Compositions of pentadecanoic acid (C15: 0) and uses thereof

Abstract

Disclosed herein are compositions comprising pentadecanoic acid (C15: 0) and / or one or more phenolic compounds, and uses of such compositions.

Description

[0001] Cross-references

[0002] This application claims priority to Singapore Patent Application No. 10202303170R filed on November 7, 2023, the entire contents of which are expressly incorporated herein by reference. Field of the Invention

[0003] The present invention generally relates to compositions and methods for therapeutically and / or prophylactically treating, ameliorating and / or regulating metabolic syndrome, obesity and obesity-related disorders, and in particular, the present invention relates to compositions and methods for treating non-alcoholic fatty liver disease (NAFLD). Background Art

[0004] Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and affects approximately 25% of all adults worldwide. In Asia, the prevalence of NAFLD is estimated to be approximately 30% and is predicted to increase further within the next 10 years.

[0005] NAFLD is defined as the accumulation of triglycerides in the liver exceeding 5% of the total liver weight in the absence of significant alcohol consumption. About 1 / 5 of people with NAFLD progress to non-alcoholic steatohepatitis (NASH), which is characterized by fatty degeneration, infiltration of inflammatory cells and fibrosis at different stages (from no fibrosis to late tissue scarring). NASH may progress to cirrhosis or even hepatocellular carcinoma. NAFLD is strongly associated with obesity, type 2 diabetes, hypertension and dyslipidemia, and is expected to cause major public health challenges in conjunction with the pandemic of obesity and diabetes.

[0006] Currently, there are no approved pharmacological therapies for the treatment of NAFLD or NASH. Many pharmacological interventions have been tried in NAFLD / NASH with limited benefit overall, and thus, there remains a need to find treatments for NAFLD. SUMMARY OF THE INVENTION

[0008] In one aspect, provided is the use of pentadecanoic acid (C15:0) in the preparation of a composition for lowering LDL (low-density lipoprotein) cholesterol in a subject.

[0009] In another aspect, provided is a use of pentadecanoic acid (C15:0) in the preparation of a composition for promoting a healthy gut microbiome in a subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The invention will be better understood with reference to the detailed description when considered in conjunction with the non-limiting examples and accompanying drawings, in which:

[0012] Figure 1Shown are changes (%) in liver proton density fat fraction (PDFF). Figure 1 A-1C: Absolute individual changes in liver PDFF after 12 weeks of intervention for the control group; the diet group not containing C15:0; and the diet group containing C15:0. Figure 1 D-1F: Changes in liver PDFF distribution for the control group; the diet group not containing C15:0; and the diet group containing C15:0. The results showed that the changes in liver PDFF distribution in participants of the two diet groups (containing or not containing C15:0) were more significant than in the control group.

[0013] Figure 2 The changes in plasma concentrations of C15:0 in the different intervention groups are shown. The results show that at the end of the study, the concentration of C15:0 was significantly higher in the group that received the C15:0 supplemented diet compared to the other two groups.

[0014] Figure 3 The changes in plasma LDL cholesterol levels in the different intervention groups are shown. The results showed that the reduction in LDL-cholesterol was significantly greater in the group that received the C15:0 supplemented diet compared to the other two groups.

[0015] Figure 4 Changes in microbiome species in the different intervention groups are shown. Model posterior distributions from the Bayesian mixed model show pairwise comparisons of control versus diet without C15:0; control versus diet with C15:0; and diet without C15:0 versus diet with C15:0. Darker grey represents the 66% of the posterior value and lighter grey represents the 95% of the posterior value. In the pairwise comparisons, the former served as the reference. DETAILED DESCRIPTION OF THE INVENTION

[0017] The inventors of the present invention surprisingly discovered that consumption of pentadecanoic acid (C15:0) can significantly reduce levels of low-density lipoprotein (LDL) cholesterol and / or promote a healthy gut microbiome.

[0018] Therefore, in one aspect, there is provided a use of pentadecanoic acid (C15:0) in the preparation of a composition for reducing low-density lipoprotein (LDL) cholesterol in a subject. In another aspect, there is provided a use of pentadecanoic acid (C15:0) in the preparation of a composition for promoting a healthy intestinal microbiome in a subject. In one example, there is also provided a method of reducing LDL cholesterol and / or promoting a healthy intestinal microbiome in a subject, the method comprising administering pentadecanoic acid (C15:0) to the subject.

[0019] Pentadecanoic acid (C15:0) is an odd-chain saturated fatty acid with a 15-carbon backbone. It is composed of the molecular formula CH3(CH2) 13 CO2H and structural formula Pentadecanoic acid is found primarily in dairy fat, as well as in ruminant meat and some fish and plants. It is rare in nature, accounting for only about 1% of all fatty acids in milk.

[0020] As used herein, the term "fatty acid" refers to a carboxylic acid with an aliphatic chain. There are two main types of fatty acids: saturated fatty acids and unsaturated fatty acids. Saturated fatty acids do not have double bonds between the carbon atoms in their chain, which means that they are "saturated" with hydrogen atoms. Unsaturated fatty acids have one or more double bonds in the carbon chain, which makes them less saturated with hydrogen. It can be further divided into monounsaturated fatty acids (MUFA) containing one double bond, and polyunsaturated fatty acids (PUFA) containing two or more double bonds.

[0021] Most fatty acids are even-chain, meaning they are made up of an even number of carbon atoms. Some fatty acids have an odd number of carbon atoms; they are called odd-chain fatty acids (OCFAs).

[0022] The term "low-density lipoprotein" or "LDL" for short refers to one of the five major classes of lipoproteins that are responsible for transporting cholesterol, triglycerides, and other fats in the blood. Although LDL is necessary for normal body function, such as building cell membranes, maintaining hormone levels, and helping transport fat-soluble vitamins, excessive amounts of LDL cholesterol can be harmful. High levels of LDL cholesterol are often associated with diseases and conditions such as atherosclerosis, coronary artery disease, heart attack (myocardial infarction), stroke, and peripheral arterial disease. Atherosclerosis is a narrowing of the arteries caused by a buildup of cholesterol plaques. It can lead to stroke, heart attack, dementia, and other health challenges. Coronary artery disease (CAD), also known as ischemic heart disease, occurs when the coronary arteries that supply blood to the heart muscle become hardened and narrowed. The arteries become hardened and narrowed due to atherosclerosis. A heart attack occurs when blood flow in one of the heart's coronary arteries decreases or stops, causing a myocardial infarction. A stroke is an interruption of blood flow to a part of the brain. There are two main types of stroke: ischemic stroke, which occurs when the blood supply to a part of the brain is blocked or reduced; and hemorrhagic stroke, which occurs when blood vessels in the brain leak or rupture and cause cerebral hemorrhage. Peripheral arterial disease (PAD) is a vascular disease that causes abnormal narrowing of arteries other than those supplying the heart or brain. PAD can occur in any blood vessel, but it is more common in the legs than in the arms. Since the compositions disclosed herein effectively reduce the low-density lipoprotein (LDL) cholesterol of the subject, the compositions may also effectively treat or prevent diseases, disorders or conditions associated with high levels of LDL cholesterol, including but not limited to the diseases listed above. In some specific examples, the compositions disclosed herein may effectively reduce low-density lipoprotein (LDL) cholesterol in a subject, wherein the subject suffers from one or more of the above-mentioned diseases, disorders or conditions, or is at risk of developing one or more of the above-mentioned diseases, disorders or conditions.

[0023] In some other examples, compositions disclosed herein effectively reduce low-density lipoprotein (LDL) cholesterol of a subject, wherein the subject suffers from a disease, disorder or condition associated with a high amount of liver fat or is at risk of developing a disease, disorder or condition associated with a high amount of liver fat, including but not limited to NAFLD, NASH, alcoholic fatty liver disease (AFLD), alcoholic hepatitis, alcoholic cirrhosis, liver fibrosis, liver failure and hepatocellular carcinoma. In some other examples, compositions as disclosed herein also effectively treat or prevent such diseases, disorders or conditions. The present invention also provides a method for treating a subject so that the desired condition is improved by administering compositions as described herein to the subject. The condition may be, for example, NAFLD, metabolic syndrome or obesity.

[0024] NAFLD refers to a condition in which there is excess fat accumulation in the liver of people who drink little or no alcohol. The most common form of NAFLD is a non-serious condition called hepatic steatosis (fatty liver), in which fat accumulates in liver cells. The diagnosis of NAFLD is usually first suspected when a person is found to have a mild elevation in their liver blood test, although NAFLD can be present in normal liver blood tests. NAFLD is usually confirmed by imaging studies, most commonly liver ultrasound or magnetic resonance imaging (MRI).

[0025] In some examples, a subject is at risk for developing NAFLD, which refers to a subject having one or more comorbidities of NAFLD, such as obesity, abdominal obesity, metabolic syndrome, and cardiovascular disease.

[0026] The terms "reduce", "reducing" or "reduction" used in the context of reducing LDL cholesterol levels refer to a reduction in the level of LDL cholesterol compared to the level of LDL cholesterol when a composition as disclosed herein is not administered. For example, the reduction may be at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% compared to the level of LDL cholesterol before administration or when a composition as disclosed herein is not administered.

[0027] The level of LDL cholesterol generally refers to the plasma level of LDL cholesterol, which can be measured using routine laboratory tests.

[0028] As used herein, the terms "treat" and "treating" include partially, substantially or completely achieving one or more of the following: reducing the extent of a disease, disorder or condition; improving or ameliorating clinical symptoms or indicators associated with the disease, disorder or condition, and / or reducing the number, frequency, duration or severity of clinical symptoms; delaying or inhibiting the development or progression of the disease, disorder or condition.

[0029] As used herein, the terms "prevent" or "preventing" refer to partially, substantially, or completely reducing the risk of onset of a disease, disorder, or condition, and / or preventing the clinical symptoms of a disease, disorder, or condition from occurring in a subject who may be susceptible to the disease, disorder, or condition but does not yet experience or display symptoms of the disease, disorder, or condition.

[0030] In some instances, promoting a healthy intestinal microbiome includes increasing the abundance of beneficial microorganisms in the intestinal tract and / or reducing the abundance of potentially harmful or pathogenic microorganisms in the intestinal tract. In some instances, the intestinal tract refers to the intestinal tract of a mammal. In a specific instance, the intestinal tract is a human intestinal tract.

[0031] In some instances, the microorganism is a bacterium. Examples of beneficial bacteria include, but are not limited to, Bifidobacterium adolescentis, Bacteroides ovatus, Bifidobacterium longum, Bifidobacterium bifidum, Bacteroides fragilis, Lactobacillus rhamnosus, Lactobacillus acidophilus, Faecalibacterium prausnitzii, Akkermansia muciniphila, Ruminococcus bromii, Lactobacillus plantarum and Enterococcus faecium, in particular Bifidobacterium adolescentis and Bacteroides ovatus. Examples of potentially harmful or pathogenic bacteria include, but are not limited to, Bacteroides dorei, Bacteroides stercoris, and Fusobacterium mortiferum.

[0032] Bacteria are routinely identified by morphological and biochemical tests, supplemented as needed by specialized tests such as serotyping and antibiotic inhibition patterns. Species identification may also be confirmed using molecular techniques or by their genetic sequences (sometimes directly from clinical samples).

[0033] Bifidobacterium adolescentis is a beneficial bacterium commonly found in the human intestine, especially in the large intestine. It belongs to the genus Bifidobacterium and is known to have probiotic properties. Bifidobacterium adolescentis plays a vital role in maintaining intestinal health by helping digest complex carbohydrates and fiber and producing short-chain fatty acids (SCFAs) such as acetate and lactate, which are important for colon health. In addition, it helps support the immune system, reduce inflammation, and maintain the balance of the intestinal microbiota.

[0034] Bacteroides ovatus is commonly found in the human gut and plays an important role in digesting complex carbohydrates and dietary fiber. Bacteroides ovatus is known for its ability to produce enzymes that break down polysaccharides, helping to convert these into simpler sugars that can be further fermented into SCFAs such as butyrate, acetate, and propionate. Bacteroides ovatus plays an important role in supporting a healthy and balanced intestinal environment.

[0035] Bifidobacterium longum is naturally present in the human gastrointestinal tract, especially in the large intestine. Bifidobacterium longum helps digest complex carbohydrates and dietary fiber, breaking them down into SCFAs such as acetate and lactate. Bifidobacterium longum supports the immune system by inhibiting the growth of harmful bacteria and pathogens, producing antimicrobial substances, and enhancing the body's immune response. Bifidobacterium longum also has anti-inflammatory effects, which can help alleviate the symptoms of gastrointestinal disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD).

[0036] Bifidobacterium bifidum is naturally found in the human gastrointestinal tract, especially in the colon, as well as in the vagina and mouth. It is one of the first bacteria to colonize the intestines of infants (especially breastfed infants), and it plays a vital role in maintaining overall gut health throughout life. Bifidobacterium bifidum helps digest complex carbohydrates and fiber, breaking them down into simpler compounds that can be absorbed and used by the body. It also helps prevent gastrointestinal infections by producing lactic acid, which lowers the pH of the intestinal environment, making it less suitable for harmful pathogens. Bifidobacterium bifidum strengthens the immune system by stimulating the production of antibodies and other immune cells. It also helps prevent infection by competing with pathogenic bacteria for nutrients and attachment sites in the intestine. It also has anti-inflammatory effects and can help relieve symptoms of gastrointestinal diseases such as IBS and IBD.

[0037] Bacteroides fragilis helps digest complex carbohydrates and proteins, breaking them down into simpler substances that can be absorbed by the body. It also helps produce SCFAs. Bacteroides fragilis is known to play a role in regulating the immune system. It can produce polysaccharide A, a molecule that has been shown to help maintain a balanced immune response and reduce inflammation. This has implications for preventing autoimmune diseases and promoting gut health.

[0038] Lactobacillus rhamnosus is widely recognized for its probiotic properties and is normally found in the human intestine, particularly in the small intestine. Lactobacillus rhamnosus is known for its ability to support intestinal health by enhancing intestinal barrier function, improving digestion, and helping to prevent and treat diarrhea, particularly antibiotic-associated diarrhea and infectious diarrhea in children. Lactobacillus rhamnosus also plays a role in boosting the immune system by stimulating the production of antibodies and enhancing the activity of certain immune cells. It helps prevent gastrointestinal infections and may also reduce the incidence of respiratory infections.

[0039] Lactobacillus acidophilus is one of the most well-known and widely used probiotics, naturally found in the human intestines, mouth and vagina. Lactobacillus acidophilus plays an important role in maintaining a healthy balance of intestinal flora. It helps break down lactose into lactic acid, making it particularly beneficial for individuals with lactose intolerance. It also helps with food digestion and nutrient absorption, supporting overall intestinal health. Lactobacillus acidophilus enhances immune function by stimulating antibody production and activating certain immune cells. It also produces bacteriocins, which are substances that inhibit the growth of harmful bacteria, helping to prevent infection. Lactobacillus acidophilus is effective in preventing and treating a variety of gastrointestinal infections, including those caused by pathogens such as E. coli, Salmonella and Helicobacter pylori. It is also commonly used to prevent and reduce the symptoms of antibiotic-associated diarrhea. Lactobacillus acidophilus can help lower cholesterol levels by breaking down bile in the intestines, preventing it from being reabsorbed, thereby lowering cholesterol levels in the bloodstream.

[0040] Faecalibacterium prausnitzii is one of the most abundant and important bacteria in the human gut microbiota, particularly in the large intestine. Faecalibacterium prausnitzii is known to produce butyrate, a SCFA with powerful anti-inflammatory properties. Butyrate serves as an energy source for colonocytes and helps maintain the integrity of the intestinal lining, reducing the risk of leaky gut syndrome and systemic inflammation. By producing butyrate and other SCFAs, Faecalibacterium prausnitzii plays a key role in supporting a healthy intestinal environment. It helps maintain a balanced intestinal microbiota, which is essential for proper digestion, nutrient absorption, and overall gastrointestinal health. Low levels of Faecalibacterium prausnitzii have been associated with various inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis. Faecalibacterium prausnitzii also contributes to the regulation of the immune system by modulating the production of cytokines.

[0041] Akkermansia muciniphila specializes in breaking down mucin, which is essential for the maintenance and regeneration of the mucus layer that protects the intestinal lining. By doing so, it helps maintain a healthy intestinal barrier, preventing harmful pathogens and toxins from entering the bloodstream. Akkermansia muciniphila has been shown to be associated with improved glucose metabolism, reduced inflammation, and reduced body fat. Akkermansia muciniphila has also been found to have anti-inflammatory effects, in part, by promoting the production of beneficial SCFAs such as acetate and propionate. High levels of Akkermansia muciniphila are associated with healthier body weight and reduced fat accumulation.

[0042] Ruminococcus brockii is highly specialized in degrading resistant starches, a class of carbohydrates that resist digestion in the small intestine and reach the colon intact. Ruminococcus brockii breaks these resistant starches into simpler compounds that can be fermented by other gut bacteria, leading to the production of beneficial SCFAs such as butyrate, acetate, and propionate.

[0043] Lactobacillus plantarum is widely recognized for its multifaceted probiotic properties and is commonly found in the human intestine. Lactobacillus plantarum is known for its ability to survive in different environments, including the acidic conditions of the stomach. Lactobacillus plantarum helps maintain a healthy balance of intestinal microbiota by promoting the growth of beneficial bacteria and inhibiting the growth of harmful pathogens. It helps digest food, enhances nutrient absorption, and supports overall intestinal health. Lactobacillus plantarum has strong anti-inflammatory properties. It can modulate immune responses in the intestine, reduce inflammation and help control conditions such as IBS and IBD. Lactobacillus plantarum also supports the integrity of the intestinal barrier by producing antimicrobial substances and enhancing the production of mucin, which protects the intestinal lining from harmful bacteria and toxins. Lactobacillus plantarum is also known for its antioxidant activity, which helps neutralize free radicals in the body and reduces oxidative stress. This contributes to overall health and may help prevent chronic diseases. Lactobacillus plantarum also enhances immune function by stimulating the production of antibodies and activating immune cells. It helps prevent infection and supports the body's natural defenses. Additionally, Lactobacillus plantarum may help lower cholesterol levels by breaking down bile salts in the intestines, preventing their reabsorption, thereby reducing blood cholesterol levels.

[0044] Enterococcus faecium is naturally present in the gastrointestinal tract of humans and animals. Enterococcus faecium can contribute to the overall balance of the microbiota by inhibiting the growth of pathogenic bacteria. It produces bacteriocins, which are antimicrobial peptides that help inhibit harmful microorganisms, thereby supporting a healthy intestinal environment. Certain strains of Enterococcus faecium are used as probiotics in dietary supplements and animal feed. These strains are selected for their beneficial effects, such as improved intestinal health, enhanced digestion, and boosted immune system.

[0045] Bacteroides domitilis is part of the human gut microbiota and is found specifically in the large intestine. Alterations in the abundance of Bacteroides domitilis may be associated with certain metabolic and inflammatory conditions. Changes in Bacteroides domitilis levels may serve as a potential marker for gut dysbiosis, an imbalance in the gut microbiota that can lead to various health problems.

[0046] Bacteroides faecalis is normally found in the large intestine. Bacteroides faecalis can affect the immune system and inflammation in the intestine. Although it usually supports a balanced immune response, an imbalance in the levels of Bacteroides faecalis can potentially contribute to inflammatory conditions such as IBD. Bacteroides faecalis can become pathogenic if it is translocated outside the intestine or if the intestinal barrier lacks resistance. In this case, it can potentially contribute to infection or other health problems, especially in immunocompromised individuals.

[0047] Fusobacterium demise is known primarily for its pathogenicity. It is associated with a range of infections, particularly when it moves from its usual location in the body to other areas such as the bloodstream, where it can cause serious infections. For example, Fusobacterium demise can enter the bloodstream, leading to bacteremia, which is the presence of bacteria in the blood. This condition can develop into sepsis, a life-threatening systemic response to infection. Fusobacterium demise is often involved in intra-abdominal infections, particularly after surgery, trauma or perforation of the gastrointestinal tract. Fusobacterium demise can also cause soft tissue infections, such as cellulitis or abscesses, particularly in patients with a compromised immune system. In the oral cavity, Fusobacterium demise can cause periodontal disease and other infections. It can also involve respiratory infections, particularly when it is inhaled into the lungs. It has been observed that Fusobacterium demise shows resistance to certain antibiotics, which complicates treatment. This resistance makes it more challenging to control infections caused by Fusobacterium demise, particularly in healthcare settings.

[0048] In some examples, the composition disclosed above further comprises one or more phenolic compounds. In some other examples, the method disclosed above further comprises administering one or more phenolic compounds to the subject.

[0049] Phenolic compounds are a class of compounds that have one or more hydroxyl (-OH) groups directly bonded to an aromatic hydrocarbon group. Based on the number of phenol units in the molecule, phenolic compounds are classified as simple phenols or polyphenols. Polyphenols include tannins and phenylpropanoids, such as lignin, flavonoids, and condensed tannins. Polyphenols are found in many plants and fruits.

[0050] In some examples, the one or more phenolic compounds are olive oil polyphenols, including but not limited to hydroxytyrosol, tyrosol, oleuropein, oleocanthal, oleacein, ligstroside, pinoresinol, apigenin, luteolin, and quercetin.

[0051] Hydroxytyrosol has the chemical formula C8H 10 O3 and structural formula of phenylethanoid.

[0052] Tyrosol has the chemical formula C8H 10 O2 and structural formula of phenylethanoid.

[0053] Oleuropein is a glycosylated secoiridoid terpenoid, a class of phenolic bitter compounds with the chemical formula C 25 H 32 O 13 and structural formula

[0054] Olive oil irritant aldehyde is a chemical with the formula C 17 H 20 O5 and structural formula of phenylethanol.

[0055] Oleoresin is a substance with the chemical formula C 17 H 20 O6 and structural formula of secoiridoids.

[0056] Ligustrum lucidum is a kind of 25 H 32 O 12 and structural formula of secoiridoid glycosides.

[0057] Rosinol is a kind of 20 H 22 O6 and structural formula of tetrahydrofuranols.

[0058] Apigenin is a chemical compound with the formula C 15 H 10 O5 and structural formula of flavonoids.

[0059] Luteolin is a kind of 15 H 10 O6 and structural formula of flavonoids.

[0060] Quercetin is a chemical compound with the formula C 15 H 10 O7 and structural formula of flavonols.

[0061] In some examples, the composition disclosed above further comprises one or more fatty acids other than pentadecanoic acid (C15:0). In some other examples, the method disclosed above further comprises administering one or more fatty acids other than pentadecanoic acid (C15:0) to the subject.

[0062] In some examples, the one or more fatty acids include, but are not limited to, myristic acid (C14:0), palmitic acid (C16:0), palmitoleic acid (C16:1), heptadecanoic acid (C17:0), heptadecenoic acid (C17:1), stearic acid (C18:0), oleic acid (C18:1), linoleic acid (C18:2), linolenic acid (C18:3), arachidic acid (C20:0), eicos-9-enoic acid (C20:1), docosanoic acid (C22:0), erucic acid (C22:1), tetracosanoic acid (C24:0), and docosenoic acid (C24:1). In such examples, pentadecanoic acid (C15:0) comprises at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or at least about 50%, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99% w / w of the total fatty acids present in the composition.

[0063] In some examples, administering a composition comprising pentadecanoic acid (C15:0) and / or one or more phenolic compounds to a subject also reduces the level of total cholesterol and / or triglycerides in the subject.

[0064] In some examples, administering a composition comprising pentadecanoic acid (C15:0) and one or more phenolic compounds to a subject achieves a synergistic effect in lowering LDL cholesterol levels.

[0065] As used herein, the term "synergy" or "synergistic effect" when used in conjunction with a description of the efficacy of a combination of agents refers to any measured effect of the combination that is greater than that predicted from the sum of the effects of the individual agents.

[0066] The inventors of the present invention have also found that consuming one or more phenolic compounds can significantly reduce liver fat. Therefore, in one aspect, there is provided the use of one or more phenolic compounds in the preparation of a composition for reducing liver fat in a subject. In an example, there is also provided a method for reducing liver fat in a subject, the method comprising administering one or more phenolic compounds to the subject. In some instances, the composition further comprises pentadecanoic acid (C15:0). In some other instances, the method further comprises administering pentadecanoic acid (C15:0) to the subject.

[0067] The term "liver fat" as used herein refers to the accumulation of fat (mainly triglycerides) in liver cells. Typically, the liver contains a small amount of fat, but when the fat content exceeds about 5-10% of the liver weight, it is called fatty liver disease. Since the composition disclosed herein effectively reduces the liver fat of the subject, the composition can also effectively treat or prevent diseases, disorders or conditions associated with high amounts of liver fat, including but not limited to NAFLD, NASH, AFLD, alcoholic hepatitis, alcoholic cirrhosis, liver fibrosis, liver failure and hepatocellular carcinoma.

[0068] Liver fat can be detected using various imaging techniques, such as magnetic resonance imaging (MRI), ultrasound, computed tomography (CT), and transient elastography (e.g. ). MRI provides a more detailed and quantitative assessment of liver fat. MRI techniques such as proton density fat fraction (PDFF) can measure the percentage of fat in the liver. Ultrasound is a common non-invasive method for detecting fatty liver. Fatty liver appears brighter (hyperechoic) on ultrasound images, but it cannot quantify the exact amount of fat. CT can detect liver fat, but its sensitivity is lower than MRI and it involves radiation exposure. Transient elastography is a non-invasive technique that uses ultrasound to measure liver stiffness and fat content. The controlled attenuation parameter (CAP) value estimates the amount of fat in the liver, and in some instances, MRI techniques, particularly PDFF, are the preferred method for detecting and quantifying liver fat.

[0069] The terms "reduce", "reducing" or "reduction" used in the context of reducing liver fat refer to a decrease in the amount of liver fat compared to the amount of liver fat when a composition as disclosed herein is not administered. For example, the reduction can be at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% compared to the amount before administration or when a composition as disclosed herein is not administered.

[0070] Compositions as disclosed herein are preferably administered orally. Therefore, in some instances, the composition is contained in an acceptable excipient and / or carrier for oral consumption. The composition can be solid, semisolid or liquid at room temperature (about 25° C.). Suitable forms of the composition include, but are not limited to, liquids, powders, gels, pastes, solids, concentrates, solutions and suspensions. The composition can be further modified and / or packaged into any commonly used orally deliverable form, including but not limited to capsules, soft gels, tablets, syrups, emulsions.

[0071] In some instances, the composition is in the form of a health supplement, such as a dietary supplement or a nutritional supplement. In some instances, the composition is in the form of a food.

[0072] As used herein, the term "dietary supplement" refers to a composition used to supplement the diet of a human or animal. Dietary supplements generally do not provide significant amounts of calories, but may contain other micronutrients (eg, vitamins or minerals).

[0073] As used herein, the term "nutritional supplement" refers to a composition comprising a dietary supplement in combination with a source of calories. In some examples, the nutritional supplement provides balanced amounts of carbohydrates, protein, and / or fat.

[0074] In some examples, the nutritional supplement is a meal replacement or supplement, such as a nutritional drink, concentrate or shake, or a nutritional or energy bar.

[0075] Other nutrients may also be included in the supplement. Nutrients are natural bioactive compounds that have health promoting, disease preventing or medicinal properties. One or more inert ingredients may also be included in the supplement, particularly if it is desired to limit the number of calories added to the diet by the supplement.

[0076] As used herein, the term "food" refers to any food or feed suitable for human or other mammal or non-mammal consumption. In some instances, the amount of pentadecanoic acid (C15:0) and / or phenolic compounds in the food has been fortified (e.g., enriched or concentrated), for example, by incorporation into one or more ingredients of the food. Fortification is preferably at a level in order to provide an effective dose of pentadecanoic acid (C15:0) and / or phenolic compounds.

[0077] In some instances, food is the food of preparation and packaging.Preparation can be not limited to include cooking, mixing, seasoning (flavoring), seasoning (seasoning), blending, boiling, frying, baking or other methods known in the art, and the example of suitable food includes but is not limited to: baked goods, puddings, sweets, snack foods or frozen candies or novelties (novelties) (such as ice cream), frozen meals prepared, snack products (such as, potato chips), soups, spreads (spreads), sauces (sauces), salad dressings, meat products prepared, cheese, yogurt and any other fat or oily food and food ingredients (such as, wheat flour).In some other instances, food is beverage, such as milk (dairy products, almonds, soybeans or oat milk), fruit juice, tea, coffee or chocolate beverage.In some other instances, food is animal feed.

[0078] Flavorings and coloring agents can also be incorporated into supplements or foods. Emulsifiers can be added for stability. Preservatives can also be added to extend the shelf life of the product.

[0079] In some examples, the supplement or food has a low to average calorie content, such as about 50 to 600, or about 100 to 550, or about 150 to 500, or about 200 to 450, or about 250 to 400, or about 300 to 350 kcal per serving, or less than about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, or 600 kcal per serving.

[0080] In some examples, the pentadecanoic acid (C15:0) present in the composition is substantially in free acid form. This means that a single pentadecanoic acid (C15:0) molecule is not esterified with glycerol.

[0081] In some examples, particularly examples where the composition is used as a supplement or food, the composition contains no or substantially no other active ingredients, particularly drugs, that can be used to reduce LDL cholesterol and / or reduce liver fat in a subject. Examples of such active ingredients include, but are not limited to: HMG-CoA reductase inhibitors (statins), such as atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, fluvastatin, and pitavastatin; ezetimibe; PCSK9 inhibitors, monoclonal antibodies such as alirocumab and evolocumab, or small interfering RNA; bempedoic acid; lomitapide; bile acid sequestrants, such as cholestyramine, colesevelam, and colestipol; fibrates, such as fenofibrate and gemfibrozil; and omega-3 fatty acids.

[0082] The term "substantially" generally refers to an amount of at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% of the total amount. In some specific examples, the pentadecanoic acid (C15:0) present in the composition is substantially in the free acid form, which means that at least 90%, or at least 95%, or at least 99% of the pentadecanoic acid (C15:0) present in the composition is in the free acid form.

[0083] Generally, it is necessary to apply an effective amount of the composition to the subject so as to achieve the desired effect of reducing LDL cholesterol and / or promoting a healthy intestinal microbiome in the subject. In fact, the effective amount will generally depend on the weight of the subject. In addition, the effective amount for a specific subject varies according to the age and gender of the subject, health and physical condition, the level of LDL cholesterol before treatment, the assessment of medical conditions and other relevant factors. The effective amount can also be adjusted for individual subjects to provide a plasma level of pentadecanoic acid (C15:0) and / or phenolic compounds, which is enough to achieve the desired effect of reducing LDL cholesterol and / or promoting a healthy intestinal microbiome in the subject. The exact amount will be based on the specific circumstances (case-by-casebasis) or in some cases by the informed discretion of the subject. It is expected that the effective amount will fall within a relatively wide range, which can be determined by those skilled in the art by routine tests. For example, the effective amount can be determined by reference to the regulation of plasma LDL cholesterol levels in the subject.

[0084] In some examples, pentadecanoic acid (C15:0) is administered to a subject at a dose of about 1 to 10, or about 2 to 9, or about 3 to 8, or about 4 to 7, or about 5 to 6, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / kg body weight / day. In some other examples, the amount of pentadecanoic acid (C15:0) administered is about 50 to 1,000, or about 100 to 950, or about 150 to 900, or about 200 to 850, or about 250 to 800, or about 300 to 750, or about 350 to 700, or about 400 to 650, or about 450 to 600, or about 500 to 550, or about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1,000 mg / day, more specifically 300 mg / day.

[0085] In some examples, the phenolic compound is administered to a subject at a dose of about 1 to 20, or about 2 to 18, or about 3 to 16, or about 4 to 14, or about 5 to 12, or about 6 to 10, or about 7 to 9, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg / kg body weight / day. In some other examples, the phenolic compound is administered in an amount of about 50 to 1,000, or about 100 to 950, or about 150 to 900, or about 200 to 850, or about 250 to 800, or about 300 to 750, or about 350 to 700, or about 400 to 650, or about 450 to 600, or about 500 to 550, or about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1,000 mg / day, more specifically 400 mg / day.

[0086] Compositions as disclosed herein can be taken once or multiple times per day. In some instances, the composition is orally administered once or twice per day. The frequency of administration will of course depend on the dosage per unit and the desired level of intake. The dosage level / unit can be adjusted to provide a recommended level of administration per day with a reasonable number of units. In some instances, the composition is taken with or before meals. In some other instances, the composition is not taken with meals.

[0087] In some examples, when the composition constitutes a liquid, the concentration of pentadecanoic acid (C15:0) is about 0.5 to 10.0, or about 1.0 to 9.5, or about 1.5 to about 9.0, or about 2.0 to about 8.5, or about 2.5 to about 8.0, or about 3.0 to about 7.5, or about 3.5 to about 7.0, or about 4.0 to about 6.5, or about 4.5 to about 6.0, or about 5.0 to about 5.5 mg / ml, or about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 8.0, 8.2, 8.4, 8.6, 8.8, 9.0, 9.2, 9.4, 9.6, 9.8 or 10.0 mg / ml, in particular about 1.2 mg / ml.

[0088] In some examples, unit dosage forms may be provided, such as individual packages with predetermined amounts of the composition, configured for administration on a predetermined schedule.

[0089] Pentadecanoic acid (C15:0), phenolic compounds and / or other key components such as other fatty acids can be provided or obtained from a variety of sources. In some examples, pentadecanoic acid (C15:0), phenolic compounds and / or other key components such as other fatty acids are extracted from natural sources.

[0090] Compositions as disclosed herein are usually applied for a period of time to become effective and / or achieve the desired effect. In some instances, the composition is applied for about 1 week to 1 year, about 2 weeks to 11 months, about 3 weeks to 10 months, about 4 weeks to 9 months, about 5 weeks to 8 months, about 6 weeks to 7 months, about 7 weeks to 6 months, about 8 weeks to 5 months, about 9 weeks to 4 months, about 10 weeks to 3 months, or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 weeks, or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least about 1, 2, 3, 4 or 5 years. In a specific example, the composition is applied for at least about 12 weeks.

[0091] In some instances, the composition is administered for an extended period of time to become effective or achieve the desired effect, and / or to maintain the desired effect. In some instances, an "extended period of time" refers to at least about 12, 15, 18, 24, 30, 36, 48, 60, 72, or 96 months, or at least about 10, 15, or 20 years.

[0092] In some instances, the subject is female.

[0093] In some instances, the subject is of Asian ethnicity. In some embodiments, the subject is of Chinese ethnicity.

[0094] In some examples, the subject has a body mass index (BMI) of 23±5% to 35±5%, or 24±5% to 34±5%, or 25±5% to 33±5%, or 26±5% to 32±5%, or 27±5% to 31±5%, or 28±5% to 30±5%, or 23±5%, 24±5%, 25±5%, 26±5%, 27±5%, 28±5%, 29±5%, 30±5%, 31±5%, 32±5%, 33±5%, 34±5%, or 35±5%.

[0095] In some instances, the subject has no prior history of diabetes and / or diabetes other than gestational diabetes. Common methods for diagnosing diabetes include a fasting blood glucose test and a glycosylated hemoglobin test. A fasting blood glucose level of <7.0 mmol / L is generally considered non-diabetic. A glycosylated hemoglobin level of <6.5% is generally considered non-diabetic.

[0096] In some examples, the compositions as disclosed herein may also be used in conjunction with a weight loss dietary regimen.

[0097] The invention exemplarily described herein may be appropriately implemented in the presence of any one or more elements, one or more limitations not specifically disclosed herein, and thus, for example, the terms "comprising", "including", "containing", etc. should be understood broadly and without limitation. In addition, the terms and expressions employed herein are used as illustrative rather than limiting terms, and do not mean that any equivalents of the features shown and described or portions thereof are excluded in the use of such terms and expressions, but it is recognized that various modifications are possible within the scope of the invention. Therefore, it should be understood that although the present invention has been particularly disclosed through preferred examples and optional features, modifications and variations of the invention disclosed herein and specifically embodied therein may be adopted by those skilled in the art, and such modifications and variations are considered to be within the scope of the invention.

[0098] Unless the context clearly dictates otherwise, as used in this application, the singular forms "a", "an" and "the" include plural references. For example, the term "a genetic marker" includes a plurality of genetic markers, including mixtures and combinations thereof.

[0099] As used herein, the term "about" typically refers to ±5% of the stated value, more typically ±4% of the stated value, more typically ±3% of the stated value, more typically ±2% of the stated value, even more typically ±1% of the stated value, and even more typically ±0.5% of the stated value.

[0100] Throughout the disclosure, certain examples may be disclosed in the form of ranges. It should be understood that the description of ranges is merely for convenience and brevity and should not be viewed as an immutable limitation of the disclosed range. Therefore, the description of a range should be considered to have specifically disclosed all possible subranges and each numerical value within the range. For example, a description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as single digits within the range, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the range.

[0101] As used herein, "w / w", "weight", "weight %" and "weight percent" and other grammatical variations are used synonymously to indicate the ratio of the mass of one component of a composition to the mass of the entire composition (unless otherwise specified). For example, when a particular ingredient is present at 1 weight % (w / w) of a composition, the mass of the ingredient is 1% of the mass of the entire composition. Similarly, when an ingredient is present at 50% (w / w) of a composition, the mass of the ingredient is 50% of the mass of the entire composition. When only a concentration, amount or percentage is listed (without units), it is understood that the concentration or percentage is by weight.

[0102] Similarly, "v / v," "by volume," "% by volume," and "volume percent" and other grammatical variations as used herein are used synonymously to refer to the ratio of the volume of one component of a composition to the volume of the entire composition (unless otherwise indicated).

[0103] As used herein, "w / v," "weight / volume," and other grammatical variations are used to denote the ratio of the mass of one component of a composition to the volume of the entire composition (unless otherwise indicated).

[0104] Certain examples may also be described broadly and generally herein. Each narrower class and subgeneric grouping falling within the general disclosure also forms part of the present disclosure. This includes a general description of an example with the proviso or negative limitation that any subject matter is removed from that genus, regardless of whether the deleted material is specifically described herein.

[0105] The invention has been described broadly and generically herein. Each narrower species and subgeneric grouping falling within the generic disclosure also forms a part of the invention. This includes the generic description of the invention with the proviso or negative limitation that any subject matter is removed from that genus, regardless of whether the deleted material is specifically recited herein.

[0106] Other examples are within the scope of the following claims and non-limiting examples.In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. Example

[0107] method

[0108] Study Design

[0109] This study was a 12-week, double-blind, parallel-design, randomized controlled trial.

[0110] Participants

[0111] A total of 255 subjects aged 21-45 years with a BMI between 23 and 35 kg / m were recruited from the community. 2 Among Chinese women. --which is a non-invasive, simple and rapid diagnostic method--assesses the presence of NAFLD. Participants with a liver controlled attenuation parameter (CAP) score ≥268dB / m were included if they also met the other inclusion criteria. Participants had no history of diabetes except gestational diabetes, and all participants had non-diabetic fasting blood glucose (<7.0mmol / L) and glycosylated hemoglobin (HbA1c <6.5%) concentrations during the screening period. Those who demonstrated significant organ system dysfunction or disease, those who were pregnant, breastfeeding, regularly drank alcohol (≥4d per week, or ≥6 drinks per week), those who used medications known to affect metabolism or intestinal microbiota (such as antibiotics and oral contraceptives), and those with severe diarrhea and recent weight loss (≥5% in the past three months) were excluded from the study. 88 participants ultimately participated in the study.

[0112] Randomization

[0113] 88 participants were randomly assigned to one of three groups for 12 weeks: diet containing C15:0 supplement 3 (n=31), diet without C15:0 supplement (n=28), and control (usual diet without C15:0 supplement, n=29). Baseline characteristics of the 88 participants are shown in Table 1 for the 88 participants (per ITT) (values ​​are mean ± SE or median (quartile 1; quartile 3). BMI = body mass index; BDI-II = Beck Depression Inventory-II; BP = blood pressure; CAP = controlled attenuation parameter; diet + C15 = diet with C15:0 supplement; diet - C15 = diet without C15:0 supplement; HbA1C = glycated hemoglobin; HDL = high-density lipoprotein; LDL = low-density lipoprotein; PDFF = proton density fat fraction; RMR = resting metabolic rate; STAI = State Trait Anxiety Inventory.

[0114]

[0115] Table 1: Baseline characteristics of study participants

[0116] Dietary intervention

[0117] All participants received counseling from a registered dietitian focused on choosing healthier foods and reducing total energy intake to promote weight loss. They were recommended to consume a moderately low-calorie diet (1,000-1,500 kcal / d) during the 12-week intervention, resulting in an estimated energy deficit of 500-1,000 kcal / d relative to energy requirements for weight maintenance.

[0118] Throughout the 12-week intervention, participants assigned to the two diet groups were required to consume 12 frozen study meals per week (2 meals per day, 6 days per week) and soy milk (with or without 300 mg C15:0) once a day. The frozen meals each provided an average of 350 kcal, of which 36% of the energy came from carbohydrates, 21% from protein, 33% from MUFA and PUFA; and 7 g of fiber. The calorie content of soy milk supplements with or without C15:0 was 108 kcal, 38% of the energy came from carbohydrates, 22% from protein, 31% from MUFA and PUFA; and 4 g of fiber. Twice a day, the frozen meals provided a total polyphenol amount of 400 mg per day, measured using an assay kit for detecting phenolic compounds. The frozen meals and soy milk are sourced and produced from a single batch. Nutrient data tables for the frozen meals, olive oil used in the frozen meals, and soy milk supplements are provided in Tables 2 to 4.

[0119] Control participants were not provided with frozen meals or soy milk, but they had access to nutrition counseling during monthly visits, focusing on healthier food choices and weight loss.

[0120]

[0121]

[0122]

[0123]

[0124] Results Evaluation

[0125] Body fat percentage, intrahepatic lipid content, muscle and abdominal fat, liver enzymes, cardiometabolic risk factors, and gut microbiome were assessed at baseline and after 12 weeks of intervention.

[0126] Gut Microbiome

[0127] A stool sample self-collection kit consisting of a DNA / RNA shield fecal collection tube (ZymoResearch, California, United States of America) was provided to study participants. They were instructed to collect stool samples within 24 hours of clinical visits at week 0 (baseline) and week 2 (collection by courier), week 4, week 8, and week 12. Fecal samples were immediately aliquoted and stored at -80°C. A modified DNA isolation kit ( 16FFS Nucleic Acid Extraction Kit, Promega) was used for DNA isolation. Briefly, a 450 μL aliquot of stool samples in DNA / RNA protection was treated with 20 μL of 5 μg / mL lysozyme (Sigma-Aldrich), 20 μL of 10 mg / mL proteinase K (Promega), and 10 μL of 10 mg / mL RNaseA (Novagen) at 37°C for 15 minutes, followed by 15 minutes at 60°C. The samples were homogenized twice at 6 m / s for 40 seconds using Lysing Matrix E tubes (MP Biomedicals) through glass beads. After centrifugation, the supernatant was treated with 10 μL of 10 mg / mL RNaseA (Novagen) for 30 minutes at 60°C and then extracted with phenol:chloroform (1:1). The samples were purified by HPLC according to the manufacturer's protocol. 16FFS nucleic acid extraction kit (Promega), the clean supernatant was used for subsequent DNA isolation. One microgram of DNA was used for PCR-free genomic DNA library preparation for shotgun Illumina sequencing, and 7GB of data was obtained for each sample. Metagenomics data were preprocessed using KneadData to remove host contaminants, and MetaPhlan v3.0 was used for composition analysis.

[0128] result

[0129] Diet high in polyphenols reduces liver fat

[0130] Both diet groups had significantly greater reductions in body weight, BMI, and liver proton density fat fraction (PDFF) compared to the control group (body weight % change: 5.3±0.7%, 4.5±0.6%, and 2.1±0.6% in the C15:0-containing diet, 32.6±4.5%, 30.1±4.1%, and 10.3±5.9% in the non-C15:0-containing diet, and control, respectively; liver PDFF % change: 10.3±5.9% in the control group). Changes in liver PDFF distribution were more pronounced in participants on both diet groups (with or without C15:0) than in the control group ( Figure 1 ).

[0131] C15:0 biomarkers shown in plasma

[0132] Blood was collected by venipuncture after a 10-12 hour fast. Fasting glucose, insulin, HbA1C, liver enzymes, total plasma triglycerides, total cholesterol, and low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol concentrations were determined by standard methods of the National University Hospital (NUH) Referral Laboratory (approved by the College of American Pathologists). C15:0 in plasma phospholipids reflecting long-term dietary intake was determined by the dried plasma spot method combined with gas chromatography. At the end of the study, the concentration of C15:0 was significantly higher in the diet group containing C15:0 supplementation compared to the other two groups ( Figure 2 and

[0133] Table 5).

[0134]

[0135] In Table 5, values ​​are mean differences (95% CI) for 88 participants (each ITT). Data were analyzed by repeated measures ANOVA (time × diet) for parameters measured at two time points and by linear mixed models for parameters measured at four time points. * indicates p < 0.05 relative to baseline in the same group, from Sidak post hoc test. # Indicates p<0.05 relative to the change in the two dietary groups, from Sidak post hoc test. ！ Represents changes relative to the control group at p<0.05, from Sidak post hoc test. $ Denotes p<0.05 relative to changes in diet-C15, from Sidak post hoc test. b Represents change from diet-C15 at week 12 p<0.05 from Sidak post hoc test. cDenotes p<0.05 versus diet-C15 at week 12, from Sidak post hoc test. d Denotes p<0.05 relative to control at week 12, from Sidak post hoc test. BMI=body mass index, BDI-II=Beck Depression Inventory-II, BP=blood pressure, CAP=controlled attenuation parameter, diet+C15=diet with C15:0 supplement, diet-C15=diet without C15:0 supplement, HbA1C=glycosylated hemoglobin A1C, IMCL=intramyocyte lipid, PDFF=proton density fat fraction, RMR=resting metabolic rate, SAT=subcutaneous abdominal adipose tissue, STAI=state-trait anxiety inventory, VAT=visceral adipose tissue.

[0136] C15:0 supplementation reduces LDL-cholesterol

[0137] There were significant time × diet interactions for total and LDL-cholesterol and triglyceride concentrations, which were reduced only in the two diet groups but not in the control group. The reduction in LDL-cholesterol was significantly greater with C15:0 supplementation ( Figure 3 and Table 5).

[0138] C15:0 Supplementation Promotes a Healthy Gut Microbiome

[0139] C15:0 supplementation induced changes in several bacterial species in the gut microbiome. C15:0 supplementation increased the abundance of Bifidobacterium adolescentis and decreased the abundance of Bacteroides domitilis and Bacteroides faecalis ( Figure 4 ). Bifidobacterium is lower in the elderly and in patients with NASH, lower in infants delivered by cesarean section compared with those delivered naturally, and increases with breastfeeding. These findings suggest potential gut health benefits from C15:0 supplementation. However, Bacteroides domitilis and Bacteroides faecalis decreased over time in the C15:0 supplemented dietary group. The role of Bacteroides is controversial, and previous reports have described both beneficial and pathogenic effects. Bacteroides ovalis, which suppresses gastrointestinal inflammation, was upregulated in both dietary groups compared to the control group, while Fusobacterium mortis, which is associated with diarrhea, was downregulated.

Claims

1. Use of pentadecanoic acid (C15:0) in the preparation of a composition for lowering LDL (low-density lipoprotein) cholesterol in a subject.

2. Use of pentadecanoic acid (C15:0) in the preparation of a composition for promoting a healthy intestinal microbiome in a subject.

3. The use of claim 2, wherein promoting a healthy intestinal microbiome comprises increasing the amount of Bifidobacterium adolescentis and / or Bacteroides ovatus, and / or decreasing the amount of Bacteroides doreae, Bacteroides faecalis, and / or Fusobacterium mortis.

4. The use according to any one of claims 1 to 3, wherein the composition further comprises one or more phenolic compounds.

5. The use according to claim 4, wherein the phenolic compound is a polyphenol.

6. The use according to any one of claims 1 to 3, wherein the composition is in the form of a health supplement.

7. The use according to any one of claims 1 to 3, wherein the composition is in the form of a food product.

8. The use according to any one of claims 1 to 3, wherein the pentadecanoic acid (C15:0) is in the form of a free fatty acid.

9. The use of any one of claims 1 to 3, wherein the pentadecanoic acid (C15:0) is administered to the subject at a dose of about 300 mg per day.

10. The use of claim 5, wherein the polyphenol is administered to the subject at a dose of about 400 mg per day.

11. The use of any one of claims 1 to 3, wherein the composition is administered to the subject for at least 12 weeks.

12. The use according to any one of claims 1 to 3, wherein the subject suffers from non-alcoholic fatty liver disease (NAFLD).

13. The use according to any one of claims 1 to 3, wherein the subject is a female.

14. The use according to any one of claims 1 to 3, wherein the subject is of Chinese ethnicity.

15. The use according to any one of claims 1 to 3, wherein the subject has a body mass index (BMI) of 23±5% to 35±5%.

16. The use according to any one of claims 1 to 3, wherein the subject does not suffer from diabetes.

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