stearic acid. Magnesium salts of fatty acids (e.g., magnesium stearate) may be excipients, inactive ingredients, and / or may be used as lubricants for manufacturing machinery. Magnesium stearate is a GRAS listed ingredient.

[0279] In some instances, vitamin B12 is added for regulatory purposes.

[0280] In some instances, magnesium salts (e.g., magnesium stearate), calcium salts, and / or potassium salts are inactive ingredients (e.g., they have no clinical effect). For example, magnesium salts (e.g., magnesium stearate), calcium salts, and / or potassium salts can be added as filling aids (e.g., fillers) that help capsule filling machines work efficiently.

[0281] In some instances, a chromium salt is added for regulatory purposes. For example, the chromium salt can be chromium chloride. Any suitable amount of the chromium salt (e.g., chromium chloride) can be used.

[0282] In one example, the compositions described herein include at least about 20 meg of chromium per dose. In one example, the compositions described herein include about 20 meg of chromium per dose.

[0283] In one example, the compositions described herein include about 80 mcg to about 100 mcg of CrCl3 (chromium chloride) per dose.

[0284] In one example, the compositions according to the purposes of the present invention as described herein (e.g., compositions for treating and / or preventing type 2 diabetes, prediabetes, and / or its symptoms in a subject, and / or compositions in methods for treating and / or preventing type 2 diabetes, prediabetes, and / or its symptoms in a subject) further include microcrystalline cellulose. Microcrystalline cellulose can be used as an emulsifier, a filling aid, and / or an inactive ingredient. Microcrystalline cellulose (and maltodextrin) can be used as a cake excipient when punching tablets, and as a flow agent when making capsule formulations. In some instances, the compositions as described herein further include maltodextrin.

[0285] In one example, the composition comprises about 5% w / w to about 50% w / w of microcrystalline cellulose. In another example, the composition comprises about 5% w / w to about 35% w / w of microcrystalline cellulose. In another example, the composition comprises about 5% w / w to about 20% w / w of microcrystalline cellulose. In another example, the composition comprises about 5% w / w to about 15% w / w of microcrystalline cellulose. In another example, the composition comprises about 5% w / w to about 8% w / w of microcrystalline cellulose.

[0286] In one example, the composition includes at least about 5% w / w microcrystalline cellulose.

[0287] In one example, the composition includes at least about 8% w / w microcrystalline cellulose.

[0288] In another example, the composition comprises at least about 10% w / w microcrystalline cellulose. In another example, the composition comprises at least about 15% w / w microcrystalline cellulose. In other examples, the composition comprises at least about 20% w / w microcrystalline cellulose. In another example, the composition comprises at least about 25% w / w microcrystalline cellulose. In another example, the composition comprises at least about 30% w / w microcrystalline cellulose. In yet another example, the composition comprises at least about 35% w / w microcrystalline cellulose. In another example, the composition comprises at least about 40% w / w microcrystalline cellulose. In another example, the composition comprises at least about 45% w / w microcrystalline cellulose. In another example, the composition comprises at least about 50% w / w microcrystalline cellulose.

[0289] In one example, the composition includes about 5% w / w microcrystalline cellulose.

[0290] In one example, the composition includes about 8% w / w microcrystalline cellulose.

[0291] In another example, the composition includes about 10% w / w microcrystalline cellulose. In another example, the composition includes about 15% w / w microcrystalline cellulose. In other examples, the composition includes about 20% w / w microcrystalline cellulose. In another example, the composition includes about 25% w / w microcrystalline cellulose. In yet another example, the composition includes about 30% w / w microcrystalline cellulose. In another example, the composition includes about 35% w / w microcrystalline cellulose. In another example, the composition includes about 40% w / w microcrystalline cellulose. In another example, the composition includes about 45% w / w microcrystalline cellulose. In another example, the composition includes about 50% w / w microcrystalline cellulose.

[0292] In one example, the compositions described herein include at least about 30 mg of microcrystalline cellulose per dose. As described elsewhere herein, a dose can be formulated as two capsules.

[0293] In one example, the compositions described herein include at least about 40 mg of microcrystalline cellulose per dose.

[0294] In one example, the compositions described herein include at least about 50 mg of microcrystalline cellulose per dose. In one example, the compositions described herein include at least about 60 mg of microcrystalline cellulose per dose. In one example, the compositions described herein include at least about 70 mg of microcrystalline cellulose per dose. In one example, the compositions described herein include at least about 80 mg of microcrystalline cellulose per dose. In one example, the compositions described herein include at least about 90 mg of microcrystalline cellulose per dose. In one example, the compositions described herein include at least about 100 mg of microcrystalline cellulose per dose.

[0295] In one example, the compositions for use according to the present invention as described herein (e.g., compositions for treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject, and / or compositions for use in methods of treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof) further include magnesium stearate. Magnesium stearate can be used as an emulsifier, a filling aid, and / or an inactive ingredient.

[0296] In one example, the composition includes about 0.2% w / w to about 1.5% w / w of magnesium stearate. In another example, the composition includes about 0.5% w / w to about 1.4% w / w of magnesium stearate. In another example, the composition includes about 0.6% w / w to about 1.3% w / w of magnesium stearate.

[0297] In one example, the composition includes at least about 0.2% w / w magnesium stearate. In another example, the composition includes at least about 0.3% w / w magnesium stearate. In another example, the composition includes at least about 0.4% w / w magnesium stearate. In other examples, the composition includes at least about 0.5% w / w magnesium stearate.

[0298] In another example, the composition includes at least about 0.6% w / w magnesium stearate.

[0299] In another example, the composition includes at least about 0.7% w / w of magnesium stearate. In yet another example, the composition includes at least about 0.8% w / w of magnesium stearate. In another example, the composition includes at least about 0.9% w / w of magnesium stearate.

[0300] In another example, the composition includes at least about 1.0% w / w magnesium stearate.

[0301] In another example, the composition includes at least about 1.1% w / w magnesium stearate. In another example, the composition includes at least about 1.2% w / w magnesium stearate. In another example, the composition includes at least about 1.3% w / w magnesium stearate. In another example, the composition includes at least about 1.4% w / w magnesium stearate. In another example, the composition includes at least about 1.5% w / w magnesium stearate.

[0302] In one example, the composition includes about 0.2% w / w magnesium stearate. In another example, the composition includes about 0.3% w / w magnesium stearate. In another example, the composition includes about 0.4% w / w magnesium stearate. In other examples, the composition includes about 0.5% w / w magnesium stearate.

[0303] In another example, the composition includes about 0.6% w / w magnesium stearate.

[0304] In another example, the composition includes about 0.7% w / w magnesium stearate. In yet another example, the composition includes about 0.8% w / w magnesium stearate. In another example, the composition includes about 0.9% w / w magnesium stearate.

[0305] In another example, the composition includes about 1.0% w / w magnesium stearate.

[0306] In another example, the composition includes about 1.1% w / w magnesium stearate. In another example, the composition includes about 1.2% w / w magnesium stearate. In another example, the composition includes about 1.3% w / w magnesium stearate. In another example, the composition includes about 1.4% w / w magnesium stearate. In another example, the composition includes about 1.5% w / w magnesium stearate.

[0307] In one example, the compositions described herein include at least about 4 mg of magnesium stearate per dose. As described elsewhere herein, a dose can be formulated as two capsules.

[0308] In one example, the compositions described herein include at least about 5 mg of microcrystalline cellulose per dose.

[0309] In one example, the compositions described herein include at least about 6 mg of magnesium stearate per dose. In one example, the compositions described herein include at least about 7 mg of magnesium stearate per dose. In one example, the compositions described herein include at least about 8 mg of magnesium stearate per dose. In one example, the compositions described herein include at least about 9 mg of magnesium stearate per dose. In one example, the compositions described herein include at least about 10 mg of magnesium stearate per dose.

[0310] In one example, the compositions for use according to the present invention as described herein (e.g., compositions for treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject, and / or compositions for use in methods for treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof) further include silicon dioxide. Silicon dioxide can be used as an emulsifier, a filling aid, and / or an inactive ingredient.

[0311] In one example, the composition includes about 0.5% w / w to about 4% w / w silicon dioxide. In another example, the composition includes about 0.7% w / w to about 3% w / w silicon dioxide. In another example, the composition includes about 0.9% w / w to about 2% w / w silicon dioxide.

[0312] In one example, the composition includes at least about 0.5% w / w silicon dioxide.

[0313] In another example, the composition includes at least about 1% w / w silicon dioxide.

[0314] In another example, the composition includes at least about 1.5% w / w silicon dioxide. In other examples, the composition includes at least about 2% w / w silicon dioxide. In another example, the composition includes at least about 2.5% w / w silicon dioxide. In another example, the composition includes at least about 3% w / w silicon dioxide. In yet another example, the composition includes at least about 3.5% w / w silicon dioxide. In another example, the composition includes at least about 4% w / w silicon dioxide.

[0315] In one example, the composition includes about 0.5% w / w silicon dioxide.

[0316] In another example, the composition includes about 1% w / w silicon dioxide.

[0317] In another example, the composition includes about 1.5% w / w silicon dioxide. In other examples, the composition includes about 2% w / w silicon dioxide. In another example, the composition includes about 2.5% w / w silicon dioxide. In another example, the composition includes about 3% w / w silicon dioxide. In yet another example, the composition includes about 3.5% w / w silicon dioxide. In another example, the composition includes about 4% w / w silicon dioxide.

[0318] In one example, the compositions described herein include at least about 4 mg of silicon dioxide per dose. As described elsewhere herein, a dose can be formulated as two capsules.

[0319] In one example, the compositions described herein include at least about 5 mg of silicon dioxide per dose. In one example, the compositions described herein include at least about 6 mg of silicon dioxide per dose. In one example, the compositions described herein include at least about 7 mg of silicon dioxide per dose. In one example, the compositions described herein include at least about 8 mg of silicon dioxide per dose.

[0320] In one example, the compositions described herein for use according to the present invention (e.g., compositions for treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject, and / or compositions for use in methods of treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof) further include vitamin B12. Vitamin B12 may be included in the compositions described herein for regulatory purposes. In one example, the composition includes at least 15% of the recommended daily intake (RDI), i.e., 0.38 mcg up to 2.4 mcg (EU) and 2.5 mcg for the USA.

[0321] In one example, the compositions described herein include at least about 0.76 μg (mcg) of vitamin B 12 per dose. In one example, the compositions described herein include at least about 0.9 μg (mcg) of vitamin B 12 per dose.

[0322] The composition can be formulated into any suitable form. For example, it can be in the form of a tablet or capsule. In one example, the composition is formulated into an acid-resistant tablet or capsule. Generally, "capsule" refers to both empty and filled capsules, while "shell" specifically refers to an empty capsule, unless the context otherwise requires.

[0323] In some instances, the compositions described herein are contained within a capsule (e.g., within a shell). In some instances, the compositions described herein are contained within an acid-resistant capsule (e.g., within an acid-resistant shell). As will be apparent to one skilled in the art, when reference is made to the % w / w of an ingredient present in a composition, this does not take into account any weight attributable to the capsule (thus only the % w / w of the composition within the capsule is considered).

[0324] In one example, acid-resistant tablets or capsules include film coatings, wherein the film coating includes hydroxypropyl methylcellulose (HPMC). HPMC is a semisynthetic, inert, viscoelastic polymer used in various applications. For example, HPMC can be used as an excipient in oral tablets and capsule formulations, wherein, according to grade, it serves as a release control agent to delay the release of pharmaceutical compounds into the digestive tract. In tablets, HPMC can also be used as a component of a binding agent and / or tablet coating.

[0325] In one example, the composition for use according to the invention as described herein is comprised within a (capsule) shell, wherein the shell comprises hydroxypropylmethylcellulose (HPMC).

[0326] Those skilled in the art will understand the meaning of "acid-resistant" in the context of the present invention, particularly in the context of the ingestible compositions described herein. For example, the compositions described herein can be formulated as acid-resistant tablets or capsules, or can be included in an acid-resistant capsule (e.g., an acid-resistant shell) that dissolves upon reaching the duodenum, allowing the microbial cells and spores to be released and colonize the upper part of the intestinal tract.

[0327] In one example, the composition is present in a capsule, wherein the capsule includes about 80 mg to about 100 mg of HPMC. For example, the capsule may include at least about 80 mg of HPMC. In one example, the capsule includes at least about 90 mg of HPMC. In one example, the capsule includes at least about 100 mg of HPMC. In one example, the capsule includes about 80 mg of HPMC. In one example, the capsule includes about 90 mg of HPMC. In another example, the capsule includes about 100 mg of HPMC.

[0328] Typically, HPMC is present as a film coating on the outer surface of the capsules described herein.

[0329] Compositions as described herein can be in unit dosage form. When compositions as described herein are in unit dosage form, one tablet or capsule can be administered, and this constitutes a dosage, alternatively two tablets or capsules can be administered, and this constitutes a dosage. Those skilled in the art can determine suitable dosage and regimen based on the following examples. Therefore, in one example, the dosage of a composition according to the present invention includes multiple small tablets or capsules (e.g., two).

[0330] As used herein, the term "dosage form" refers to an amount of a drug that is taken at one time, optionally at fixed intervals. This is also referred to herein as a "dose."

[0331] In one example, the invention provides a solid unit dosage form for oral administration.

[0332] In a specific example, the dosage of the composition described herein includes: about 300 mg of fermented rice bran, about 38 mg of L-cysteine, about 30 mg of microcrystalline cellulose, about 4 mg of magnesium stearate, about 4 mg of silicon dioxide, about 2 mg of dextrin and about 5,000 cfu of Bacillus bacteria. Optionally, the dosage of the composition described herein can further include about 0.76 μg (mcg) of vitamin B12 and / or any suitable amount of chromium chloride. In this specific example, the dosage can be formulated as two tablets or capsules. In other words, the amount of the component can represent the total amount of the component present in the dosage (i.e., in two tablets or capsules). Therefore, the skilled person will understand that at least each of these components, in at least these amounts, provides an effective dosage according to the present invention. Thus, in one embodiment, a dose of the composition described herein comprises at least about 300 mg of fermented rice bran, at least about 38 mg of L-cysteine, at least about 30 mg of microcrystalline cellulose, at least about 4 mg of magnesium stearate, at least about 4 mg of silicon dioxide, at least about 2 mg of dextrin, and at least about 5,000 cfu of Bacillus bacteria. Optionally, a dose of the composition described herein may further comprise at least about 0.76 μg (mcg) of vitamin B12 and / or any suitable amount of chromium chloride.

[0333] In a specific example, a dose of the composition described herein includes: about 552 mg of fermented rice bran, about 150 mg of L-cysteine, about 40 mg of microcrystalline cellulose, about 4.8 mg of magnesium stearate, about 4 mg of silicon dioxide, about 4 mg of dextrin, and about 100,000 cfu of Bacillus bacteria. Optionally, the dose of the composition described herein can further include about 0.9 μg (mcg) of vitamin B12 and / or any suitable amount of chromium chloride. In this specific example, the dose can be formulated as two tablets or capsules. In other words, the amount of the component can represent the total amount of the component present in the dose (i.e., in two tablets or capsules). Therefore, the skilled person will understand that at least each of these components, in at least these amounts, provides an effective dose according to the present invention. Thus, in one embodiment, a dose of the composition described herein comprises at least about 552 mg of fermented rice bran, at least about 150 mg of L-cysteine, at least about 40 mg of microcrystalline cellulose, at least about 4.8 mg of magnesium stearate, at least about 4 mg of silicon dioxide, at least about 4 mg of dextrin, and at least about 100,000 cfu of Bacillus bacteria. Optionally, a dose of the composition described herein may further comprise at least about 0.9 μg (mcg) of vitamin B12 and / or any suitable amount of chromium chloride.

[0334] Typically, HPMC is present as a film coating on the outer surface of the capsules described herein.

[0335] The compositions described herein can be used as (or as a part of) a dietary supplement, a nutraceutical, a food composition, a medical food, or a pharmaceutical.

[0336] As used herein, the term "dietary supplement" or "food supplement" refers to a composition that is taken in addition to or between meals.

[0337] As used herein, the term "food composition" refers to any type of composition that can be eaten and / or drunk without causing symptoms of toxicity in a subject that eats or drinks the respective composition.

[0338] Provided herein are uses of the compositions described herein for degrading glucose. Thus, in one example, a composition comprising one or more strains of the genus Bacillus, rice bran, L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate is provided for use in degrading glucose. The term "degrading glucose" is described elsewhere herein and is equally applicable here.

[0339] The composition can be used to degrade glucose in a subject (e.g., can be used in vivo). The subject can be any suitable subject, for example, the subject can be a human. The subject can be a human who intends to take or has taken a carbohydrate (e.g., glucose).

[0340] In one example, the composition can be used to metabolize glucose in the digestive tract of a subject. The term "metabolize glucose" is described elsewhere herein and is equally applicable here. In one example, the composition can be used to metabolize glucose in the intestine of a subject. In a specific example, the composition can be used to metabolize glucose in the small intestine of a subject. More specifically, the composition can be used to metabolize glucose in the duodenum of a subject.

[0341] In one example, the composition can be used to reduce glucose absorption by a subject's blood. One skilled in the art can determine the reduction in glucose absorption by the blood in the presence of a composition provided herein (compared to when the composition is not used) using methods known in the art.

[0342] When the composition is used to degrade glucose in a subject, it can be used to reduce the blood glucose concentration in the subject. Those skilled in the art can determine the reduction in blood glucose concentration in the presence of a composition provided herein (compared to when not using the composition) using methods known in the art.

[0343] Also provided is use of a composition described herein (eg, a composition comprising one or more species of Bacillus, rice bran, L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate) for controlling blood glucose in a subject.

[0344] Also provided herein is use of a composition described herein (e.g., a composition comprising one or more species of Bacillus, rice bran, L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate) for:

[0345] (a) reducing the level of one or more of the following in the subject's blood: HbA1c, glucose (e.g., fasting blood glucose), insulin, intact proinsulin, and / or hsCRP;

[0346] (b) reducing the subject's HOMA-IR score; and / or

[0347] (c) increasing the level of adiponectin in the blood of a subject.

[0348] "HbA1c," "glucose," such as fasting blood glucose, "insulin," "intact proinsulin," "hsCRP," "HOMA-IR score," and "adiponectin" are described elsewhere herein and are equally applicable herein.

[0349] The subject may be any suitable subject, for example, the subject may be a human. The subject may be a human who intends to take or has taken a carbohydrate (eg, glucose).

[0350] In some instances, the composition according to the present invention is in the form of a pharmaceutical preparation, including the composition of the present invention. As will be clear to those skilled in the art, a pharmaceutical preparation is a preparation suitable for administration to a subject (e.g., for degrading glucose). The pharmaceutical preparation can be used for administration to a subject to prevent and / or treat a disease, disorder, or ailment (e.g., for treating and / or preventing type 2 diabetes, prediabetes, and / or its symptoms in a subject, and / or for administering in a method for treating and / or preventing type 2 diabetes, prediabetes, and / or its symptoms in a subject). As used herein, the pharmaceutical preparation includes an effective dose of the composition of the present invention.

[0351] As used herein, "pharmaceutical composition" refers to a composition with pharmacological activity or other direct effects to alleviate, treat or prevent a disease, and / or its finished dosage form or preparation, and for human use. Pharmaceutical compositions or pharmaceutical preparations are typically produced under Good Manufacturing Practice (GMP) conditions. Pharmaceutical compositions or preparations can be sterile or non-sterile. If non-sterile, such pharmaceutical compositions or preparations typically meet the microbial quality standards and standards for non-sterile pharmaceutical products described in the United States Pharmacopoeia (USP) or the European Pharmacopoeia (EP). Therefore, compositions as described herein can be formulated into pharmaceutical compositions. In some instances, the pharmaceutical composition is non-sterile.

[0352] Treatment methods and uses

[0353] As described elsewhere herein, the compositions described herein can be used to degrade glucose in vitro or in vivo.

[0354] The inventors have unexpectedly discovered that a composition comprising one or more species of Bacillus, rice bran, L-cysteine, and a high molecular weight, low-osmotic pressure carbohydrate can be advantageously used to safely improve the cardiometabolic profile of a subject, particularly a subject with type 2 diabetes and / or prediabetes (as exemplified in the examples below). Thus, the composition can advantageously provide a valuable supplement to existing treatment regimens for subjects with type 2 diabetes and / or prediabetes.

[0355] Thus, provided is a composition comprising one or more species of Bacillus, rice bran, L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate for treating and / or preventing type 2 diabetes, prediabetes, and / or symptoms thereof in a subject.

[0356] Also provided is a method for treating and / or preventing type 2 diabetes, prediabetes and / or symptoms thereof in a subject, comprising administering to the subject a composition comprising one or more species of Bacillus, rice bran, L-cysteine ​​and a high molecular weight, low osmotic pressure carbohydrate.

[0357] Diabetes mellitus, also commonly referred to as diabetes, is a metabolic disorder that causes elevated blood sugar levels due to a relative or absolute deficiency of the pancreatic hormone insulin. Insulin is secreted from the pancreas into the blood in response to blood sugar levels, and its main function is to direct blood sugar to storage sites in the body, thereby controlling blood sugar levels. Type 2 diabetes, formerly known as adult-onset or non-insulin-dependent diabetes mellitus, is a chronic disease marked by disturbances in both glucose and lipid metabolism. Type 2 diabetes is characterized by insulin resistance and impaired beta cell function, which include impaired first-phase insulin release, reduced beta cell pulse mass, and insulin deficiency. In other words, in patients with type 2 diabetes, the body is resistant to the effects of insulin and / or cannot produce enough insulin to maintain normal blood sugar levels. Individuals with type 2 diabetes have a combination of increased insulin resistance and decreased insulin secretion, which, combined, can lead to hyperglycemia, as discussed below. Dyslipidemia is also an important component of the metabolic disturbances that characterize type 2 diabetes.

[0358] Insulin resistance refers to a physiological condition in which the natural hormone insulin becomes less effective in lowering blood sugar, for example, because cells become less responsive to insulin's action to promote glucose transport from the blood to muscle and other tissues (e.g., decreased sensitivity to insulin). Insulin resistance ranges from normal (insulin sensitive) to insulin resistance (IR). In some instances, insulin resistance may mean that insulin is unable to elicit its normal anabolic response at the maximum dose of the hormone. The inadequate response to insulin leads to decreased glucose uptake (primarily in muscle and adipose tissue) and increased hepatic gluconeogenesis, both of which lead to elevated circulating blood glucose concentrations. To maintain homeostasis and prevent hyperglycemia (excessively high serum glucose levels), pancreatic beta cells increase their insulin secretion, leading to hyperinsulinemia (high blood insulin levels). In the early stages of diabetes (but before developing type 2 diabetes), the pancreas is able to overcome insulin resistance and maintain normal blood sugar levels by increasing insulin production. However, in the later stages of diabetes, compensatory insulin secretion from the pancreas is unable to overcome the body's insulin resistance, and normal blood (e.g., plasma) glucose concentrations can no longer be maintained, leading to hyperglycemia. Symptoms of hyperglycemia are polyuria (excretion of large amounts of urine in a given period) and polydipsia (extreme thirst). Chronic hyperglycemia has a deleterious effect on pancreatic beta-cell function through glucose desensitization (further reducing the body's insulin sensitivity, i.e., increasing insulin resistance) as well as beta-cell failure and apoptosis, which impair insulin secretion. This ultimately leads to overt type 2 diabetes, typically characterized by a fasting venous whole blood glucose concentration exceeding 7.0 mmol / l (126 mg / dL).

[0359] The terms "type 2 diabetes," "T2D," or "TIID" are well defined in the art. Similarly, the term "insulin resistance" is well defined in the art.

[0360] Type 2 diabetes is consistent with the remarkable decline of life expectancy, and is a kind of expensive disease, and it needs long-term medical care to limit the development of the short-term and long-term complications associated with this disease.These complications include hyperinsulinemia, hyperglycemia, hypoglycemia (serum glucose < 50mg / dL), ketoacidosis, increased risk of infection, microvascular complications (such as retinopathy, nephropathy), neuropathy complications and macrovascular disease, such as cardiovascular disease (CVD) caused by severe arteriosclerosis.The morbidity and mortality rate relevant to diabetes are mainly caused by these complications.For example, diabetes is the main cause of blindness, and is also the important cause of lower limb amputation and kidney disease.

[0361] Symptoms of type 2 diabetes are well known to those skilled in the art. Non-limiting examples of symptoms of type 2 diabetes include increased thirst, frequent urination, increased hunger, unintended weight loss, fatigue, blurred vision, slow healing of sores, frequent infections, numbness or tingling in the hands and feet, and darkened areas of skin, typically in the armpits and neck.

[0362] As used herein, "symptom" refers to a manifestation indicative of a disease, disorder, or ailment. In other words, a symptom refers to a phenotype associated with a disease, disorder, or ailment that can be used to facilitate diagnosis of the disease, disorder, or ailment. In some cases, a combination of symptoms may be required to facilitate diagnosis of a disease, disorder, or ailment.

[0363] "Prediabetes" refers to one or more early diabetes-related conditions, including impaired glucose utilization, abnormal or impaired fasting glucose levels, impaired glucose tolerance, impaired insulin sensitivity, and insulin resistance. Prediabetes is associated with the simultaneous presence of insulin resistance and beta-cell dysfunction, which begin before changes in blood glucose are detectable. Prediabetes is typically characterized by blood glucose levels that are higher than normal but below the diabetic threshold, meaning the likelihood of developing diabetes is high.

[0364] Symptoms of prediabetes include, but are not limited to, increased thirst, frequent urination, increased hunger, unintended weight loss, fatigue, blurred vision, slow-healing sores, frequent infections, numbness or tingling in the hands and feet, genital itching or thrush, and darkened areas of skin, usually in the armpits and neck.

[0365] Symptoms of type 2 diabetes and / or prediabetes can also include insulin resistance, beta-cell dysfunction, unregulated glycemic control, chronic systemic and / or intestinal inflammation, hyperinsulinemia, hyperglycemia, hypoglycemia (serum glucose <50 mg / dL), ketoacidosis, increased risk of infection, microvascular complications (i.e., retinopathy, nephropathy), neuropathy complications, and macrovascular disease, such as cardiovascular disease (CVD) due to severe arteriosclerosis.

[0366] Advantageously, the composition according to the present invention can be used to improve the symptoms of type 2 diabetes and prediabetes described above. The inventors have clearly demonstrated that the composition as described herein (AB001) can be used to stabilize blood glucose levels and / or improve glycemic control, particularly for subjects with type 2 diabetes and / or prediabetes. Advantageously, the composition as described herein can also be used to reduce insulin resistance, beta cell dysfunction and / or inflammation (e.g., chronic systemic inflammation and / or intestinal inflammation) in subjects with type 2 diabetes and / or prediabetes. In some instances, inflammation can be intestinal and / or pancreatic inflammation.

[0367] Thus, administering the composition to a subject can, in a subject suffering from type 2 diabetes and / or symptoms thereof:

[0368] (a) reducing the level of one or more of HbA1c, glucose (e.g., fasting blood glucose), insulin, intact proinsulin, or hsCRP in the blood;

[0369] (b) reduction in HOMA-IR score; and / or

[0370] (c) Increase the level of adiponectin in the blood.

[0371] Thus, administering the composition to a subject can, in a subject suffering from type 2 diabetes and / or symptoms thereof:

[0372] (a) reducing the level of one or more of HbA1c, glucose (e.g., fasting blood glucose), insulin, intact proinsulin, or hsCRP in the blood;

[0373] (b) reduction in HOMA-IR score; and / or

[0374] (c) Increase the level of adiponectin in the blood.

[0375] Those skilled in the art can easily diagnose type 2 diabetes and / or prediabetes using conventional methods known in the art (e.g., using reference values ​​known in the art). For example, there are many tests that can be used to determine whether a human subject suffers from prediabetes and / or type 2 diabetes. Such tests include, for example, A1C test, fasting plasma glucose test (FPG), urine glucose test, random blood glucose test, and oral glucose tolerance test (OGTT). Examples of reference values ​​using these methods are provided below. In some instances, several tests are used in combination to arrive at a diagnosis.

[0376] Type 2 diabetes is typically diagnosed using a glycated hemoglobin (A1C) test. The A1c (glycosylated hemoglobin, glycosylated hemoglobin, HbA1c, or A1c) test is used to assess a person's blood sugar control. This test displays the average blood sugar level over the past 90 days, expressed as a percentage. For example, this blood test might indicate the average blood sugar level over the past two to three months. Hemoglobin is a protein found only in red blood cells. Since the average lifespan of a red blood cell is approximately three months, the A1c test will reflect the red blood cells present in the blood at the time of the test; this is why A1c can be used as an average measure of blood sugar control. Hemoglobin's primary function is to transport oxygen from the lungs to all cells in the body. Hemoglobin becomes glycated, or coated with glucose in the bloodstream. Glucose in the blood will attach to the hemoglobin, and elevated glucose levels will be reflected on the surface of the hemoglobin, resulting in a higher A1c level. Typically, a blood sample is used for testing (and diagnosis), particularly a whole blood sample or a sample extracted from whole blood (such as serum and / or plasma). Those skilled in the art will be able to readily identify the appropriate sample type depending on the parameter to be determined. Non-limiting examples of reference values ​​that can be used for this test are as follows: less than 5.7% is normal, 5.7% to <6.5% is diagnostic of prediabetes (which indicates impaired blood sugar regulation), and a result of 6.5% or higher in two separate tests indicates diabetes.

[0377] A fasting blood glucose test can also be used to identify type 2 diabetes and / or prediabetes. The FPG test is a blood test that is used to check blood sugar levels after fasting. Fasting involves not eating or drinking anything (except water) for at least eight hours (e.g., before the test is performed). Typically, a blood sample is collected after fasting overnight. Prolonged fasting triggers a hormone called glucagon, which is produced by the pancreas and causes the liver to release glucose (blood sugar) into the blood. If you do not have diabetes, your body will respond by producing insulin to prevent hyperglycemia (high blood sugar). However, if your body cannot produce enough insulin or cannot respond appropriately to insulin, fasting blood sugar levels will remain high. Typically, blood samples are used for testing (and diagnosis), particularly whole blood samples or samples extracted from whole blood (e.g., serum and / or plasma). Those skilled in the art will be able to easily identify the appropriate sample type based on the parameters to be determined. Non-limiting examples of result interpretation are as follows: less than 100 mg / dL (5.6 mmol / L) is normal, 100 to <126 mg / dL (5.6 to 6.9 mmol / L) is diagnosed as prediabetes (indicating impaired fasting glucose / impaired fasting glycemia), and 126 mg / dL (7 mmol / L) or higher on two separate tests is diagnosed as diabetes.

[0378] An oral glucose tolerance test (OGTT) can also be used to identify type 2 diabetes and / or prediabetes. The glucose tolerance test (GTT), also known as the oral glucose tolerance test (OGTT), is a procedure that helps diagnose diabetes or insulin resistance. The GTT determines a person's ability to handle a glucose load by determining how quickly glucose is cleared from the blood. This test can show whether a person can metabolize a standard, measured amount of glucose. This test is used less frequently than other tests, except during pregnancy. Before the test, participants will be asked not to eat or drink certain liquids for up to 8 to 12 hours. Participants may also be asked not to take certain medications before the test, as these medications may affect the test results. For the test itself, blood will be drawn to measure your blood sugar level. The next step is to drink a very sweet glucose drink. Further blood samples will then be drawn at regular intervals (30 or 60 minutes) or a single test will be performed 2 hours later. Typically, a whole blood sample is used for testing (and diagnosis). Non-limiting examples of result interpretation are as follows: a fasting value (before the test) of less than 6 mmol / L and less than 7.8 mmol / L at 2 hours is normal, a fasting value (before the test) of 6.0 to 7.0 mmol / L and 7.8 to 11.1 mmol / L at 2 hours is diagnosed as prediabetes (indicating impaired glucose tolerance), and a fasting value (before the test) of more than 7.0 mmol / L and more than 11.1 mmol / L at 2 hours indicates diabetes.

[0379] With reference to normal blood sugar (euglycemia) reference values, in some instances, when measured using the above tests, the following cutoff numbers can be used: A1C test - less than 5.7%; FPG test less than 100 mg / dl; and OGTT less than 7.8 mmol / L at 2 hours. In addition, normal blood sugar (euglycemia) can be indicated by an interstitial glucose level of 70-180 mg / dL (where >180 mg / dL indicates hyperglycemia and <70 mg / dL indicates hypoglycemia).

[0380] As will be apparent to those skilled in the art, as used herein, "interstitial glucose" refers to glucose in the interstitial fluid. Glucose is typically transported from the capillary endothelium to the interstitial fluid by simple diffusion of concentration gradients without the need for active transport proteins. The amount of glucose delivered is determined by the blood flow to this area. Typically, interstitial glucose values ​​(e.g., levels) are determined by the rate at which glucose diffuses from plasma to the interstitial fluid and the rate at which subcutaneous tissue cells absorb glucose. Interstitial glucose levels can be measured using conventional methods known in the art. For example, interstitial glucose levels can be measured using a continuous glucose monitoring (CGM) system (as used in the Examples section below). The glucose sensors of these CGM systems are constructed as needle-shaped sensors that are inserted into subcutaneous adipose tissue to contact interstitial fluid (ISF).

[0381] In some examples, the composition is used to treat and / or prevent type 2 diabetes and / or its symptoms.

[0382] Thus, in some examples, a composition comprising one or more species of Bacillus, rice bran, L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate is provided for treating and / or preventing type 2 diabetes and / or its symptoms in a subject.

[0383] In some examples, a method of treating and / or preventing type 2 diabetes and / or its symptoms in a subject is also provided, comprising administering to the subject a composition comprising one or more species of Bacillus, rice bran, L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate.

[0384] As discussed elsewhere herein, the inventors unexpectedly demonstrated that AB001 had beneficial effects on glycemic control (measured as time spent in normoglycemia, assessed by continuous blood glucose measurements, and using biomarkers of glycemic control, i.e., HbA1c and fasting blood glucose) and on biomarkers of inflammation (e.g., chronic systemic inflammation assessed using adiponectin or hsCRP as biomarkers), insulin resistance, and beta-cell dysfunction (assessed using blood insulin and intact proinsulin as biomarkers and the HOMA-IR score) in patients with type 2 diabetes compared to placebo. Thus, the inventors have advantageously demonstrated that the compositions described herein (AB001) can be used to stabilize blood glucose levels and / or improve glycemic control in subjects with type 2 diabetes, prediabetes, and / or symptoms thereof. Advantageously, the compositions described herein can also be used to reduce insulin resistance, beta-cell dysfunction, and / or inflammation (e.g., chronic systemic inflammation and / or intestinal inflammation) in subjects with type 2 diabetes, prediabetes, and / or symptoms thereof. In some instances, the inflammation can be intestinal and / or pancreatic inflammation. In addition, the inventors unexpectedly observed that in patients with type 2 diabetes, after using AB001, the changes in lipid profile (triglyceride concentration, total cholesterol and HDL-cholesterol) and other parameters of metabolic syndrome were more favorable than when using placebo. Advantageously, the compositions described herein can therefore be used to treat and / or prevent the symptoms of metabolic syndrome in subjects with type 2 diabetes and / or prediabetes. For more information, see Pfützner et al, Fasting Intact Proinsulin Is a Highly Specific Predictor of Insulin Resistance in Type 2 Diabetes, Diabetes Care 27: 682-687, 2004, which is incorporated herein by reference.

[0385] Patients with type 2 diabetes and / or prediabetes may experience symptoms of metabolic syndrome. As used herein, "metabolic syndrome" refers to a combination of insulin resistance, dyslipidemia, and hypertension. Symptoms of metabolic syndrome include, but are not limited to, hypertension, hypertriglyceridemia, hyperglycemia, hyperuricemia, and other metabolic disorders. The present invention can be used to improve the symptoms of metabolic syndrome. As described elsewhere herein, in patients with type 2 diabetes, changes in lipid profiles (triglyceride concentrations, total cholesterol, and HDL-cholesterol) and other parameters of metabolic syndrome were more favorable after use of AB001 than with placebo. Advantageously, the compositions described herein can therefore be used to treat and / or prevent the symptoms of metabolic syndrome in subjects with type 2 diabetes and / or prediabetes.

[0386] Thus, in some examples, the composition is administered to a subject (e.g., a subject having type 2 diabetes, prediabetes, and / or symptoms thereof):

[0387] (a) can reduce one or more levels of HbA1c or glucose;

[0388] (b) can lower fasting blood sugar levels;

[0389] (c) can lower insulin levels;

[0390] (d) can reduce the HOMA-IR score of insulin resistance;

[0391] (e) can reduce intact proinsulin;

[0392] (f) can reduce hsCRP in the blood; and / or

[0393] (g) It can increase the level of adiponectin in the blood.

[0394] This shows that the result of supplementing AB001 is that the intestinal tract has lower absorption of glucose. Therefore, in some instances, the composition is administered to a subject (e.g., a subject suffering from type 2 diabetes, prediabetes and / or its symptoms) to reduce the absorption of glucose by the subject's blood. Those skilled in the art can use methods known in the art (e.g., using conventional methods known in the art, measuring blood sugar in the presence or absence of a composition as described herein) to determine the reduction in glucose absorption by blood in the presence of a composition provided herein (compared to when the composition is not used). Those skilled in the art believe that it is an indicator that the composition reduces glucose in blood and interstitial fluid and that macrovascular risk and overall health are significantly improved.

[0395] AB001 has no active hypoglycemic effect and does not affect normal blood sugar levels in healthy individuals or patients with diabetes. This has been observed in various clinical settings and individual patient cases. In clinical studies, AB001 was not associated with an increased risk of hypoglycemia, and its proposed mode of action is inconsistent with such findings.

[0396] Thus, in some examples, the composition is administered to a subject (e.g., a subject having type 2 diabetes, prediabetes, and / or symptoms thereof):

[0397] (a) reducing the level of one or more of HbA1c, glucose (e.g., fasting blood glucose), insulin, intact proinsulin, or hsCRP in the blood;

[0398] (b) reduction in HOMA-IR score; and / or

[0399] (c) Increase the level of adiponectin in the blood.

[0400] In some examples, the composition is administered to a subject (e.g., a subject having type 2 diabetes, prediabetes, and / or symptoms thereof):

[0401] (a) reducing the level of two or more of HbA1c, glucose (e.g., fasting blood glucose), insulin, intact proinsulin, or hsCRP in the blood;

[0402] (b) reduction in HOMA-IR score; and / or

[0403] (c) Increase the level of adiponectin in the blood.

[0404] In some examples, the composition is administered to a subject (e.g., a subject having type 2 diabetes, prediabetes, and / or symptoms thereof):

[0405] (a) reducing the levels of three or more of HbA1c, glucose (e.g., fasting blood glucose), insulin, intact proinsulin, or hsCRP in the blood;

[0406] (b) reduction in HOMA-IR score; and / or

[0407] (c) Increase the level of adiponectin in the blood.

[0408] In some instances, administration of the composition to a subject (e.g., a subject with type 2 diabetes, prediabetes, and / or symptoms thereof) reduces the level of one or more (e.g., two or more, or three or more) of HbA1c, glucose (e.g., fasting blood glucose), insulin, intact proinsulin, or hsCRP in the blood. In some instances, administration of the composition to a subject (e.g., a subject with type 2 diabetes, prediabetes, and / or symptoms thereof) reduces the HOMA-IR score.

[0409] Typically, the levels of HbA1c, glucose (e.g., fasting blood glucose), insulin, intact proinsulin, or hsCRP in the subject's blood, as well as the HOMA-IR score, are determined based on a blood sample obtained from the subject, particularly a whole blood sample or a sample extracted from whole blood (e.g., serum and / or plasma). A person skilled in the art will be able to readily identify the appropriate sample type depending on the parameter to be determined.

[0410] The terms "decrease," "decreased," "reduce," "reduced," "reduction," or "downregulate," "lower" are all used herein and generally refer to a decrease, e.g., a decrease by a certain amount, e.g., a statistically significant amount. For the avoidance of doubt, in the context of the present invention, "reduced," "reduce," "reduction," "decreased," or "decrease" refers to a decrease compared to a reference level / control.

[0411] In the context of the present invention, a reference level / control may be a level prior to administration of a composition described herein.

[0412] In some examples, administration of the composition to a subject (e.g., a subject with type 2 diabetes, prediabetes, and / or symptoms thereof) reduces the level of HbA1c in the blood. In other words, administration of the composition to a subject (e.g., a subject with type 2 diabetes, prediabetes, and / or symptoms thereof) reduces the level of HbA1c in the blood compared to the level of HbA1c in the blood before administration of the composition. HbA1c levels can be determined using conventional methods known in the art, as described in the Examples section below, for example, using an HbA1c test. HbA1c and HbA1c tests are discussed in more detail elsewhere herein. HbA1c levels can be used to identify impaired blood glucose regulation in a subject and, therefore, can be used as a biomarker for glycemic control, as described in the Examples section below.

[0413] In some instances, the level of glucose in the blood (e.g., fasting blood glucose) is reduced by administering the composition to a subject (e.g., a subject suffering from type 2 diabetes, prediabetes, and / or its symptoms). In other words, the level of glucose in the blood before administration of the composition to a subject (e.g., a subject suffering from type 2 diabetes, prediabetes, and / or its symptoms) is compared with the level of glucose in the blood (e.g., the level of glucose in the blood before administration of the composition after fasting), thereby reducing the level of glucose in the blood (e.g., after fasting). Blood glucose can be measured using conventional methods known in the art (as described in the Examples section below), for example, fasting blood glucose can be measured using the FPG test discussed in more detail elsewhere herein. Fasting blood glucose levels can be used as a biomarker for glycemic control, as discussed in the Examples section below.

[0414] As used herein, "fasting blood glucose" refers to the level of glucose in the blood after fasting. Typically, in the context of the present invention, fasting will last between 8 and 12 hours, for example, between 8 and 10 hours, and during this short period of time, the subject does not consume any food or drink (in some cases, a small amount of water may be consumed). Therefore, as used herein, "fasting blood glucose" generally refers to the level of glucose in the blood after fasting for at least 8 hours, for example, after fasting for 8 to 12 hours.

[0415] In some instances, administration of the composition to a subject (e.g., a subject with type 2 diabetes, prediabetes, and / or its symptoms) reduces blood insulin levels. In other words, administration of the composition to a subject (e.g., a subject with type 2 diabetes, prediabetes, and / or its symptoms) reduces blood insulin levels compared to blood insulin levels before administration of the composition. Insulin is a peptide hormone secreted in the body by the beta cells of the pancreatic islets of Langerhans and regulates blood glucose levels. Insulin works by directly binding to receptors on the cell plasma membrane. These receptors are present on all cells, but their density depends on the cell type, with the highest density on hepatocytes and adipocytes. The insulin receptor is a heterotetrameric glycoprotein composed of two subunits: an α subunit and a β subunit. The extracellular α subunit has an insulin binding site. The transmembrane β subunit has tyrosine kinase activity. When insulin binds to the α subunit, it activates the tyrosine kinase activity in the β subunit, resulting in the translocation of glucose transporters from the cytoplasm to the cell surface. These glucose transporters allow glucose in the blood to flow into cells, thereby lowering blood glucose levels.

[0416] Insulin causes the following effects in cells:

[0417] Hepatocytes: promote glycogenolysis and inhibit gluconeogenesis;

[0418] Fat cells: promote lipogenesis and inhibit lipolysis;

[0419] Muscle cells: Promote glycogen production and protein synthesis. Inhibit protein catabolism;

[0420] Pancreatic beta cells: inhibiting glucagon release; and

[0421] Brain cells: involved in appetite regulation.

[0422] Conditions such as diabetes tend to increase the level of insulin in the blood. Those skilled in the art will be able to readily determine the level of insulin in the blood using conventional methods known in the art (as described in the Examples section below). As is known to those skilled in the art, blood insulin levels can be used as a biomarker for insulin resistance, as discussed in the Examples section below.

[0423] In some instances, administration of the composition to a subject (e.g., a subject with type 2 diabetes, prediabetes, and / or its symptoms) reduces the HOMA-IR score. In other words, administration of the composition to a subject (e.g., a subject with type 2 diabetes, prediabetes, and / or its symptoms) reduces the HOMA-IR score compared to the HOMA-IR before administration of the composition. "HOMA-IR" refers to insulin resistance estimated by the steady-state model assessment. The steady-state model assessment estimated insulin resistance (HOMA-IR) developed by Matthews et al. has been widely used in studies to estimate insulin resistance. Compared to the "gold" standard euglycemic clamp method for quantifying insulin resistance, quantification using HOMA-IR is more convenient. It is calculated by multiplying fasting plasma insulin (FPI) by fasting plasma glucose (FPG) and then dividing by a constant 22.5, i.e., HOMA-IR=(FPI×FPG) / 22.5. A low HOMA-IR value indicates high insulin sensitivity, while a high HOMA-IR value indicates low insulin sensitivity (insulin resistance). Those skilled in the art will be able to easily determine fasting plasma insulin (FPI) and fasting plasma glucose (FPG) levels using conventional methods known in the art. Therefore, those skilled in the art will be able to easily determine individual HOMA-IR scores using conventional methods known in the art.

[0424] In some instances, administration of the composition to a subject (e.g., a subject suffering from type 2 diabetes, prediabetes, and / or its symptoms) reduces the level of intact proinsulin in the blood. In other words, administration of the composition to a subject (e.g., a subject suffering from type 2 diabetes, prediabetes, and / or its symptoms) reduces the level of intact proinsulin in the blood compared to the level of intact proinsulin in the blood before administration of the composition. Proinsulin is produced in pancreatic β cells and is typically further processed into insulin and C-peptide. It only appears in low concentrations in the blood (e.g., plasma) of healthy subjects. The increased insulin demand caused by insulin resistance in the late stage of type 2 diabetes can lead to increased expression of proinsulin in the blood. Intact proinsulin is rapidly degraded. In clinical practice, fasting morning intact proinsulin can be used as a highly specific indicator of clinically relevant insulin resistance, as the basis for selecting insulin resistance therapy, and to monitor the therapeutic effect on β cell dysfunction. Those skilled in the art will be able to easily measure the level of intact proinsulin in the blood using conventional methods known in the art (as described in the Examples section below). As known to those skilled in the art, intact proinsulin levels can be used as biomarkers for β cell dysfunction and / or insulin resistance.

[0425] In some instances, the level of hsCRP in the blood is reduced by administering the composition to a subject (e.g., a subject suffering from type 2 diabetes, prediabetes and / or its symptoms). In other words, the level of hsCRP in the blood is reduced by administering the composition to a subject (e.g., a subject suffering from type 2 diabetes, prediabetes and / or its symptoms) compared with the level of hsCRP before administering the composition. C-reactive protein (CRP) is a protein in the blood that increases when there is inflammation, and for many years, CRP has been used as an indicator of infection and inflammation associated with the disease. The hs-CRP test can accurately measure low levels of CRP to identify low but sustained levels of inflammation. Therefore, as known to those skilled in the art, hsCRP levels can be used as biomarkers of inflammation, particularly chronic systemic inflammation. Those skilled in the art will be able to easily measure the level of hs-CRP in the blood using conventional methods known in the art (as described in the Examples section below).

[0426] In some instances, administration of the composition to a subject (e.g., a subject with type 2 diabetes, prediabetes, and / or symptoms thereof) reduces the level of adiponectin in the blood. In other words, administration of the composition to a subject (e.g., a subject with type 2 diabetes, prediabetes, and / or symptoms thereof) increases the level of adiponectin in the blood compared to the level of adiponectin in the blood before administration of the composition. Adiponectin is the most abundant peptide hormone secreted by adipocytes. Adiponectin is a hormone released by your adipose (fat) tissue that contributes to insulin sensitivity and inflammation. Low levels of adiponectin are associated with several diseases, including type 2 diabetes and atherosclerosis. Adiponectin can be used as a biomarker for inflammation, particularly chronic systemic inflammation. One skilled in the art will be able to readily determine the level of adiponectin in the blood using conventional methods known in the art (as described in the Examples section below).

[0427] The terms "increased," "increase," "up-regulated," "higher," and "higher" are all used herein to generally refer to an increase (e.g., an increase by a certain amount (e.g., a statistically significant amount)). For the avoidance of doubt, in the context of the present invention, "increased" or "increase" refers to an increase compared to a reference level / control.

[0428] In the context of the present invention, a reference level / control may be a level prior to administration of a composition described herein.

[0429] In some examples, administering the composition to a subject (e.g., a subject having type 2 diabetes, prediabetes, and / or symptoms thereof) controls the subject's blood glucose (e.g., whole blood glucose, plasma glucose, and / or serum glucose) and / or interstitial glucose.

[0430] In some examples, administering the composition to a subject (eg, a subject having type 2 diabetes, prediabetes, and / or symptoms thereof) controls the subject's blood glucose (eg, whole blood glucose, plasma glucose, and / or serum glucose).

[0431] In some examples, administering the composition to a subject (eg, a subject having type 2 diabetes, prediabetes, and / or symptoms thereof) controls interstitial glucose in the subject.

[0432] Therefore, in a particular instance, the blood glucose level and / or interstitial glucose level of the subject is stabilized to the subject (e.g., a subject suffering from type 2 diabetes, prediabetes and / or a subject with its symptoms). In a particular instance, the blood glucose level of the subject is stabilized to the subject (e.g., a subject suffering from type 2 diabetes, prediabetes and / or a subject with its symptoms). In another example, the interstitial glucose level of the subject is stabilized to the subject (e.g., a subject suffering from type 2 diabetes, prediabetes and / or a subject with its symptoms).

[0433] As discussed elsewhere herein, this shows that AB001 has four glucose control effects. For example, this shows that the bacillus strain of AB001 and the enzyme secreted thereof serve as additional glucose digestive agents (in other words, in addition to the microbial community (such as intestinal microbial community) of the subject existing before taking AB001, the bacillus strain of AB001 and the enzyme secreted thereof work) to further reduce the absorption of glucose by the blood. Therefore, in some instances, glucose is degraded to a subject (such as a subject suffering from type 2 diabetes, prediabetes and / or its symptoms). In some instances, the glucose in the subject's digestive tract is degraded by administering the composition to the subject. In some instances, the glucose in the subject's intestine (particularly the small intestine) is degraded by administering the composition to the subject. More specifically, the glucose in the subject's duodenum is degraded by administering the composition according to the present invention's purposes. Glucose degradation and the glucose degradation composition according to the present invention's purposes are described elsewhere herein. The text related to "glucose degradation" and "glucose degradation composition" provided elsewhere herein is equally applicable here.

[0434] As discussed elsewhere herein, glucose can be metabolized (i.e., glucose can be degraded via metabolism). Therefore, in some instances, glucose is metabolized to a subject (e.g., a subject suffering from type 2 diabetes, prediabetes and / or its symptoms) administered said composition. In some instances, the glucose in the subject's digestive tract is metabolized to the subject administered said composition. "Metabolism" is defined elsewhere herein and is also applicable here. In some instances, the glucose in the subject's intestine is metabolized to the subject administered according to the composition of the present invention. In one example, the glucose in the subject's small intestine is metabolized to the subject administered according to the composition of the present invention purposes. More specifically, the glucose in the subject's duodenum is metabolized to the subject administered according to the composition of the present invention purposes.

[0435] This indicates that the result of supplementing AB001 is that the intestinal absorption of glucose is lower. Therefore, in some instances, administration of the composition to a subject (e.g., a subject suffering from type 2 diabetes, prediabetes, and / or its symptoms) reduces the absorption of glucose by the subject's blood. One skilled in the art can determine the reduction in glucose absorption by the blood in the presence of a composition provided herein (compared to when the composition is not used) using methods known in the art (e.g., using conventional methods known in the art, measuring blood glucose in the presence or absence of a composition as described herein).

[0436] Thus, in some instances, administration of the composition to a subject (e.g., a subject suffering from type 2 diabetes, prediabetes, and / or symptoms thereof) reduces glucose absorption by the interstitial fluid of the subject. One skilled in the art can determine the reduction in glucose absorption by the interstitial fluid in the presence of a composition provided herein (compared to when the composition is not used) using methods known in the art (e.g., using conventional methods known in the art, measuring interstitial glucose in the presence or absence of a composition as described herein).

[0437] In some instances, administration of the composition to a subject (e.g., a subject with type 2 diabetes, prediabetes, and / or symptoms thereof) reduces the subject's blood glucose and / or interstitial glucose concentration. One skilled in the art can determine the reduction in blood glucose concentration and / or interstitial glucose concentration (compared to when not using the composition) in the presence of the composition provided herein using methods known in the art.

[0438] In some instances, administration of the composition to a subject (e.g., a subject suffering from type 2 diabetes, prediabetes, and / or symptoms thereof) reduces the subject's blood glucose concentration. One skilled in the art can determine the reduction in blood glucose concentration in the presence of a composition provided herein (compared to when the composition is not used) using methods known in the art.

[0439] In some instances, administration of the composition to a subject (e.g., a subject with type 2 diabetes, prediabetes, and / or symptoms thereof) reduces the subject's interstitial glucose concentration. One skilled in the art can determine the reduction in interstitial glucose concentration in the presence of a composition provided herein (compared to when the composition is not used) using methods known in the art.

[0440] The compositions provided herein are effective when administered to a subject at an appropriate frequency for an appropriate length of time. Appropriate length of time and frequency can be readily determined by one skilled in the art or a corresponding physician.

[0441] In some instances, the composition (e.g., an effective amount of a composition described herein) is taken in. In some instances, the composition (e.g., an effective amount of a composition described herein) is taken in daily for an appropriate length of time. In other words, the composition for use according to the present invention can be administered daily.

[0442] In some instances, the composition (e.g., an effective amount of a composition described herein) is taken in for at least 1 day. In some instances, the composition (e.g., an effective amount of a composition described herein) is taken in daily for at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least 7 days.

[0443] In some instances, the composition (e.g., an effective amount of a composition described herein) is taken daily for at least one week. In some instances, the composition (e.g., an effective amount of a composition described herein) is taken daily for at least two weeks.

[0444] In some instances, the composition (e.g., an effective amount of a composition described herein) is taken daily for at least four weeks. In some instances, the composition (e.g., an effective amount of a composition described herein) is taken daily for at least six weeks. In some instances, the composition (e.g., an effective amount of a composition described herein) is taken daily for at least six months.

[0445] For example, one dose (e.g., two capsules or tablets of a composition described herein) can be taken daily for at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least 7 days. For example, one dose (e.g., two capsules or tablets of a composition described herein) can be taken daily for at least 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days.

[0446] For example, one dose (e.g., two capsules or tablets of a composition described herein) can be taken daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, or at least six weeks. For example, one dose (e.g., two capsules or tablets of a composition described herein) can be taken daily for one week, two weeks, three weeks, four weeks, five weeks, or six weeks.

[0447] As used herein, "ingestion" refers to the absorption (eg, taking) of a substance by an organism (eg, a subject, preferably a human). In the context of the present invention, ingestion is preferably performed via the mouth, wherein the subject is a human.

[0448] As will be clear to those skilled in the art, the compositions according to the present invention as described herein can be used in combination with one or more other treatment methods (e.g., drugs) for preventing and / or treating type 2 diabetes, prediabetes, and / or its symptoms. Therefore, the compositions according to the present invention as described herein can be used to supplement one or more other treatment methods (e.g., drugs) for preventing and / or treating type 2 diabetes, prediabetes, and / or its symptoms.

[0449] In one example, the compositions according to the purposes of the present invention as described herein can be administered to (e.g., taken in) a subject who is undergoing one or more treatment methods (e.g., drugs) for preventing and / or treating type 2 diabetes, prediabetes, and / or its symptoms. The treatment methods (e.g., drugs) for preventing and / or treating type 2 diabetes, prediabetes, and / or its symptoms are well known in the art. Non-limiting examples of the treatment methods (e.g., drugs) for preventing and / or treating type 2 diabetes, prediabetes, and / or its symptoms are described in the Examples section below.

[0450] The composition for use according to the present invention (e.g., a composition for treating and / or preventing type 2 diabetes, prediabetes and / or its symptoms in a subject, and / or a composition for use in a method for treating and / or preventing type 2 diabetes, prediabetes and / or its symptoms in a subject) can be orally administered in the form of an aqueous solution, tablet, capsule, granule, or the like.

[0451] The compositions described herein are administered to a subject (preferably a human being) in an effective amount (in an effective dose). An "effective amount" refers to an amount that produces a desired (therapeutic or non-therapeutic) response, either alone or in combination with other dosages. The effective amount to be used will depend on, for example, the treatment (or non-therapeutic) purpose, route of administration, and the condition of the subject. For example, for a given subject, the appropriate dose of the compositions of the present invention can be determined by a physician (or the person administering the composition), while taking into account various factors known to change the effects of the compositions of the present invention, such as body weight, sex, diet, time of administration, route of administration, other drugs, and other relevant clinical factors. Dosage and dosage regimens can vary according to the specific condition, illness, symptom, or overall condition of the subject. The effective dose can be determined by in vitro or in vivo methods.

[0452] The compositions described herein are advantageously presented in dosage units. For example, the compositions can be presented in the form of capsules or tablets. Other suitable dosage units are described elsewhere herein.

[0453] An "effective amount" can include one or more dosage units administered. For example, an effective amount can be achieved by administering one or two capsules or tablets. When an effective amount includes multiple dosage units, the dosage units can be administered together or can be taken at intervals throughout the day.

[0454] Those skilled in the art can readily identify alternative appropriate effective amounts and dosage forms using routine experimentation based on the following examples.

[0455] As used herein, the terms "treating" and "treatment" refer to the administration of a composition to a subject, e.g., a symptomatic subject having an adverse condition, disorder, affliction or disease, e.g., Type 2 diabetes, prediabetes and / or symptoms thereof, to effect a reduction in the severity and / or frequency of symptoms, to eliminate symptoms and / or their underlying causes, and / or to promote improvement or remediation of damage, and / or to prevent the adverse condition, disorder, affliction or disease in an asymptomatic subject who is susceptible to, suspected of having or at risk of developing a particular adverse condition, disorder, affliction or disease.

[0456] For example, as described elsewhere herein, treatment with the compositions described herein can advantageously:

[0457] (a) reducing the level of one or more of HbA1c, glucose (e.g., fasting blood glucose), insulin, intact proinsulin, or hsCRP in the blood;

[0458] (b) reduction in HOMA-IR score; and / or

[0459] (c) Increase the level of adiponectin in the blood.

[0460] Treatment with the compositions described herein can also advantageously control blood sugar, reduce the absorption of glucose into a subject's blood, and / or lower a subject's blood glucose concentration.

[0461] As used herein, the term "prevent" or "preventing" refers to avoiding the occurrence or recurrence of symptoms and / or their underlying causes, damage, adverse conditions, illness, ailment, disease, and / or disease.

[0462] For example, in the context of the present invention, "prevention" may be avoiding the onset of one or more symptoms associated with type 2 diabetes and / or prediabetes.

[0463] As discussed elsewhere herein, the subject can be any suitable subject, for example, the subject can be the human race. Preferably, the subject is the human race. The subject can be the human race suffering from type 2 diabetes, prediabetes and / or its symptom. The clinician will be able to easily diagnose type 2 diabetes, prediabetes and / or its symptom using conventional methods known in the art (for example, using the test and reference values ​​discussed elsewhere herein). The subject can be the human race diagnosed with type 2 diabetes, prediabetes and / or its symptom and intending to consume or having consumed glucose.

[0464] Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. For example, Singleton and Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d Ed., John Wiley and Sons, NY (1994); and Hale and Marham, The Harper Collins Dictionary of Biology, Harper Perennial, NY (1991) provide those skilled in the art with a general dictionary of many of the terms used in this invention.

[0465] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, preferred methods and materials are described herein. Therefore, the terms defined below will be more fully described by reference to the entire specification. In addition, as used herein, the singular terms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Unless otherwise indicated, nucleic acids are written from left to right in a 5' to 3' direction; amino acid sequences are written from left to right in an amino to carboxyl direction, respectively. It should be understood that the present invention is not limited to the specific methods, protocols, and reagents described, as these may vary depending on the context in which they are used by those skilled in the art.

[0466] Aspects of the invention are illustrated by the following non-limiting examples.

[0467] Example

[0468] Development of the compositions described herein

[0469] The inventors had previously developed food-grade fermented rice bran for evaluation purposes. A safety study was initiated using a case study design. Approximately 1,400 people took the product regularly over a long period of time. No side effects or adverse reactions were reported.

[0470] The first indication of an effect on glucose can be derived from a safety trial (i.e., a case study design) using oral administration of fermented rice bran (without L-cysteine ​​and without dextrin) containing a Bacillus strain, in which patients with type 2 diabetes reported prolonged normoglycemia (self-testing) and increased HDL levels, decreased triglyceride levels, and decreased HbA1c levels during regular health checkups every three to six months. At the physician's order, some of these individuals stopped taking their daily sensitizer, and some reduced their dose or stopped taking their statin altogether. Some of the patients with type 2 diabetes showed HbA1c and other blood parameters typical of prediabetic patients after three to six months. (Data not shown). This safety trial suggests that a composition containing fermented rice bran and a Bacillus strain (without L-cysteine ​​and without dextrin) is beneficial for patients with type 2 diabetes.

[0471] These findings led to the AB001 formulation, fermented rice bran comprising ~70% of a Bacillus strain, which has been evaluated in a randomized, placebo-controlled clinical trial demonstrating positive effects on normoglycemia, LDL-HDL ratio, triglycerides, HbA1c, etc. The results of this clinical trial are shown in Example 1.

[0472] Prediabetes is the precursor stage to type 2 diabetes, and therefore, from a scientific and clinical perspective, the data discussed herein suggest that fermented rice bran / Bacillus strains may be an efficient and effective treatment for prediabetes. The composition may be used to avoid / prevent the progression of medical conditions to type 2 diabetes.

[0473] The composition described herein (AB001) is generally composed of naturally fermented rice bran, Bacillus subtilis and Bacillus coagulans, L-cysteine, and dextrin. It may also include magnesium stearate, calcium phosphate, and potassium phosphate. The supplement is made with an acid-resistant HPMC capsule that dissolves once it reaches the duodenum. The culture is released and colonizes the upper part of the intestine, where it remains for about a day before being eliminated from the body through feces. The bacterial strains included in the composition are selected to preferentially and efficiently metabolize glucose.

[0474] The bacterial composition of AB001 was investigated using Sanger DNA sequencing. The predominant bacterial strains found in the composition were identified as Bacillus subtilis and Bacillus coagulans. Other genera / species identified were Bacillus amyloliquefaciens, Bacillus velezensis, Bacillus MT 03, Bacillus atrophaeus, and Pediococcus pentosaceus.

[0475] Dextrins from three different suppliers were tested and found to be effective in the compositions of the present invention (data not shown). The preferred dextrin for use herein is hydrolyzed corn dextrin (e.g., Vitargo). L-cysteine ​​from three different suppliers was also tested and found to be effective (data not shown). The preferred L-cysteine ​​for use herein is of plant origin.

[0476] The composition used in Example 1 includes per dose (2 capsules): fermented rice bran (552 mg), L-cysteine ​​(150 mg), microcrystalline cellulose (40 mg), magnesium stearate (4.8 mg), dextrin (4 mg), silicon dioxide (4 mg) and at least 1×10 5 cfu of Bacillus bacteria. Optionally, for regulatory purposes, additional chromium (e.g., chromium chloride) may be added. Optionally, for regulatory purposes, at least about 20 mcg of chromium may be added per dose. For example, for regulatory purposes, about 80 mcg to about 100 mcg of chromium chloride may be added per dose.

[0477] Example 1 - Effect of a Bacteria-Based Nutritional Supplement (AB001) on Glycemic Control and Impact of biomarkers of metabolic syndrome

[0478] Overview

[0479] Background: AB001 is a nutritional supplement based on a microbial consortium of coexisting bacterial strains. The aim of this study was to investigate the potential beneficial effects of the supplement compared with placebo on glycemic control and on biomarkers of inflammation, insulin resistance, and β-cell dysfunction.

[0480] Methods: A total of 40 patients with type 2 diabetes (31 males, 9 females, age: 65.5 ± 8.0 years, BMI: 33.6 ± 5.5 kg / m 2 , HbA1c: 7.2 ± 0.9%). They were randomized to receive AB001 or placebo once daily for 6 weeks. Specifically, participants in the treatment group took two capsules of the composition (e.g., one dose of the composition) daily. Observation parameters included time in normoglycemia assessed by continuous glucose monitoring, as well as biomarkers of glycemic control, beta-cell function, insulin resistance, and chronic systemic inflammation.

[0481] Results: Time in range was stable between weeks 0-2 and 4-6 for AB001, whereas it was slightly impaired (-4%) with placebo. At endpoint, significant improvements compared with baseline were seen with AB001, but not with placebo, for biomarkers of glycemic control (AB001 vs. placebo, HbA1c: -0.3% vs. 0.1%, fasting glucose: -14% vs. +8%, all p < 0.05), insulin resistance (insulin: -17% vs. +14%, HOMA-IR: -26% vs. +21%, all p < 0.05), beta-cell dysfunction (intact proinsulin: -40% vs. -2%, p < 0.05), and chronic systemic inflammation (adiponectin: +8% vs. -8%; p < 0.05, hsCRP: -31% vs. +27%, ns). Furthermore, more favorable changes in lipid profiles and other metabolic syndrome parameters were observed in patients with TIID with AB001 compared with placebo. There were no differences between the two groups in the number and type of adverse events.

[0482] Conclusions: The results observed with AB001 overall demonstrate improved cardiometabolic profiles. AB001 is a valuable addition to any existing treatment portfolio for patients with type 2 diabetes.

[0483] introduce

[0484] As described elsewhere herein, de Faire Medical AB (Stockholm, Sweden, www.defairemedical.com) has developed AB001, a nutritional supplement based on fermented rice bran with Bacillus subtilis and Bacillus coagulans, which contribute to the product's prebiotic and probiotic properties. In part, the product's effects are driven by the secretion of bioactive substances (such as enzymes) that break down complex organic molecules into nutrients, reactants, and energy. For example, the bacterial strains included in the product, such as Bacillus subtilis and Bacillus coagulans, bind to dextrin and L-cysteine ​​and preferentially metabolize glucose and other more complex carbohydrate molecules. A more detailed mechanism of action is described elsewhere herein. AB001 has no active hypoglycemic effect and does not affect normal blood sugar levels in healthy individuals or patients with diabetes. The product complies with the European regulatory framework as a nutritional supplement. In this double-blind study, AB001 or placebo was given as a nutritional supplement for six weeks in addition to standard of care treatment interventions in patients with type 2 diabetes in the advanced stage of the disease.

[0485] Patients and methods

[0486] This prospective, double-blind, placebo-controlled, single-center, parallel study was conducted in accordance with international and local ethical and scientific standards. The protocol was approved by the responsible ethical review board (Rhineland-Palatinate State Medical Association ( The study was approved by the German Center for Consumer Protection and Food Safety (German Federal Office for Consumer Protection and Food Safety, Bundesamt für Verbraucherschutz und Lebenmittelsicherheit). The study was registered with the German Register of Clinical Studies (DRKS number DRKS00023745).

[0487] The primary objective was to determine the effect of AB001 on glycemic control (time in normoglycemia) compared with placebo, assessed by continuous blood glucose measurements with the Freestyle Libre 2 device (Abbott Diagnostics, Wiesbaden-Delkenheim, Germany) after 2, 4, and 6 weeks of treatment. Secondary objectives were to determine the effect of dietary supplementation on HbA1c, lipids, uric acid, insulin sensitivity (assessed by the HOMA score

[16] ), β-cell dysfunction (insulin and intact proinsulin [17, 18]), chronic systemic inflammation and cardiovascular risk (total adiponectin and hsCRP, [19, 20]), and tolerability of the nutritional supplement (type and nature of (serious) adverse events) compared with placebo.

[0488] To be eligible for the study, patients had to be adults diagnosed with type 2 diabetes (HbA1c between 6.0% and 9.9% while being treated with any type or combination of standard-of-care therapies). They could not have type 1 diabetes, any acute or chronic gastrointestinal disease, anemia, acute hyperthyroidism, a known allergy to probiotic nutritional supplements, or any major life-threatening illness.

[0489] Prior to participation, participants signed a written informed consent. Thereafter, blood was drawn for safety analysis and to identify potential exclusion criteria. At the baseline visit (V1), participants were randomly assigned to the two study groups and blood was drawn to determine efficacy parameters. The entire observation period was six weeks. Subcutaneous sensors for continuous glucose monitoring (CGM, FreeStyle Libre, Abbott) were provided over the next two weeks. Three follow-up visits (V2, V3, V4) were planned with an interval of 2 weeks to replace the CGM sensor and draw blood for efficacy analysis. The end of the fourth visit marked the termination of the individual patient's participation in this study.

[0490] All safety and efficacy parameters were measured in a central laboratory. Insulin, intact proinsulin, and total adiponectin were measured using immunoassays (TecoMedical, Sissach, CH). Lipids, hsCRP, glucose, and HbA1c were measured using standard laboratory analyzers (Cobas c513, Roche Diagnostics, Basel, CH). At each treatment visit, patients were asked whether they had experienced any (serious) adverse events.

[0491] Standard exploratory and descriptive analytical methods were used to evaluate the data to understand the qualitative and quantitative nature of the collected data. For quantitative variables, the arithmetic mean, median, standard deviation, and minimum and maximum values ​​were determined. Appropriate parametric and nonparametric statistical tests were used to compare the collected results. For normally distributed data sets, Student's t-test was used to compare changes from baseline to endpoint and to compare changes from baseline between groups. A p-value < 0.05 was considered statistically significant.

[0492] The composition used per dose (2 capsules) includes: fermented rice bran (552 mg), L-cysteine ​​(150 mg), microcrystalline cellulose (40 mg), magnesium stearate (4.8 mg), dextrin (4 mg), silicon dioxide (4 mg) and at least 1×10 5 cfu of Bacillus bacteria. Optionally, for regulatory purposes, additional chromium (e.g., chromium chloride) may be added. Optionally, for regulatory purposes, at least about 20 mcg of chromium may be added per dose. For example, for regulatory purposes, about 80 mcg to about 100 mcg of chromium chloride may be added per dose.

[0493] Participants in the experimental treatment group took two capsules of the composition (eg, one dose of the composition) daily.

[0494] result

[0495] A total of 46 patients were screened, of whom 40 met the inclusion / exclusion criteria and were eligible for the study (31 males, 9 females, mean age: 65.4 ± 8.0 years (range: 44-89 years), BMI: 33.3 ± 5.3 kg / m 2 (Range: 21.5kg / m 2 -42.8kg / m 2All included patients were studied per protocol. After randomization, there were slightly more women in the placebo group. The vast majority of patients were receiving multiple antidiabetic medications, indicating an advanced stage of disease. Baseline characteristics of the patients in the two treatment groups and the nature and distribution of their diabetes treatment are provided in Table 1.

[0496] The primary variable measured was the time spent in normoglycemia between weeks 0 and 2 and weeks 4 and 6, as determined with the aid of FreeStyle Libre analysis software. It is important to note that no data were available before patients began taking the study supplement. Therefore, there was no true baseline to understand the direct effects of AB001 supplementation on the time spent in normoglycemia for comparison. Figure 1 A comparison between the first and last sensor analysis in this experiment is provided.

[0497] As can be seen, blood sugar control was stable in patients taking AB001, while there was a slight but non-significant impairment in the placebo group.

[0498] The differences seen in most clinical examination parameters (weight, blood pressure, waist circumference) were numerically favorable to AB001 but not significant. Only a significant reduction in hip circumference was observed with AB001 (from 121 ± 11 cm to 116 ± 11 cm, p < 0.005) compared to placebo (116 ± 11 cm vs. 116 ± 10 cm, ns).

[0499] To explore the effects of AB001 on glycemic control and biomarkers of potential diabetic exacerbation (insulin resistance, beta-cell dysfunction, and chronic systemic inflammation), a panel of biochemical parameters was measured at baseline and endpoint. The results are provided in Table 2, and the percentage changes from baseline are given in Table 2 for both groups. Figure 2 Available in.

[0500] Hemoglobin A1c and fasting glucose significantly improved with AB001, whereas no change (HbA1c) or impairment (fasting glucose) was observed with placebo.

[0501] Intact proinsulin, insulin, and HOMA-IR scores were determined as indicators of insulin resistance and beta-cell dysfunction [16-18]. All patients showed significant improvement with AB001, whereas their condition worsened with placebo. All changes from baseline and between-group differences with AB001 reached statistical significance. These findings suggest that AB001 had a significant positive effect on insulin resistance in this trial.

[0502] The biomarkers identified in this study as indicative of chronic systemic inflammation were total adiponectin and hsCRP [19, 20]. Adiponectin significantly increased after AB001 treatment, whereas adiponectin decreased after placebo. These observations were also highly significant for the between-group changes (p < 0.001). AB001 resulted in a greater than 30% decrease in hsCRP values, whereas hsCRP values ​​increased by more than 20% after placebo. However, due to the high variability observed, the between-group changes did not reach statistical significance.

[0503] A similar pattern was observed for other laboratory biomarkers of metabolic syndrome (triglycerides, cholesterol, and uric acid) (see Table 2). There was a statistically significant improvement in triglyceride concentrations with AB001, but not with placebo. There was a strong trend favoring AB001 for total cholesterol and HDL cholesterol levels. Less pronounced impairments in LDL cholesterol and uric acid were observed with AB001 than with placebo. These findings are consistent with the overall positive laboratory profile observed with AB001 compared with placebo.

[0504] The supplement was well tolerated, and no serious adverse events were reported in this trial. A total of 33 adverse events were reported, 18 of which occurred with placebo and 15 with AB001. Symptoms related to problems occurring in the gastrointestinal tract were seen in six patients receiving placebo and only one with AB001. Hypoglycemia was reported six times in two patients receiving AB001 and four times in four patients receiving placebo. The reported adverse events indicate that the nutritional supplement had no specific side effects in this trial. Furthermore, no clinically relevant changes occurred in any other values ​​of the safety biochemistry panel performed before and after the study during the study.

[0505] discuss

[0506] Diabetes mellitus is a chronic systemic disease associated with complications in most organs of the body. It is an epidemic that affects ~9% of the world’s population

[21] . Changes in pancreatic β-cell function and insulin resistance lead to relative insulin deficiency and impaired cellular responses to insulin. The most prominent symptom of the disease is hyperglycemia, which can cause several serious secondary complications [22, 23]. Antidiabetic drugs are usually used according to national and international treatment guidelines [24, 25], and the most commonly used drug, metformin, has limited efficacy and may have adverse effects on the composition of the intestinal bacterial microbiota. Recently, it has been found that the intestinal microbiome of diabetic patients is altered, such as an increase in the ratio of Bacteroides species to Clostridium species in the intestine and an increase in the number of various opportunistic pathogens [26-29]. Circulating Gram-positive enteric bacteria have been detected in blood samples of diabetic patients

[28] . Changes in the intestinal microbiome may lead to metabolic endotoxemia through the release of lipopolysaccharides, thereby stimulating inflammation and insulin resistance

[30] . Epithelial enteroendocrine L cells play a role in generating inflammation, and their number is positively or negatively correlated with the abundance of 25 bacterial taxa in the intestine [31, 32].

[0507] Based on these findings, the effects of probiotic supplementation on diabetes and diabetes-related complications have become the focus of modern research. Animal studies have shown positive results, such as reductions in blood glucose, hemoglobin A1c (HbA1c), and insulin resistance levels [33, 34]. In addition, the first human studies were conducted to investigate the clinical effects of probiotics on glycemic control [14, 35, 36]. In these placebo-controlled trials, probiotic fermented milk, probiotic yogurt, bread, and kefir, mainly containing different strains of Lactobacillae, and brewer's yeast were administered for 6 to 12 weeks. In a meta-analysis of these studies, significant improvements in HbA1c, fasting blood glucose, and HOMA-IR scores were reported, while no significant improvements were seen in insulin and fasting proinsulin levels

[37] .

[0508] The development of AB001 differs from these interventions in that specific bacterial strains have been selected that preferentially metabolize glucose and other carbohydrates and should therefore provide a more robust effect on glucose levels and insulin resistance. The hypothesis of a more pronounced effect was confirmed within the limitations of this study protocol, particularly when a panel of laboratory biomarkers was employed that characterizes the diabetic phenotype by indicating the severity of underlying diabetic exacerbations

[38] .

[0509] The result of AB001 supplementation appears to be a reduction in glucose absorption through the intestine. Similar effects and corresponding biochemical findings are seen when drugs belonging to the SGLT-1 inhibitor class (α-glucosidase inhibitors, such as acarbose or voglibose) are used in conventional diabetes treatment. The difference between the two approaches is that SGLT-1 inhibitors actively retain glucose molecules in the intestine, where they are ultimately metabolized by bacteria produced in the large intestine, and the end product is methane gas. Therefore, patients receiving SGLT-1 inhibitors often complain of severe problems such as flatulence and bloating [39, 40]. The majority of patients in both treatment groups were already on insulin at various treatment regimens, indicating a somewhat advanced stage of disease. The positive effects of AB001 on biomarkers of potential diabetes exacerbation would have to be very clear, with sustained positive and significant results seen on almost all of the studied indicators.

[0510] in conclusion

[0511] "The results observed with AB001 across the board demonstrated improvements in cardiometabolic profiles, whereas the opposite was true for all parameters observed with placebo. Given the intensive background diabetes treatment received by the participating patients, these results strongly suggest that AB001 is a valuable addition to any existing treatment portfolio for patients with type 2 diabetes."

[0512] References

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[0533] 21.International Diabetes Federation.IDF Diabetes Atlas 2019https: / / www.diabetesatlas.org

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[0553] 41. Kayibanda JF, Girouard C, Grégoire JP, Demers E, Moisan. Adherence to the evidence-based heart failure drug treatment: Are there sex-specific differences among new users? J.Res Social Adm Pharm. 2018; 14: 915-920 <L

[0554] Table 1. Patient characteristics in two treatment groups

[0555]

[0556] Table 2. Results of glycemic and cardiodiabetic parameters at baseline and endpoint

[0557]

[0558] The reader's attention is drawn to all papers and documents filed concurrently with or previous to this application, which are available to the public with this specification, and the contents of all such papers and documents are incorporated herein by reference.

[0559] All features disclosed in this application (including any accompanying claims, abstract and drawings), and / or all steps of any method or process so disclosed, may be combined in any combination, unless at least some of such features and / or steps in a combination are mutually exclusive.

[0560] Each feature disclosed in this specification (including any accompanying claims, abstract and drawings) may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Accordingly, unless expressly stated otherwise, each feature disclosed is one example only of a series of equivalent or similar features.

[0561] The invention is not limited to the details of any foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this application (including any accompanying claims, abstract and drawings), or to any novel feature or any novel combination of steps of any method or process so disclosed.

Claims

1. A composition comprising one or more species of Bacillus genus, rice bran, L-cysteine ​​and a high molecular weight, low osmotic pressure carbohydrate for use in treating and / or preventing type 2 diabetes, prediabetes and / or symptoms thereof in a subject.

2. A method for treating and / or preventing type 2 diabetes, prediabetes and / or symptoms thereof in a subject, comprising administering to the subject a composition comprising one or more species of Bacillus, rice bran, L-cysteine ​​and a high molecular weight, low osmotic pressure carbohydrate.

3. The composition for use according to claim 1 or the method according to claim 2, wherein The composition is used for treating and / or preventing type 2 diabetes and / or its symptoms.

4. A composition or method for use according to any one of the preceding claims, wherein administering the composition to the subject: (a) reducing the level of one or more of HbA1c, glucose, insulin, intact proinsulin, and / or hsCRP in the blood; (b) reduction in HOMA-IR score; and / or (c) Increase the level of adiponectin in the blood.

5. A composition or method for use according to any one of the preceding claims, wherein The composition is administered to the subject to control blood sugar.

6. A composition or method for use according to any one of the preceding claims, wherein Administering the composition to the subject degrades glucose.

7. A composition or method for use according to any one of the preceding claims, wherein Administering the composition to the subject metabolizes glucose in the subject's digestive tract, optionally wherein administering the composition to the subject metabolizes glucose in the subject's intestine, more optionally wherein administering the composition to the subject metabolizes glucose in the subject's small intestine.

8. A composition or method for use according to any one of the preceding claims, wherein Administering the composition to the subject reduces glucose absorption into the subject's blood.

9. A composition or method for use according to any one of the preceding claims, wherein Administering the composition to the subject lowers the subject's blood glucose concentration.

10. A composition or method for use according to any one of the preceding claims, wherein The one or more species of Bacillus are selected from Bacillus subtilis and Bacillus coagulans.

11. The composition or method for use according to claim 10, wherein The composition includes Bacillus subtilis and Bacillus coagulans.

12. The composition or method for use according to claim 10 or 11, wherein: a) the Bacillus subtilis species is selected from the group consisting of Bacillus subtilis strain DFM 0326 (LMG P-32899) and Bacillus subtilis strain DFM 1015 (LMG P-32900); and / or c) The Bacillus coagulans species is Bacillus coagulans strain DFM 0705 (LMG P-32921).

13. A composition or method for use according to any one of the preceding claims, wherein The high molecular weight low osmotic pressure carbohydrate is dextrin.

14. A composition or method for use according to any one of the preceding claims, wherein The composition further comprises one or more bacterial species selected from the group consisting of Bacillus amyloliquefaciens, Bacillus velezensis, Bacillus sp MT 03, Bacillus atrophaeus and Pediococcus pentosaceus.

15. A composition or method for use according to any one of the preceding claims, wherein The composition comprises at least about 20% w / w L-cysteine.

16. A composition or method for use according to any one of the preceding claims, wherein The composition comprises at least about 1×10 5 Bacillus bacteria.

17. A composition or method for use according to any one of the preceding claims, wherein The composition comprises at least about 73% w / w rice bran.

18. A composition or method for use according to any one of the preceding claims, wherein The composition includes at least about 0.5% w / w high molecular weight low osmotic pressure carbohydrate.

19. A composition or method for use according to any one of the preceding claims, wherein The composition further comprises one or more of the following: vitamin B12, magnesium salt of fatty acid, calcium phosphate, potassium phosphate, silicon dioxide and cellulose, optionally wherein the magnesium salt of fatty acid is magnesium stearate.

20. A composition or method for use according to any one of the preceding claims, wherein The composition is formulated into acid-resistant tablets or capsules.

21. The composition or method for use according to claim 20, wherein The acid-resistant tablet or capsule comprises a film coating, wherein the film coating comprises hydroxypropyl methylcellulose (HPMC).

22. A composition or method for use according to any one of the preceding claims, wherein The one or more species of the genus Bacillus are not genetically modified.

23. A composition or method for use according to any one of the preceding claims, wherein The composition is for daily administration.

24. Use of a composition comprising one or more species of Bacillus, rice bran, L-cysteine ​​and a high molecular weight, low osmotic pressure carbohydrate for degrading glucose.

25. A composition comprising one or more species of Bacillus, rice bran, L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate for use in: (a) reducing the level of one or more of the following in the subject's blood: HbA1c, glucose, insulin, intact proinsulin, and / or hsCRP; (b) reducing the subject's HOMA-IR score; and / or (c) increasing the level of adiponectin in the blood of a subject.

26. Use of a composition comprising one or more species of Bacillus, rice bran, L-cysteine, and a high molecular weight, low osmotic pressure carbohydrate for controlling blood glucose in a subject.

27. The use according to any one of claims 24 to 26, wherein: a) the Bacillus subtilis species is selected from the group consisting of Bacillus subtilis strain DFM 0326 (LMG P-32899) and Bacillus subtilis strain DFM 1015 (LMG P-32900); and / or c) The Bacillus coagulans species was Bacillus coagulans strain DFM 0705 (LMG P-32921).

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