Postbiotic composition containing bacterial lysate for oral administration for the treatment of solid tumors

Abstract

The present invention relates to orally administered postbiotic compositions, and discloses orally administered postbiotic compositions used for the treatment of solid tumors in patients, particularly colon cancer and / or lung cancer. The compositions comprise lysates of probiotic microorganisms belonging to the genera Bacillus, Bifidobacterium, Lactobacillus, Saccharomyces, and Streptococcus.

Description

Technical Field

[0001] Technical Field of the Invention The present invention relates to a postbiotic composition containing lysates of probiotic microorganisms as immunomodulators and angiogenesis regulators, which composition is extremely safe including for long-term intake. Such a composition can be used as a food supplement.

[0002] Therefore, the present invention is included in the technical field of treatment methods aimed at contributing to the effects of cancer treatments such as chemotherapy, radiotherapy, immunotherapy, especially colorectal cancer and / or lung cancer treatment.

Background Art

[0003] Background Cancer is one of the major causes of morbidity and mortality worldwide. Therefore, over the past decades, huge resources have been invested in developing effective treatment methods for this disease. These are treatment methods such as radiotherapy, chemotherapy, or immunotherapy combined with surgery when experts determine that surgery is possible in the case of cancer accompanied by a tumor mass.

[0004] However, although these treatment methods are often effective, it is a well-known fact that the side effects have a high toxicity on the patient's body. This deteriorates the patient's general condition, casts doubt on the suitability of the treatment method, and at the same time motivates experts to search for alternative therapies.

[0005] Generally, alternative cancer treatments do not play a role in directly curing the cancer itself. However, they help to cope with cancer symptoms and treatment-associated symptoms such as anxiety, fatigue, nausea and vomiting, pain, insomnia, and stress.

[0006] Alternative medicine is a general term referring to techniques not normally provided by medical providers. As researchers investigate these treatment methods and the evidence for alternative therapies increases, physicians and other medical providers are incorporating them into treatment plans in parallel with standard treatments. It is an approach sometimes referred to by experts as integrative medicine.

[0007] Combining these evidence-based integrative medicine approaches with standard treatments may potentially alleviate many of the symptoms associated with cancer and its treatment. However, alternative and integrative therapies are often not effective enough to completely replace standard treatments.

[0008] That is why science is constantly exploring from multiple angles potential alternatives to conventional cancer treatments that are effective in eradicating the disease without harming the patient's body.

[0009] There are publications that discuss the dynamics of the gut microbiota, its fluctuations over time and due to disease, and other factors that change the gut environment and contribute to improving the overall condition of patients, from various perspectives.

[0010] There is growing evidence that the gut microbiota not only functionally plays a role in the development and progression of cancer, but also plays a crucial role in the efficacy and toxicity of chemotherapy and immunotherapy agents. The response to oncological therapeutic interventions may vary depending on the state of the gut microbiota. Loss of gut microbiota diversity can directly and indirectly impact the efficacy and toxicity of chemotherapy through immunomodulation.

[0011] Postbiotics are defined as a collection of molecules, including non-functional microbial cells, organelles, cellular metabolites, and probiotic metabolic bioproducts, that, when ingested in sufficient quantities, influence physiological processes and maintain the ability to regulate the gut microbiota and preserve its homeostasis.

[0012] Therefore, facing the technical challenges of current oncology treatment, the industry is actively working to develop orally administered therapies and compositions that enhance the effectiveness of cancer treatment. The following patent documents are cited as evidence.

[0013] Patent application number CN114847483A provides a composition comprising Bifidobacterium longum BL21 and a microbial inoculant containing Bifidobacterium longum BL21 for the purpose of preventing, mitigating, or treating colorectal cancer.

[0014] Patent application CN102475776A discloses a novel cancer suppressant used to control various types of cancer. This product is prepared from various raw materials, including the minerals selenium, magnesium, zinc, vitamin E, vitamin C, garlic, probiotics, and buttercup root powder.

[0015] International patent application WO2019169179A1 describes a method for improving the effectiveness of cancer treatments, including formulations comprising probiotics and digestive enzymes.

[0016] However, none of the prior art literature found discloses a stable composition, primarily composed of dried bacterial lysates, that, when taken orally, has effective immunomodulatory and angiogenic regulatory activity to improve the quality of life for patients with solid tumors, as described herein.

[0017] It is also worth mentioning Spanish patent applications P201930242 and P201930280. These are patent applications by the inventors describing a composition for modulating the human gut microbiota obtained from a lysate of probiotic microorganisms, a method for producing the same, and a food supplement containing the composition, which is useful for the prevention and treatment of disorders caused, or at least promoted, by abnormalities in the gut microbiota in the human microbiome. However, these applications do not disclose the specific compositions of the present invention or their effects on cancer patients. Those skilled in the art will understand that although there are many compositions in the prior art that have demonstrated anti-inflammatory capabilities in in vitro experiments, these results cannot be easily reproduced in humans. A simple search of databases will yield many results in vitro, but not in humans, because when the effectiveness is actually verified, no effect is found. Such negative results are not published. Lu K, Dong Recent paper by S, Wu X, Jin R, and Chen H (2021) Probiotics The article *in Cancer. Front. Oncol. 11:638148. DOI: 10.3389 / FONC.2021.638148* points out these problems and the need for further research to determine the most effective microbial composition (see the conclusion section of the paper). [Overview of the Initiative] [Problems that the invention aims to solve]

[0018] Therefore, the present invention aims to solve the problems of the prior art by using an orally administered postbiotic composition obtained from the lysate of probiotic microorganisms, which is used as an immunomodulator and angiogenesis regulator for improving the health status of patients with solid tumors, particularly colon cancer and / or lung cancer. [Means for solving the problem]

[0019] In this report, the expressions "oral administration composition", "composition of the present invention", and "postbiotic composition" are synonymous and used interchangeably.

[0020] As used herein, the term "microorganism" includes both bacteria and yeast.

[0021] In the context of the present invention, immunomodulatory action means that cell walls, cell lysates, and molecular groups of non-viable cells regulate the innate immune response by cytokine release, thereby enhancing the immune response against cancer, particularly colorectal cancer and / or lung cancer.

[0022] ' In the context of the present invention, the regulatory activity of angiogenesis refers to the formation of new capillaries generated by the lysate during embryogenesis.

[0023] In a first aspect, the present invention relates to a postbiotic composition for oral administration for use in the treatment of solid tumors, the composition comprising lysates of the following probiotic microorganisms in weight percentage amounts relative to the total weight of the microbial lysates in the composition, characterized in that. - Lysates of bacteria of the genus Bacillus from 6% to 19%; - Lysates of bacteria of the genus Bifidobacterium from 4% to 8%; - Lysates of bacteria of the genus Lactobacillus from 15% to 25%; - Lysates of yeast of the genus Saccharomyces from 50% to 60%; - Lysates of bacteria of the genus Streptococcus from 1.5% to 5%.

[0024] In certain embodiments, the solid tumor is selected from the group consisting of colorectal cancer and / or lung cancer.

[0025] Another additional object of the present invention relates to a postbiotic composition for oral administration, which contains lysates of the following probiotic microorganisms in weight percentage amounts relative to the total weight of the microbial lysates of the composition: - Lysates of bacteria of the genus Bacillus are from 6% to 19%; - Lysates of bacteria of the genus Bifidobacterium are from 4% to 8%; - Lysates of bacteria of the genus Lactobacillus are from 15% to 25%; - Lysates of yeasts of the genus Saccharomyces are from 50% to 60%; - Lysates of bacteria of the genus Streptococcus are from 1.5% to 5%, which is used for the treatment of cancer in a subject, wherein the cancer is positive for the PD1 / PDL1 pathway, and in particular, the cancer positive for the PD1 / PDL1 pathway is colorectal cancer and / or lung cancer.

[0026] Another additional object of the present invention relates to a pharmaceutical composition comprising an effective pharmacological amount of the composition according to the first aspect of the present invention and a pharmaceutically acceptable excipient.

[0027] To supplement the description of the invention and obtain a deeper understanding, drawings are attached as an essential part of the description. The drawings are for illustrative purposes and not limiting, and show graphs of experimental results obtained in Examples X to Y included in this specification.

Brief Description of the Drawings

[0028] [Figure 1]The graph shows the percentage of cell viability after 24-hour exposure to the postbiotic composition of the present invention at different concentrations in a THP-1 cell line differentiated with PMA, as measured by the MTT assay. The bar graph represents the mean of six technically repeated experiments, and the error bar corresponds to the standard deviation. Negative control (C-) indicates cells that were not exposed to any compound. Positive control (C+) indicates cells that were exposed to LPS (lipopolysaccharide), an inflammatory stimulant. The selected concentrations were 15.63, 7.81, and 3.91 μg / ml, which do not affect cell viability. The term "postbiotic" refers to the postbiotic composition of the present invention. [Figure 2.a] The graph shows the secretion levels of proteins IL-6 (Figure 2.a), IL-8 (Figure 2.b), IL-18 (Figure 2.c), and TNF-α (Figure 2.d) by LPS-stimulated THP-1 cells under different concentrations of the postbiotic composition of the present invention. The bar graph shows the mean values ​​from three replicated experiments, and the error bars correspond to the standard deviation. The negative control (C-) represents the condition in which cells were not exposed to any compound. The positive control (C+) represents the condition in which cells were exposed to the inflammatory stimulus of LPS. The term "postbiotic" refers to the postbiotic composition of the present invention. [Figure 2.b] The graph shows the secretion levels of proteins IL-6 (Figure 2.a), IL-8 (Figure 2.b), IL-18 (Figure 2.c), and TNF-α (Figure 2.d) by LPS-stimulated THP-1 cells under different concentrations of the postbiotic composition of the present invention. The bar graph shows the mean values ​​from three replicated experiments, and the error bars correspond to the standard deviation. The negative control (C-) represents the condition in which cells were not exposed to any compound. The positive control (C+) represents the condition in which cells were exposed to the inflammatory stimulus of LPS. The term "postbiotic" refers to the postbiotic composition of the present invention. [Figure 2.c]The graph shows the secretion levels of proteins IL-6 (Figure 2.a), IL-8 (Figure 2.b), IL-18 (Figure 2.c), and TNF-α (Figure 2.d) by LPS-stimulated THP-1 cells under different concentrations of the postbiotic composition of the present invention. The bar graph shows the mean values ​​from three replicated experiments, and the error bars correspond to the standard deviation. The negative control (C-) represents the condition in which cells were not exposed to any compound. The positive control (C+) represents the condition in which cells were exposed to the inflammatory stimulus of LPS. The term "postbiotic" refers to the postbiotic composition of the present invention. [Figure 2.d] The graph shows the secretion levels of proteins IL-6 (Figure 2.a), IL-8 (Figure 2.b), IL-18 (Figure 2.c), and TNF-α (Figure 2.d) by LPS-stimulated THP-1 cells under different concentrations of the postbiotic composition of the present invention. The bar graph shows the mean values ​​from three replicated experiments, and the error bars correspond to the standard deviation. The negative control (C-) represents the condition in which cells were not exposed to any compound. The positive control (C+) represents the condition in which cells were exposed to the inflammatory stimulus of LPS. The term "postbiotic" refers to the postbiotic composition of the present invention. [Figure 3] Representative photographs of control embryos and embryos treated with the inventive postbiotic composition (IGEN-1806) 48 hours after fertilization (hpf: hours post-fertilization). [Figure 4] Fluorescent image showing the locations of DLAV (dorsal longitudinal anastomotic vessels) and ISV (internodal vessels). [Figure 5] Representative fluorescence images showing the vascular systems of untreated embryos 48 hours post-fertilization (hpf) (DMSO, 1% dimethyl sulfoxide), a positive control (KRN633, selective vascular endothelial growth factor receptor inhibitor), and embryos exposed to the postbiotic composition of the present invention (IGEN-1806) at specified concentrations. [Figure 6] Representative fluorescence images showing the vascular systems of untreated embryos (DMSO 1%), positive control (KRN633), and embryos exposed to the postbiotic composition of the invention (IGEN-1806) at specified concentrations 72 hours later (hpf). [Figure 7]Luminescence observed by a PD-1 / PD-L1 blockade bioassay when cells were cultured in the presence of 100 μg / ml atezolizumab or 1 mg / ml, 0.1 mg / ml, or 0.01 mg / ml of the postbiotic composition of the present invention (IGEN-1806). [Modes for carrying out the invention]

[0029] Detailed description of the invention As previously stated, the inventors recognized the need to develop an orally administered postbiotic composition that can be given as a food supplement to improve the health status of patients with solid tumors, particularly colorectal cancer and / or lung cancer. This composition is easy to administer, non-toxic, and further enhances the effects of chemotherapy, radiotherapy, or immunotherapy.

[0030] In this specification, the terms “treatment” and “to treat” refer to medical procedures performed on subjects with cancer, aimed at curing, improving, stabilizing, or preventing the progression of a disease, condition, or disorder. This term includes active treatment specifically aimed at improving the disease, condition, or disorder. Furthermore, this term also includes palliative treatment, i.e., treatment aimed at alleviating symptoms rather than curing the disease, condition, or disorder; preventive treatment, i.e., treatment aimed at minimizing, or partially or completely suppressing, the onset of the associated disease, condition, or disorder; and supportive treatment, i.e., treatment used to complement other specific treatments aimed at improving the associated disease, condition, or disorder. Treatment is understood to be intended to cure, improve, stabilize, or prevent a disease, condition, or disorder, but is not required to actually result in a cure, improvement, stabilization, or prevention. The effect of treatment may be measured or evaluated, depending on the disease, condition, or disorder, by methods described herein and known in the prior art. Such measurement and evaluation may be qualitative and / or quantitative. Therefore, for example, the characteristics or properties of a disease, condition or disorder and / or the symptoms of a disease, condition or disorder can be reduced to any effect or any quantity. In the context of subjects suffering from cancer, particularly colorectal cancer and / or lung cancer, the terms “treatment” and “to treat” refer to the medical management of a subject with the intention of curing, improving or stabilizing the cancer, and improving the symptoms associated with this disease. Based on this, an orally administered composition was developed. This composition contains lysates of microorganisms and may be accompanied by other components, and has been found to exhibit remarkable benefits in humans and animals due to its immunomodulatory and angiogenic modulating effects.

[0031] In this invention, immunomodulatory action means that postbiotics, composed of cell lysates and molecules derived from non-viable cells, have the ability to regulate the innate immune response. The inventors have confirmed that administering the compositions described in this specification has the ability to regulate pro-inflammatory mediators that have the ability to act against infections and cancer cells. The latter is shown in Example 1. In this invention, angiogenesis regulator refers to a lysate that has the property of inducing the formation of new capillaries during embryonic development, i.e., an angiogenesis-promoting effect. The inventors have demonstrated that administering the compositions described in this specification has the ability to induce new angiogenesis only in the early stages of zebrafish embryonic development and to improve the bioavailability of nutrients. This is shown in Example 2.

[0032] Typically, probiotics positively influence the composition of the gut microbiota and enhance immune function by interacting with various immune cells. The health benefits of their administration are widely recognized. However, in cancer patients, particularly those with colorectal or lung cancer, where the gut environment is hostile, probiotics usually struggle to survive due to suboptimal growth conditions. The administration of cytotoxic drugs alters the structure and function of the gut microbiota. For these reasons, the use of probiotics may not yield significant results in observing positive health effects. However, the compositions of this invention are characterized by their rapid and remarkable effects not only on tumor masses (see Example 3) but also on the patient's overall condition.

[0033] Probiotics are live microorganisms that, once established in the digestive tract, provide health benefits through their own physiological activity. This requires them to survive gastric juice, digestive enzymes, and bile acids, and it is customary to add sufficient amounts to achieve noticeable effects. Postbiotics, on the other hand, are inanimate microorganisms and / or their components, thus eliminating the need for this activity and offering a technological advantage.

[0034] In addition to their potential to directly modulate the composition of the gut microbiota, postbiotics may indirectly mediate the effectiveness of cancer treatments by immunoprotecting the host through the modulation, stimulation, and regulation of the immune response. They offer a safe alternative to probiotics.

[0035] Therefore, a first aspect of the present invention relates to a postbiotic composition for oral administration, the composition containing probiotic microbial lysates in the following proportions by weight percentage of the total weight of microbial lysates: - Bacillus bacteria lysate: 6% to 19% - Bifidobacterium bacterial lysates: 4% to 8% - 15% to 25% bacterial lysates from the genus Lactobacillus - 50% to 60% lysate of Saccharomyces yeast - 1.5% to 5% bacterial lysates of the genus Streptococcus It is used to treat solid tumors.

[0036] In certain embodiments, the solid tumor is colorectal cancer and / or lung cancer.

[0037] In a particular embodiment, an orally administered postbiotic composition used for the treatment of solid tumors comprises the following amounts of probiotic microbial lysates in weight percentage of the total weight of microbial lysates in the composition: - Bacillus bacteria lysate: 13% to 19% - Bifidobacterium bacterial lysates make up 4% to 8% - 15% to 25% bacterial lysates from the genus Lactobacillus - 50% to 60% lysate of Saccharomyces yeast - 1.5% to 5% bacterial lysates from the genus Streptococcus.

[0038] In certain embodiments, the solid tumor is colorectal cancer and / or lung cancer.

[0039] According to the present invention, the composition may contain microbial lysates in weight percentages of 1% to 99.5%. In particular, it may contain microbial lysates in weight percentages of 5% to 99%, especially 10% to 96%, especially 25% to 95%, or especially 50% ± 10%.

[0040] The compositions of the present invention may include additional components, additives, and other substances such as salts, excipients, etc., that facilitate the packaging, preparation, and / or administration of the compositions, but do not affect the immunomodulatory or angiogenic capabilities of the postbiotic compositions of the present invention.

[0041] In this invention, probiotic microbial lysates are understood to refer to the product obtained after a culture process, followed by mechanical or chemical disruption of the cells to obtain a product containing fragments of the microorganism, as well as all components contained therein. Similarly, this specification specifies that these are dried microbial lysates. Since these lysates are subsequently subjected to drying techniques by the manufacturing method, dried bacterial lysates may optionally take the form of a dried powder.

[0042] In a preferred embodiment of the present invention, the bacterial lysate of the genus Bacillus is a species selected from the group consisting of Bacillus clausii, Bacillus coagulans, Bacillus licheniformis, Bacillus pumilus, Bacillus subtilis, Bacillus mesentericus, Bacillus paralicheniformes, and combinations thereof. Preferably, these are Bacillus clausii, Bacillus coagulans, Bacillus licheniformis, Bacillus mesentericus, and Bacillus subtilis.

[0043] Bacillus pumilus and Bacillus mesentericus are synonymous. In fact, Bacillus mesentericus is listed in the NCBI Taxonomy Browser database (Schoch CL et al., NCBI). Taxonomy: a comprehensive update on curation, resources and tools. Database As disclosed in (Oxford). 2020: baaa0622. PubMed: 32761142 PMC: PMC7408187), it is another name for Bacillus pumilus (taxonomic ID: 1408).

[0044] In other embodiments, bacterial lysates of the genus Bifidobacterium are Bifidobacterium animalis subspecies lactis. Bifidobacterium lactis, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium lactis, Bifidobacterium longum, Bifidobacterium infantis, Bifidobacterium animalis, and combinations thereof, preferably Bifidobacterium lactis.

[0045] In other embodiments, bacterial lysates of the genus Lactobacillus include Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus casei, and Lactobacillus fermentum. Lactobacillus paracasei, Lactobacillus plantarum, Lactobacillus reuteri, Lactobacillus rhamnosus, Lactobacillus salivarius, Species selected from the group consisting of Lactobacillus helveticus, Lactobacillus gasseri, Lactobacillus johnsonii, Lactobacillus brevis, Lactobacillus kefiri, and combinations thereof, preferably Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus reuteri, and Lactobacillus rhamnosus It is rhamnosus.

[0046] In other specific embodiments of the present invention, the lysate of a yeast of the genus Saccharomyces is a species selected from the group consisting of Saccharomyces cerevisiae, Saccharomyces boulardi, and combinations thereof, preferably Saccharomyces cerevisiae.

[0047] In another specific embodiment of the present invention, the bacterial lysate of the genus Streptococcus is the species Streptococcus thermophilus.

[0048] In certain embodiments, the compositions of the present invention do not contain lysates of microorganisms present in the digestive tract, and preferably do not contain bacterial lysates of the genera Akkermansia, Enterococcus, and Escherichia.

[0049] In a preferred embodiment of the present invention, the composition of the present invention contains a lysate of Bacillus bacteria in an amount of about 6% to 19%, preferably 13% to 19%, by weight percentage of the total lysate of the composition. In a preferred embodiment, the amount of Bacillus bacteria lysate may be about 14%, 15%, 16%, 17%, or 18% of the total lysate in the composition.

[0050] In certain embodiments, the weight percentages of Bacillus licheniformis, Bacillus mesentericus, and Bacillus subtilis are approximately equal, higher than the weight percentages of Bacillus clausii and Bacillus coagulans, which are also approximately equal.

[0051] In a preferred embodiment of the present invention, the composition of the present invention contains a bacterial lysate of the genus Bifidobacterium in a weight percentage of about 4% to 8%, preferably in the range of 5% to 7%, of the total lysates of the composition. In a preferred embodiment, the amount of bacterial lysate of the genus Bifidobacterium may be about 5%, 6%, 7%, or 8% of the total lysates in the composition.

[0052] In a preferred embodiment of the present invention, the composition of the present invention contains bacterial lysates of the genus Lactobacillus in the range of about 15% to 25%, preferably 20% to 24%, by weight percentage of the total lysates in the composition. In a preferred embodiment, the amount of bacterial lysates of the genus Lactobacillus may be about 20%, 21%, 22%, 23%, 24%, or 25% of the total lysates in the composition.

[0053] In certain embodiments, the weight percentages of Lactobacillus acidophilus, Lactobacillus bulgaricus, and Lactobacillus casei differ from each other, as do the weight percentages of Lactobacillus fermentum, Lactobacillus reuteri, and Lactobacillus rhamnosus. The weight percentages among these three species are approximately equivalent.

[0054] In another specific embodiment, the weight percentage of Lactobacillus casei is higher than that of other Lactobacillus species.

[0055] In another specific embodiment, the weight percentage of Lactobacillus casei is higher than that of Lactobacillus acidophilus, the weight percentage of Lactobacillus acidophilus is higher than that of Lactobacillus bulgaricus, the weight percentage of Lactobacillus bulgaricus is higher than that of Lactobacillus fermentum, Lactobacillus reuteri, and Lactobacillus rhamnosus, and the weight percentages of these three species are approximately equal.

[0056] In a preferred embodiment of the present invention, the composition comprises a lysate of a Saccharomyces yeast, wherein its weight percentage is in the range of about 50% to 60% of the total amount of lysates in the composition, preferably in the range of 52% to 57% of the total amount of lysates in the composition. In a preferred embodiment, the amount of Saccharomyces yeast lysate can be about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, or 60% of the total amount of lysates in the composition.

[0057] In preferred embodiments of the present invention, the composition contains a bacterial lysate of the genus Streptococcus in the range of about 1.5% to 5%, preferably about 3% to 4%, by weight percentage of the total lysate of the composition. In preferred embodiments, the amount of bacterial lysate of the genus Streptococcus is preferably about 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3% of the total lysate of the composition. In other preferred embodiments, the amount of bacterial lysate of the genus Streptococcus is preferably about 3.5%, 4%, 4.5%, or 5% of the total lysate of the composition.

[0058] In a particular embodiment of the present invention, the composition comprises the following amount of probiotic lysate in weight percent of the total lysate of the composition: - Bacillus bacterial lysates make up approximately 13% to 17% - Bifidobacterium bacterial lysates make up approximately 4.5% to 7.5%; - Lactobacillus bacterial lysates make up approximately 20% to 22% - Saccharomyces yeast lysates make up approximately 53% to 57% - Bacterial lysates from the genus Streptococcus make up approximately 2.5% to 3.5%.

[0059] This composition is called composition "A".

[0060] In another specific embodiment of the present invention, the composition comprises, by weight percentage of the total lysates in the composition, the following amounts of probiotic microbial lysates: - Approximately 15% to 17% of the lysate of Bacillus bacteria; - Bifidobacterium bacterial lysates make up approximately 4.6% to 6%; - Lactobacillus bacterial lysates make up approximately 20.5% to 21.8% - Saccharomyces yeast lysates make up approximately 54% to 56% - Bacterial lysates from the genus Streptococcus make up approximately 2.8% to 3.2%.

[0061] This composition is called composition "B".

[0062] In another specific embodiment of the present invention, the composition comprises the following amount of probiotic lysate in weight percent of the total lysate of the composition: - Bacillus bacterial lysates make up approximately 6% to 19%; - Bacterial lysates of the genus Bifidobacterium lactis: approximately 4% to 8%, preferably approximately 4.5% to 7.5%; - Lactobacillus bacterial lysates make up approximately 15% to 25% - Saccharomyces yeast lysates make up approximately 50% to 60% - Approximately 1.5% to 5% lysates of bacteria of the genus Streptococcus.

[0063] This composition is called composition "C".

[0064] In another specific embodiment of the present invention, the composition comprises the following amounts of probiotic microbial lysate, expressed as a weight percent of the total lysate of the composition: - Bacillus bacterial lysates make up approximately 13 to 17% - Contains approximately 4% to 8%, preferably approximately 4.5% to 7.5%, of bacterial lysates from the genus Bifidobacterium lactis. - Lactobacillus bacterial lysates make up approximately 20% to 22% - Saccharomyces yeast lysates make up approximately 53% to 57% - Approximately 2.5% to 3.5% of bacterial lysates from the genus Streptococcus.

[0065] This composition is called composition "D".

[0066] In another specific embodiment of the present invention, the composition comprises, by weight percentage of the total lysates in the composition, the following amounts of probiotic microbial lysates: - Bacillus bacterial lysates make up approximately 15% to 17% - Bacterial lysates of the genus Bifidobacterium lactis make up approximately 4.6% to 6%. - Lactobacillus bacterial lysates make up approximately 20.5% to 21.8% - Saccharomyces yeast lysates make up approximately 54% to 56% - Bacterial lysates from the genus Streptococcus make up approximately 2.8% to 3.2%.

[0067] This composition is called composition "E".

[0068] In another specific embodiment of the present invention, the composition comprises, by weight percentage of the total lysates in the composition, the following amounts of probiotic microbial lysates: - Bacterial lysates of Bacillus clausii, Bacillus coagulans, Bacillus licheniformis, Bacillus subtilis, and Bacillus mesentericus make up approximately 6% to 19%; - Bifidobacterium lactis bacterial lysates make up approximately 4% to 8% - Bacterial lysates of Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus reuteri, and Lactobacillus rhamnosus make up approximately 15% to 25%; - Saccharomyces cerevisiae yeast lysate makes up approximately 50% to 60%; - Bacterial lysates of Streptococcus thermophilus are present at approximately 1.5% to 5%.

[0069] This composition is called composition "F".

[0070] In another specific embodiment of the present invention, the composition comprises, by weight percentage of the total lysates in the composition, the following amounts of probiotic microbial lysates: - Bacterial lysates of Bacillus clausii, Bacillus coagulans, Bacillus licheniformis, Bacillus subtilis, and Bacillus mesentericus make up approximately 13% to 17%; - Bifidobacterium lactis bacterial lysates are present in approximately 4.5% to 7.5% of the solution. - Bacterial lysates of Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus reuteri, and Lactobacillus rhamnosus account for approximately 20% to 22%; - Saccharomyces cerevisiae yeast lysate accounts for approximately 53% to 57%; - Bacterial lysates of Streptococcus thermophilus make up approximately 2.5% to 3.5%.

[0071] This composition is called composition "G".

[0072] In another specific embodiment of the present invention, the composition comprises, by weight percentage of the total lysates in the composition, the following amounts of probiotic microbial lysates: - Approximately 15% to 17% of bacterial lysates from Bacillus clausii, Bacillus coagulans, Bacillus licheniformis, Bacillus subtilis, and Bacillus mesentericus; - Bifidobacterium lactis bacterial lysates make up approximately 4.6% to 6%; - Bacterial lysates of Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus reuteri, and Lactobacillus rhamnosus account for approximately 20.5% to 21.8%; - Saccharomyces cerevisiae yeast lysate accounts for approximately 54% to 56%; - Bacterial lysates of Streptococcus thermophilus account for approximately 2.8% to 3.2%.

[0073] This composition is called composition "H".

[0074] In another specific embodiment of the present invention, the composition comprises, by weight percentage of the total amount, the following amounts of probiotic lysate: - Bacterial lysates of Bacillus licheniformis, Bacillus pumilus, and Bacillus subtilis account for approximately 6% to 19%, and the weight percentages of Bacillus licheniformis, Bacillus pumilus, and Bacillus subtilis are roughly equivalent; - Bifidobacterium lactis bacterial lysates make up approximately 4% to 8%; -Bacterial lysates of Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus reuteri, Lactobacillus rhamnosus, and Lactobacillus bulgaricus make up approximately 15 to 25%. The weight percentage of Lactobacillus casei is higher than that of Lactobacillus acidophilus, Lactobacillus acidophilus is higher than that of Lactobacillus bulgaricus, and Lactobacillus bulgaricus is higher than that of Lactobacillus fermentum. The weight percentages of the three strains of Lactobacillus reuteri and Lactobacillus rhamnosus are almost the same. - Saccharomyces cerevisiae yeast lysate makes up approximately 50% to 60%; - Bacterial lysates of Streptococcus thermophilus are present at approximately 1.5% to 5%.

[0075] This composition is called composition "I".

[0076] In another specific embodiment of the present invention, the composition comprises the following amount of probiotic lysate in weight percent of the total amount: - Bacterial lysates from Bacillus licheniformis, Bacillus pumilus, and Bacillus subtilis make up approximately 13% to 17%. The weight percentages of Bacillus licheniformis, Bacillus pumilus, and Bacillus subtilis are almost the same. - Bifidobacterium lactis bacterial lysates make up approximately 4.5% to 7.5%; - Bacterial lysates of Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus reuteri, Lactobacillus rhamnosus, and Lactobacillus bulgaricus make up approximately 20% to 22%. The weight percentage of casei is higher than that of Lactobacillus acidophilus, Lactobacillus acidophilus is higher than that of Lactobacillus bulgaricus, Lactobacillus bulgaricus is higher than that of Lactobacillus fermentum, Lactobacillus reuteri, and Lactobacillus rhamnosus, and the weight percentages of these three strains are roughly equivalent. - Saccharomyces cerevisiae yeast lysate accounts for approximately 53% to 57%; - Bacterial lysates of Streptococcus thermophilus make up approximately 2.5% to 3.5%.

[0077] This composition is called composition "J".

[0078] In another specific embodiment of the present invention, the composition contains the following amounts of probiotic lysate in weight percent of the total amount: - Bacterial lysates from Bacillus licheniformis, Bacillus pumilus, and Bacillus subtilis make up approximately 15% to 17%. The weight percentages of Bacillus licheniformis, Bacillus pumilus, and Bacillus subtilis are almost the same. - Bifidobacterium lactis bacterial lysates make up approximately 4.6% to 6%; - The bacterial lysates of Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus reuteri, Lactobacillus rhamnosus, and Lactobacillus bulgaricus were approximately 20.5% to 21.8%, with Lactobacillus casei having a higher weight percentage than Lactobacillus acidophilus, and Lactobacillus acidophilus being more abundant than Lactobacillus bulgaricus. Lactobacillus bulgaricus is higher than Lactobacillus fermentum, Lactobacillus reuteri, and Lactobacillus rhamnosus, and the weight percentages of these three strains are roughly the same. - Saccharomyces cerevisiae yeast lysate accounts for approximately 54% to 56%; - Bacterial lysates of Streptococcus thermophilus account for approximately 2.8% to 3.2%.

[0079] This composition is called composition "K".

[0080] In another specific embodiment of the present invention, the composition contains the following amounts of probiotic lysate in weight percent of the total amount: - The bacterial lysates of Bacillus licheniformis, Bacillus mesentericus, Bacillus subtilis, Bacillus clausii, and Bacillus coagulans were 15% to 17%, with the weight percentages of Bacillus licheniformis, Bacillus pumilus, and Bacillus subtilis being the same, and higher than those of Bacillus clausii and Bacillus coagulans, and these were also nearly identical. - Bifidobacterium lactis bacterial lysates present at 4.6% to 6%; - The bacterial lysates of Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus reuteri, Lactobacillus rhamnosus, and Lactobacillus bulgaricus were 20.5% to 21.8%, with Lactobacillus casei having a higher weight percentage than Lactobacillus acidophilus, and Lactobacillus acidophilus being more effective than Lactobacillus bulgaricus. Lactobacillus bulgaricus is higher than Lactobacillus fermentum, Lactobacillus reuteri, and Lactobacillus rhamnosus, and the weight percentages of these three strains are the same. - Saccharomyces cerevisiae yeast lysate is 54% to 56%; - Bacterial lysates of Streptococcus thermophilus were present at 2.8% to 3.2%.

[0081] This composition is called composition "L".

[0082] In another specific embodiment of the present invention, the composition comprises the following amount of probiotic lysate in weight percent of the total amount: - The bacterial lysates of Bacillus licheniformis, Bacillus mesentericus, Bacillus subtilis, Bacillus clausii, and Bacillus coagulans range from 15% to 17%, with the weight percentages being the same for Bacillus licheniformis, Bacillus pumilus, and Bacillus subtilis. The weight percentage for Bacillus clausii is 0.3%, and the weight percentage for Bacillus coagulans is also 0.3%. - Bifidobacterium lactis bacterial lysates present at 4.6% to 6%; - The bacterial lysates of Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus reuteri, Lactobacillus rhamnosus, and Lactobacillus bulgaricus were 20.5% to 21.8%, with Lactobacillus casei having a higher weight percentage than Lactobacillus acidophilus, and Lactobacillus acidophilus being more abundant than Lactobacillus bulgaricus. Lactobacillus bulgaricus is higher than Lactobacillus fermentum, Lactobacillus reuteri, and Lactobacillus rhamnosus, and the weight percentages of these three strains are the same. - Saccharomyces cerevisiae yeast lysate is 54% to 56%; - The dissolved content of Streptococcus thermophilus is 2.8% to 3.2%.

[0083] This composition is called composition "M".

[0084] In another specific embodiment of the present invention, the composition comprises the following amounts of probiotic microbial lysate in weight percent of the total amount: - The bacterial lysates of Bacillus licheniformis, Bacillus mesentericus, Bacillus subtilis, Bacillus clausii, and Bacillus coagulans, as well as the weight percentages of Bacillus licheniformis, Bacillus pumilus, and Bacillus subtilis, are identical. The weight percentages for Bacillus licheniformis are 5%, Bacillus mesentericus is 5%, Bacillus subtilis is 5%, Bacillus clausii is 0.3%, and Bacillus coagulans is 0.3%. - Bifidobacterium lactis bacterial lysates present at 4.6% to 6%; - The bacterial lysates of Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus reuteri, Lactobacillus rhamnosus, and Lactobacillus bulgaricus were 20.5% to 21.8%, with Lactobacillus casei having a higher weight percentage than Lactobacillus acidophilus, and Lactobacillus acidophilus being more abundant than Lactobacillus bulgaricus. Lactobacillus bulgaricus is higher than Lactobacillus fermentum, Lactobacillus reuteri, and Lactobacillus rhamnosus, and the weight percentages of these three strains are the same. - Saccharomyces cerevisiae yeast lysate is 54% to 56%; - 2.8% to 3.2% bacterial lysates of Streptococcus thermophilus.

[0085] This composition is called composition "N".

[0086] In another specific embodiment of the present invention, the composition comprises the following amount of probiotic lysate in weight percent of the total amount: - Bacillus licheniformis bacterial lysates are present at 4% to 6% - Bacillus mesentericus bacterial lysates present at 4% to 6%; - Bacillus subtilis bacterial lysates present at 4% to 6%; - Bacillus clausii bacterial lysates present at 0.1% to 0.5%; - Bacillus coagulans bacterial lysates are present in a concentration of 0.1% to 0.5%. However, the total amount of bacterial lysates from the genus Bacillus must be between 15% and 17% by weight. - Bifidobacterium lactis bacterial lysates present at 4.6% to 6%; - Bacterial lysates of Lactobacillus casei: 4% to 6%; - Bacterial lysates of Lactobacillus acidophilus: 2.7% to 4.7%; - Lactobacillus bulgaricus bacterial lysates present in a concentration of 2.6% to 4.6%; - Bacterial lysates of Lactobacillus fermentum: 2% to 4%; - Lactobacillus reuteri lysate present in 2% to 4% of the product; - Bacterial lysates of Lactobacillus rhamnosus: 2% to 4%; However, the total amount of bacterial lysates from the genus Bacillus must be between 20.5% and 21.8% by weight. - Saccharomyces cerevisiae yeast lysate is 54% to 56%; - Bacterial lysates of Streptococcus thermophilus were present at 2.8% to 3.2%.

[0087] This composition is called composition "O".

[0088] In another specific embodiment of the present invention, the composition comprises the following amount of probiotic lysate in weight percent of the total amount: - 5% bacterial lysate of Bacillus licheniformis; - 5% bacterial lysate of Bacillus mesentericus; - Bacillus subtilis bacterial lysate is 5%; - Bacillus clausii bacterial lysate is 0.3%; - Bacillus coagulans bacterial lysate is 0.3%; - 5% bacterial lysate of Bifidobacterium lactis; - 5% bacterial lysate of Lactobacillus casei; - Lactobacillus acidophilus bacterial lysate is 3.7%; - Lactobacillus bulgaricus bacterial lysate is 3.6%; - 3% bacterial lysate of Lactobacillus fermentum; - 3% bacterial lysate of Lactobacillus reuteri; - 3% bacterial lysate of Lactobacillus rhamnosus; - 55% bacterial lysates of Saccharomyces cerevisiae; - 3% bacterial lysate of Streptococcus thermophilus.

[0089] This composition is called composition "P".

[0090] In another specific embodiment, the postbiotic composition essentially consists of a lysate of probiotic microorganisms in an amount expressed as a weight percentage of the total amount, as disclosed in the preceding embodiments.

[0091] The following shows the amounts in which each additional component or additive may be included to optionally constitute a composition according to the first aspect of the present invention.

[0092] In other specific embodiments of the present invention, additional components or additives are as follows: carbohydrates (fructose, xylitol, sorbitol, fructooligosaccharides, inulin), antioxidants (resveratrol, β-carotene), vitamins (vitamins C, D, K, B1, B9, E, B3, B5, A, B3, B6, H, D3, B12, biotin, riboflavin, pyridoxine, pantothenic acid), prebiotics (galactooligosaccharides, inulin, o Ligofructose, amino acids (cysteine, tyrosine, resin, methionine, phenylalanine, glycine, glutamine, alanine, carnitine, glutamine, arginine), lipids (eicosapentaenoic acid, docosahexaenoic acid, arachidonic acid), trace elements (sodium, potassium, magnesium, phosphorus, calcium, copper, zinc, manganese, chromium, iodine, selenium), digestive enzymes (papain, amylase, lactase, bromelain), whey.

[0093] These micronutrients and macronutrients regulate the gut microbiota and promote the dominance of certain species associated with good health, such as Bifidobacterium, Lactobacillus, Akkermansia, Fecalibacterium, Eubacterium, Roseburia, Ruminococcus, and Blautia. Among macronutrients, carbohydrates such as galactooligosaccharides, fructooligosaccharides, and inulin have a Bifidobacterium-promoting effect and regulate beneficial microorganisms. Unsaturated fats similarly increase the beneficial microbiota. Antioxidants such as polyphenols regulate the ratio of Firmicutes to Bacteroidetes. Vitamins such as A, C, D, and E have a positive effect on Bifidobacteria, Akkermansia, and Lactobacillus. Trace elements such as calcium, magnesium, phosphorus, selenium, and zinc are effective against Akkermansia, Bifidobacterium, and Ruminococcus. Prebiotic intake is associated with the growth of Bifidobacterium and Lactic acid bacteria. In general, macronutrients and micronutrients influence the composition and diversity of the gut microbiota.

[0094] In a particular embodiment of the present invention, the composition of the soluble and additional components is as shown in Table 1. The additional components are one or more of resveratrol, astaxanthin, bromelain, papain, fermented rice starch, corn starch, and FOS, and each of these components is included in different amounts as shown in Table 1.

[0095] Table 1: List of additional components to the composition of the present invention per 100 mg of probiotic lysate.

[0096] [Table 1]

[0097] In the specific example shown in Table 1, the composition of the probiotic lysate accounts for 26.4% of the total weight of the composition of the present invention.

[0098] In a particular embodiment of the present invention, the composition of the present invention is obtained by a method comprising the following steps. - The microbial species selected for composition preparation are cultured using standard conditions established for the microbial species described herein. - Filter or centrifuge the microbial species until a suitable biomass of the selected microorganisms is obtained. - The obtained biomass is dissolved by a freeze-thaw and sonication cycle. This ensures at least 90%, 91%, 92%, 94%, preferably at least 95%, 96%, 97%, 98%, and more preferably 99%, 100% of the bacterial lysate. - To obtain the probiotic microbial lysate composition of the invention, different bacterial strains are mixed in a ratio selected based on weight percentage.

[0099] Those skilled in the art know how to find suitable protocols for the growth of microorganisms in a composition, and for their dissolution, as these are common procedures in the prior art.

[0100] In certain embodiments, the method for obtaining the composition of the present invention includes an additional step: drying the bacterial lysate biomass by spray drying or freeze-drying to obtain a powdered product containing all the bacterial strains selected to prepare the composition of the present invention.

[0101] In certain embodiments, the composition of the present invention is provided in the form of a dry powder.

[0102] When the composition of the present invention is provided in the form of a dry powder, it must be dissolved in water or another liquid that does not affect the properties of the composition's components before ingestion by the patient. The advantages of a dry powder are that it is easy to transport and store, and that it enhances the stability and durability of the composition. In this specification, dry powder means having a moisture content of less than 10%, preferably less than 5%, and more preferably less than 1%.

[0103] In certain embodiments, the compositions of the present invention are obtained from cultures of probiotic microorganisms of the genera described herein. These contain a certain amount of colony-forming units (CFUs). In the present invention, colony-forming units are a microbiological term. They are an indicator of the amount of living microorganisms present in a culture medium.

[0104] The lysate preparation process involves heat treatment with alternating heating and cooling cycles. Each batch of viable cell culture is resuspended in distilled water in a 1:2 ratio and subjected to a sterilization cycle at 121°C for 20 minutes in an autoclave. It is then frozen at -20°C for 12 hours and thawed at room temperature the following day.

[0105] After thawing, sonication (500W output, 40% amplitude, 10-second intervals) is performed for 20 minutes to obtain lysed cell aggregates from the probiotic batch (using Qsonica Q500). The final solution is freeze-dried to obtain a powdered lysate of probiotic microorganisms. The powder should be stored in a cool, heat-free environment. The viability rate ultimately does not exceed approximately 7E3 CFU / ml, which effectively means 100% cell death.

[0106] In certain embodiments of the present invention, the CFU content of Bacillus bacteria relative to the total CFU of the composition is in the range of 3.49% to 20.94%, preferably 10.98% to 15.75%. In absolute terms, the culture medium cultured before cell lysis contains 1E+11 to 5E+11 cells, preferably 2E+11 to 3E+11 cells, most preferably about 2.86E+11 cells.

[0107] In another specific embodiment, if the species of the genus Bacillus are Bacillus clausii, Bacillus coagulans, Bacillus licheniformis, Bacillus mesentericus and Bacillus subtilis, then before cell lysis, each culture contains 3E+9 to 9E+9 Bacillus clausii cells, Bacillus coagulans Bacillus coagulans cells range from 3E+9 to 9E+9, Bacillus licheniformis cells from 9E+10 to 3E+11, Bacillus mesentericus cells from 6E+10 to 9E+10, and Bacillus subtilis cells from 9E+10 to 3E+11.

[0108] In certain embodiments of the present invention, the composition is started with a number of Lactobacillus bacteria representing 28.64% to 66.82%, preferably 40.66% to 57.36%, of the total CFU. In absolute terms, the culture medium before proceeding to cell lysis contains 8E+11 to 3E+12 cells, preferably 9E+11 to 2E+12, and most preferably about 1.07E+12 Lactobacillus cells.

[0109] In another specific embodiment, if the species of the genus Lactobacillus are Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus paracasei, Lactobacillus fermentum, Lactobacillus reuteri, and Lactobacillus rhamnosus, then before cell lysis, each culture contains 5E+10 to 9E+10 cells for Lactobacillus acidophilus, 5E+10 to 9E+10 cells for Lactobacillus bulgaricus, and Lactobacillus casei Lactobacillus casei has 2E+11 to 8E+11 cells, Lactobacillus fermentum has 3E+10 to 9E+10 cells, Lactobacillus reuteri has 3E+10 to 9E+10 cells, and Lactobacillus rhamnosus has 1E+11 to 6E+11 cells.

[0110] In certain embodiments of the present invention, multiple bacteria of the genus Streptococcus are used, comprising CFUs ranging from 5.72% to 38.15%, preferably 10.98% to 20.75%, relative to the total CFU of the composition. In absolute terms, the culture medium cultured before proceeding to cell lysis contains 1E+11 to 6E+11 cells, preferably 2E+11 to 4E+11 cells, most preferably about 3.00E+11 cells. In certain embodiments, the species of the genus Streptococcus is Streptococcus thermophilus.

[0111] In certain embodiments of the present invention, the culture begins with a bacterial load of Saccharomyces containing 11.44% to 24.79%, preferably 19.04% to 21.75%, of the total culture volume (CFU). In absolute terms, the cultured medium before proceeding to cell lysis contains 1E+11 to 7E+11 cells, preferably 4E+11 to 6E+11, and most preferably about 5.20E+11. In certain embodiments, the species of Saccharomyces is Saccharomyces cerevisiae.

[0112] In certain embodiments of the present invention, the culture begins with a bacterial load of the genus Bifidobacterium containing 10.20% to 53.64% CFU relative to the total culture. Preferably, this is 15.99% to 18.75%. In absolute terms, the cultured medium before proceeding to cell lysis contains 1E+11 to 7E+11 cells. Preferably, this is 4E+11 to 6E+11 cells, and most preferably about 4.50E+11 cells. In certain embodiments, the species of the genus Bifidobacterium is Bifidobacterium lactis.

[0113] These probiotics are cultured under standard conditions specified in the culture protocols published by the Spanish Standard Strain Collection (CECT). These protocols are provided for each bacterial species described herein.

[0114] After these microorganisms are cultured, they undergo a lysis process. First, the microbial cells are heat-treated. Each batch of viable cell cultures is subjected to a sterilization cycle in an autoclave at 121°C for 20 to 30 minutes. This temperature denatures, coagulates, and inactivates proteins. In addition, it causes membrane damage, ribosome aggregation, DNA strand breaks, and enzyme inactivation. After cooling, sonication is performed for 15 to 20 minutes. The output is 450 to 550 W, the amplitude is 38 to 43%, and the pause period is 8 to 15 seconds to obtain a mass of lysed cells from the probiotic batch (using Qsonica Q500). This achieves disruption of intermolecular interactions and DNA fragmentation. If necessary, the final solution is freeze-dried and pulverized to obtain a powdered probiotic lysate. The powder should be stored in a cool, heat-free environment.

[0115] The composition according to the present invention is the result of combining probiotic microorganisms. These microorganisms undergo processes of growth and lysis to produce an extract consisting of metabolites, proteins, DNA fragments, and other components (e.g., peptidoglycan). This extract, at appropriate doses, has the ability to remarkably alter and modify the host microbiota through several mechanisms, leading to immune system activation, reversing abnormalities in the gut microbiota, and remarkably delaying the host immune response. It consists of components such as peptidoglycan. This composition, at efficient administration, remarkably alters and modifies the host microbiota through multiple mechanisms, leading to immune system activation, reversing abnormalities in the gut microbiota, and remarkably accelerating the delay of cellular aging.

[0116] In certain embodiments, if the composition of the present invention is in powder form, it can be provided in sealed pouches conventionally used in the food and pharmaceutical industry, in accordance with the first aspect of the present invention.

[0117] Another form of nutritional supplement according to the present invention is in capsule form. For example, this includes a form in which a powdered composition is contained within a conventional gelatin capsule.

[0118] In another specific embodiment, the treatment of a solid tumor involves improving the patient's quality of life through the immunomodulatory and angiogenic modulatory properties of the composition of the present invention.

[0119] In additional embodiments, the improvement in quality of life relates to one or more of the following symptoms: anxiety, fatigue, nausea, vomiting, pain, sleep disturbances, stress, asthenia, loss of appetite, pain, shortness of breath, diarrhea.

[0120] In this invention, a solid tumor refers to one or more of the following: colorectal cancer, lung cancer, prostate cancer, breast cancer, central nervous system (CNS) cancer, pancreatic cancer, esophageal cancer, uterine cancer, lymphoma, pheochromocytoma, or sarcoma.

[0121] In preferred embodiments, the solid tumors are colorectal cancer, lung cancer, prostate cancer, central nervous system cancer, esophageal cancer, pheochromocytoma, and sarcoma.

[0122] In this invention, colon cancer and / or lung cancer are either primary or metastatic.

[0123] In certain embodiments, colorectal cancer is selected from one or more subtypes of colorectal cancer, consisting of adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, neuroendocrine carcinoma, and anaplastic carcinoma. These subtypes can be either primary or metastatic.

[0124] In certain embodiments, lung cancer is selected from one or more of the following lung cancer subtypes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Within NSCLC, the subtypes are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.

[0125] These subtypes can be either primary or metastatic.

[0126] In certain embodiments, the patient is a terminally ill cancer patient, or a terminally ill colon cancer and / or lung cancer patient. Terminally ill cancer patients typically have metastatic cancer, such as metastatic colon cancer and / or lung cancer. In this specification, a terminally ill cancer patient means a patient who, prior to being administered the composition of the present invention, receives palliative care or drugs to improve quality of life, but does not receive treatment aimed at curing the cancer, because such treatment is ineffective.

[0127] The compositions of the present invention exhibit anticancer activity because they have the ability to at least partially block or inhibit the PD-1 / PD-L1 pathway. Therefore, in certain embodiments, PD-1 / PD-L1 positive cancers are selected from PD-1 / PD-L1 positive colorectal cancer and / or lung cancer. PD-1 / PD-L1 positive cancer means cancer in which either or both markers are positively expressed by histochemical staining or other detection methods routinely used by pathologists and specialists.

[0128] In certain embodiments, a positive result is considered to occur if at least 5% of cancer cells express PD-L1, preferably at least 10%, and more preferably at least 20%. In another specific embodiment, a positive result is considered to occur if at least 5% of immune cells (T cells) express PD-1, preferably at least 10%, and more preferably at least 20%. In certain embodiments, the cancer cells are colorectal cancer cells and / or lung cancer cells.

[0129] An additional advantage of the present invention is that treatment with the compositions of the present invention improves the tolerance of chemotherapy, radiotherapy, and immunotherapy, and allows for the readmission of treatments that had been discontinued in patients due to toxicity.

[0130] Therefore, in the context of the present invention, it is established that at least one dose, preferably once daily, must be administered in an amount ranging from 100 mg to 80,000 mg of the composition of the invention, i.e., either composition AK or composition AP. In a preferred embodiment, the dose may contain 100 mg to 50,000 mg of the composition of the invention, comprising either composition AK or composition AP. In another preferred embodiment, the dose may contain 100 mg to 2,000 mg of the composition of the invention, comprising either composition AK or composition AP. In yet another preferred embodiment, the dose may contain 100 mg to 700 mg of the composition of the invention, comprising either composition AK or composition AP. In a specific embodiment of the present invention, the dosage is approximately 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 4 The formulations include 00mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, 500mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 580mg, 590mg, 600mg, 610mg, 620mg, 630mg, 640mg, 650mg, 660mg, 670mg, 680mg, or 690mg. These formulations include either one of composition AK or one of composition AP.

[0131] In certain embodiments, the composition of the present invention, comprising either composition AK or composition AP, can be administered at least once according to any of the concentrations specified in the preceding paragraph. The administration interval can be daily, every other day, or every three or four days.

[0132] In another additional embodiment, the postbiotic composition of the present invention (containing either composition AK or either composition AP) is administered daily for at least two weeks. Preferably, it is administered daily for at least three weeks, more preferably daily for at least four weeks, more preferably daily for at least five weeks, more preferably daily for at least six weeks, more preferably daily for at least seven weeks, more preferably daily for at least eight weeks, or at least nine weeks, or at least ten weeks, or at least eleven weeks, or at least twelve weeks.

[0133] Preferably, the composition of the present invention, comprising either composition AK or either composition AP, is administered 1 to 6 times per day in a single dose ranging from 100 mg to 700 mg, for at least 2 weeks.

[0134] In another specific embodiment, a composition of the present invention comprising either composition AK or either composition AP is administered in a single dose of 150 mg to 650 mg, once to five times a day, for at least three weeks.

[0135] In another specific embodiment, a composition of the present invention comprising either composition AK or either composition AP is administered in an amount of 200 mg to 600 mg per dose, two to four times per day, for at least four weeks.

[0136] In another specific embodiment, a composition of the present invention comprising either composition AK or either composition AP is administered two to four times per day in a single dose ranging from 250 mg to 550 mg, for a period of at least five weeks.

[0137] In another specific embodiment, a composition of the present invention comprising either composition AK or either composition AP is administered in an amount of 300 mg to 500 mg per dose, two to four times per day, for at least six weeks.

[0138] In another specific embodiment, a composition of the present invention comprising either composition AK or either composition AP is administered in an amount of 300 mg to 500 mg per dose, two to four times per day, for at least seven weeks.

[0139] In another specific embodiment, the composition of the present invention, comprising either composition AK or either composition AP, is administered in amounts of 300 mg to 500 mg per dose, two to four times per day, for at least eight weeks.

[0140] In another additional embodiment, treatment with the postbiotic composition is performed before, concurrently with, or after treatment of a patient with chemotherapy, radiotherapy, other cancer treatments, or treatment for colorectal cancer and / or lung cancer. If treatment with the composition of the present invention improves the patient's overall condition, chemotherapy, radiotherapy, or other cancer treatments can be performed if the physician determines that the patient can tolerate them.

[0141] In another specific embodiment, the amount of the composition varies each time it is administered to the patient throughout the day.

[0142] This beneficial effect stems from the fact that the compositions of the present invention can control angiogenesis in solid tumors. Therefore, an additional object of the present invention relates to the compositions of the present invention for use as angiogenesis promoters.

[0143] In the present invention, an angiogenesis promoter refers to a drug used to promote the development of collateral circulation that can compensate for the insufficient perfusion that occurs secondary to proper artery occlusion.

[0144] An additional object of the present invention relates to a pharmaceutical composition comprising a composition according to a first aspect of the present invention and a pharmaceutically acceptable excipient.

[0145] In the present invention, the term "pharmaceutical composition" refers to a formulation prepared to deliver one or more useful therapeutic agents to cells, cell groups, organs, or tissues in predetermined doses.

[0146] In this context, "effective pharmacological dose" refers to a non-toxic dose capable of producing a therapeutic effect. The exact amount required varies from person to person depending on the species, age, general condition, severity of the disease being treated, the specific compound used, and the method of administration. Therefore, it is impossible to determine the exact "effective dose." However, an appropriate effective dose can be determined by a person skilled in the art through standard testing. In the context of compounds and compositions for infection prevention, a pharmacologically effective dose may refer to the amount necessary to alleviate the symptoms of cancer or colorectal cancer and / or lung cancer in a subject and improve their quality of life.

[0147] Furthermore, in this invention, "pharmaceutically acceptable excipients" means therapeutically inert substances used to formulate the active ingredient that are acceptable to the patient from a pharmacological / toxicological standpoint, and acceptable to the pharmaceutical chemist who manufactures them from the standpoint of composition, formulation, stability, patient acceptability, and bioavailability.

[0148] Furthermore, another additional object of the present invention relates to a nutritional supplement comprising the compositions of the present invention for use in the treatment of patients having solid tumors, particularly colon cancer and / or lung cancer. This comprises either composition "AK" or either composition "AP".

[0149] In this invention, "food supplement" refers to a food product intended to supplement a normal diet, consisting of concentrated sources of nutrients and other substances, and having nutritional or physiological effects in single or combined forms. These refer to quantified forms, i.e., capsules, tablets, pills and other similar forms, powder pouches, liquid ampoules, bottles with droppers, and other similar liquid or powder forms that are taken in small quantities. This is defined in European Parliament Directive 2002 / 46 / EC.

[0150] In certain embodiments of the present invention, the use of the composition as a food supplement involves orally administering 100 mg to 500 mg of the composition two to six times a day. Similarly, the use of the composition for improving health status, particularly in patients with colon cancer and / or lung cancer, is also covered by the present invention.

[0151] In certain embodiments of the present invention, the use of the composition as a food supplement involves oral administration to an individual at least three times a day. Furthermore, for the treatment to be effective and achieve the desired effect, this dose should be administered to the patient at least twice a day, and up to six times a day. Preferably, the dose should be administered to the patient three, four, or five times a day, ideally three times a day.

[0152] In another specific embodiment, the amount of composition administered to the patient throughout the day varies each time.

[0153] In this invention, "dose" refers to the amount of pharmaceutical product containing the precise amount of the active ingredient necessary to address the health problem for which it is indicated, in an efficient, effective, and safe manner for the patient.

[0154] Therefore, in the context of the present invention, it is established that at least one dose, preferably once daily, must be administered in an amount ranging from 100 mg to 80,000 mg of the composition of the invention, i.e., any of compositions A, K, or any of compositions AP. In a preferred embodiment, the dose may include 100 mg to 50,000 mg of the composition of the invention, which contains any of compositions A through K, or any of compositions AP. In another preferred embodiment, the dose may include 100 mg to 2,000 mg of the composition of the invention, which contains any of compositions A, K, or any of compositions AP. In yet another preferred embodiment, the dose may include 100 mg to 700 mg of the composition of the invention, which contains any of compositions A, K, or any of compositions AP. In a specific embodied form of the present invention, the dosage is approximately 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 4 The formulation comprises 30 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, or 690 mg, and the formulation comprises either one of composition AK or one of composition AP.

[0155] In certain embodiments, if the composition is packaged in a waterproof pouch, it can be administered to a patient by dissolving or suspending it in a liquid, preferably an aqueous liquid, more preferably a beverage such as fruit juice, milk, or water. Furthermore, it can be mixed with foods such as yogurt, liquid yogurt, soup, puree, cream, or porridge. The food must be at a suitable temperature for consumption and must never be heated after the composition of the present invention has been added.

[0156] An additional object of the present invention relates to a beverage or food product containing the oral administration composition of the present invention, or the food supplement of the present invention.

[0157] The technical effects obtained from the compositions of the present invention are exerted either by acting directly on the host or by contributing to the reorganization of the human microbiome. Through this restorative and modulatory action, the inventors have surprisingly confirmed that health status is significantly improved by intervening in the human microbiome. Results in macrophages, in particular, showed that activation of the innate immune response is achieved by modulating inflammatory mediators in inflammatory states, which leads to the ability to act on cancer cells. Results using zebrafish confirmed the observation of tumor-like angiogenesis regulation during embryonic development. This effect is equivalent to the effect observed in the gut microbiome during the early postnatal settlement stage, i.e., during immune system formation. This angiogenesis-promoting effect improves the bioavailability of chemotherapy and immunotherapy in this case, and enhances the delivery of drugs to the body.

[0158] In this way, the inventors were able to confirm that orally administered compositions of the present invention are effective in regulating and reprogramming the microbiome present in the human intestinal tract. This is not a local effect, but a systemic effect because the entire body benefits from this regulation of the microbiome.

[0159] Furthermore, the present invention includes the following provisions:

[0160] 1. A postbiotic composition for oral administration, comprising the following amounts of probiotic microbial lysates in weight percentage of the total weight of microbial lysates in the composition: - Bacillus bacterial lysates make up 6% to 19%; - Bifidobacterium bacterial lysates make up 4% to 8%; - 15% to 25% bacterial lysates from the genus Lactobacillus; - 50% to 60% lysate of Saccharomyces yeast; - 1.5% to 5% bacterial lysates from the genus Streptococcus; Postbiotic compositions for use in the treatment of patients with solid tumors.

[0161] 2. A composition for use as described in Clause 1, wherein the solid tumor is selected from colorectal cancer and / or lung cancer.

[0162] 3. A composition for use as described in Clause 1, wherein the solid tumor is selected from prostate cancer, breast cancer, central nervous system (CNS) cancer, pancreatic cancer, esophageal cancer, uterine cancer, lymphoma, pheochromocytoma and / or sarcoma.

[0163] 4. A composition for use as described in any of the preceding clauses, which contains probiotic lysates in the following amounts by weight percentage of the total weight of microbial lysates in the composition: - Bacillus bacterial lysates make up 13% to 19% of the total; - Bifidobacterium bacterial lysates make up 4% to 8% of the sample; - 15% to 25% bacterial lysates from the genus Lactobacillus; - 50% to 60% lysate of Saccharomyces yeast; - 1.5% to 5% bacterial lysates from the genus Streptococcus.

[0164] 5. A composition for use as described in any of the preceding clauses, wherein the composition contains 1% to 99.5% by weight of microbial lysates, particularly 5% to 99% by weight of microbial lysates, particularly 10% to 96% by weight of microbial lysates, 25% to 95% by weight of microbial lysates, or particularly 50 ± 10% by weight of these microorganisms.

[0165] 6. In a composition for use as described in any of the preceding clauses, the bacterial lysate of the genus Bacillus is a species selected from the group consisting of Bacillus clausii, Bacillus coagulans, Bacillus licheniformis, Bacillus pumilus, Bacillus subtilis, Bacillus mesentericus, Bacillus paralicheniformes, and combinations thereof.

[0166] 7. In a composition for use as described in any of the preceding clauses, the bacterial lysates of the genus Bacillus are Bacillus clausii, Bacillus coagulans, Bacillus licheniformis, Bacillus mesentericus, and Bacillus subtilis.

[0167] 8. In a composition for use as described in any of the preceding clauses, a bacterial lysate of the genus Bifidobacterium is present, specifically Bifidobacterium animalis subspecies lactis. These include Bifidobacterium lactis, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium lactis, Bifidobacterium longum, Bifidobacterium infantis, Bifidobacterium animalis, and combinations thereof.

[0168] 9. In a composition for use as described in any of the preceding clauses, the bacterial lysate of the genus Bifidobacterium is the species Bifidobacterium lactis.

[0169] 10. In a composition for use as described in any of the preceding clauses, the bacterial lysate of Lactobacillus species is Lactobacillus lactis, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus paracasei, Lactobacillus plantarum, Lactobacillus reuteri, Lactobacillus rhamnosus, Lactobacillus salivarius, The species are selected from the group consisting of Lactobacillus helveticus, Lactobacillus gasseri, Lactobacillus johnsonii, Lactobacillus brevis, Lactobacillus kefiri, and combinations thereof.

[0170] 11. In a composition for use as described in any of the preceding clauses, the bacterial lysate of the genus Lactobacillus is of the species Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus reuteri, and Lactobacillus rhamnosus.

[0171] 12. In a composition for use as described in any of the preceding clauses, the lysate of the yeast genus Saccharomyces is a species selected from Saccharomyces cerevisiae, Saccharomyces boulardi, and combinations thereof.

[0172] 13. In a composition for use as described in any of the preceding clauses, the lysate of the yeast genus Saccharomyces is the species Saccharomyces cerevisiae.

[0173] 14. In a composition for use as described in any of the preceding clauses, the bacterial lysate of the genus Streptococcus is a species selected from the group consisting of Streptococcus thermophilus, Streptococcus salivarius, and combinations thereof.

[0174] 15. In a composition for use as described in any of the preceding clauses, the bacterial lysate of the genus Streptococcus is of the species Streptococcus thermophilus.

[0175] 16. In a composition for use as described in any of the preceding clauses, a bacterial lysate of the genus Bacillus accounts for approximately 14% to 18% of the total lysates in the composition.

[0176] 17. In a composition for use as described in any of the preceding clauses, the weight percentages of Bacillus licheniformis, Bacillus mesentericus, and Bacillus subtilis are approximately equal and higher than the weight percentages of Bacillus clausii and Bacillus coagulans, and the weight percentages of these Bacillus clausii and Bacillus coagulans are also approximately equal.

[0177] 18. In a composition for use as described in any of the preceding clauses, a bacterial lysate of the genus Bifidobacterium accounts for approximately 5% to 7% of the total lysates in the composition.

[0178] 19. In a composition for use as described in any of the preceding clauses, a bacterial lysate of the genus Lactobacillus accounts for approximately 20% to 25% of the total amount of lysates in the composition.

[0179] 20. In a composition for use as described in any of the preceding clauses, the weight percentages of Lactobacillus acidophilus, Lactobacillus bulgaricus, and Lactobacillus casei are different from each other, and different from the weight percentages of Lactobacillus fermentum, Lactobacillus reuteri, and Lactobacillus rhamnosus, with the weight percentages of the latter three being approximately the same.

[0180] 21. In a composition for use as described in any of the preceding clauses, the weight percentage of Lactobacillus casei is higher than that of other Lactobacillus species.

[0181] 22. In a composition for use as described in any of the preceding clauses, the weight percentage of Lactobacillus casei is higher than that of Lactobacillus acidophilus, the weight percentage of Lactobacillus acidophilus is higher than that of Lactobacillus bulgaricus, and the weight percentage of Lactobacillus bulgaricus is higher than that of Lactobacillus fermentum. The weight percentages of Lactobacillus reuteri and Lactobacillus rhamnosus are approximately the same.

[0182] 23. In a composition for use as described in any of the preceding clauses, a lysate of a yeast of the genus Saccharomyces accounts for approximately 52% to 57% of the total lysate of the composition.

[0183] 24. In a composition for use as described in any of the preceding clauses, the lysate of the yeast Streptococcus accounts for approximately 3% to 4% of the total amount of lysates in the composition.

[0184] 25. A composition for use as described in any of the preceding clauses, wherein the composition contains a lysate of a probiotic microorganism in weight percent of the total amount of lysate of the composition based on composition A.

[0185] 26. A composition for use as described in any of the preceding clauses, wherein the composition contains a lysate of a probiotic microorganism in a total lysate weight percentage of the composition based on composition B.

[0186] 27. A composition for use as described in any of the preceding clauses, wherein the composition comprises a lysate of a probiotic microorganism in an amount expressed as a weight percentage of the total lysate in the composition described in composition C.

[0187] 28. A composition for use as described in any of the preceding clauses, wherein the composition contains a lysate of a probiotic microorganism as a weight percentage of the total lysates in the composition described in composition D.

[0188] 29. A composition for use as described in any of the preceding clauses, wherein the composition comprises a lysate of a probiotic microorganism in an amount expressed as a weight percentage of the total lysate of the composition according to composition E.

[0189] 30. A composition for use as described in any of the preceding clauses, wherein the composition comprises a lysate of a probiotic microorganism in an amount expressed as a weight percentage of the total lysate of the composition according to composition F.

[0190] 31. A composition for use as described in any of the preceding clauses, wherein the composition comprises a lysate of a probiotic microorganism in an amount expressed as a weight percentage of the total lysate of the composition in composition G.

[0191] 32. A composition for use as described in any of the preceding clauses, wherein the composition comprises a lysate of a probiotic microorganism in an amount expressed as a weight percentage of the total lysate of the composition according to composition H.

[0192] 33. A composition for use as described in any of the preceding clauses, wherein the composition comprises a lysate of a probiotic microorganism in an amount expressed as a weight percentage of the total amount of lysates of the composition according to Composition I.

[0193] 34. A composition for use as described in any of the preceding clauses, wherein the composition comprises a lysate of a probiotic microorganism in an amount expressed as a weight percentage of the total lysate of the composition in composition J.

[0194] 35. A composition for use as described in any of the preceding clauses, wherein the composition comprises a lysate of a probiotic microorganism in an amount expressed as a weight percentage of the total lysate in composition K.

[0195] 36. A composition for use as described in any of the preceding clauses, wherein the composition comprises a lysate of a probiotic microorganism in an amount expressed as a weight percentage of the total lysate of the composition L.

[0196] 37. A composition for use as described in any of the preceding clauses, wherein the composition comprises a lysate of a probiotic microorganism in an amount expressed as a weight percentage of the total lysate of the composition according to composition M.

[0197] 38. A composition for use as described in any of the preceding clauses, wherein the composition comprises a lysate of a probiotic microorganism in an amount expressed as a weight percentage of the total lysate of the composition according to composition N.

[0198] 39. A composition for use as described in any of the preceding clauses, wherein the composition comprises a lysate of a probiotic microorganism in an amount expressed as a weight percentage of the total lysate of the composition according to composition O.

[0199] 40. A composition for use as described in a preceding clause, wherein the composition comprises a lysate of a probiotic microorganism in an amount expressed as a weight percentage of the total lysate in the composition described in composition P.

[0200] 41. A composition for use as described in any of the preceding clauses, wherein the composition comprises, essentially, an amount of probiotic microbial lysate expressed as a weight percentage of the total lysate in the composition described in composition P.

[0201] 42. A composition for use as described in any of the preceding clauses, which does not contain lysates of microorganisms present in the gastrointestinal tract, and preferably does not contain bacterial lysates of the genera Akkermansia, Enterococcus, and Escherichia.

[0202] 43. Compositions for use as described in any of the preceding clauses, comprising one or more additives selected from the following group: carbohydrates (fructose, xylitol, sorbitol, fructooligosaccharides, inulin), antioxidants (resveratrol, β-carotene), vitamins (vitamins C, D, K, B1, B9, E, B3, B5, A, B3, B6, H, D3, B12, biotin, riboflavin, pyridoxine, pantothenic acid), prebiotics (galactooligosaccharides) (Gosaccharides, inulin, oligofructose), amino acids (cysteine, tyrosine, resin, methionine, phenylalanine, glycine, glutamine, alanine, carnitine, glutamine, arginine), lipids (eicosapentaenoic acid, docosahexaenoic acid, arachidonic acid), trace elements (sodium, potassium, magnesium, phosphorus, calcium, copper, zinc, manganese, chromium, iodine, selenium), digestive enzymes (papain, amylase, lactase, bromelain), whey.

[0203] 44. A composition for use as described in any of the preceding clauses, comprising one or more of the following additives: resveratrol, astaxanthin, bromelain, papain, fermented rice starch, corn starch, and FOS.

[0204] 45. A composition for use as described in any of the preceding clauses, provided in the form of a dry powder.

[0205] 46. ​​In the composition for use described in the preceding paragraph, the dried powder is sealed in a waterproof bag or in a gelatin capsule.

[0206] 47. A composition for use as described in any of the preceding clauses, the treatment of a solid tumor includes improving the patient's quality of life.

[0207] 48. In a composition for use of a preceding clause, the improvement in quality of life is related to one or more of the following symptoms: anxiety, fatigue, nausea, vomiting, pain, sleep disturbance, stress, asthenia, loss of appetite, pain, difficulty breathing, diarrhea.

[0208] 49. A composition for use as described in any of the preceding clauses, wherein the solid tumor is one or more of the following: prostate, central nervous system, esophagus, pheochromocytoma, sarcoma.

[0209] 50. In a composition for use as described in any of the preceding clauses, the patient is a terminally ill cancer patient.

[0210] 51. In a composition for use as described in any of the preceding clauses, terminal cancer is selected from terminal prostate cancer, terminal breast cancer, terminal central nervous system (CNS) cancer, terminal pancreatic cancer, terminal esophageal cancer, terminal uterine cancer, terminal lymphoma, terminal pheochromocytoma, terminal sarcoma, terminal colon cancer and / or terminal lung cancer.

[0211] 52. A composition for use as described in any of the preceding clauses, for administration of at least one dose ranging from 100 mg to 700 mg, including approximately 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, The composition includes 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, or 690 mg.

[0212] 53. In a composition for use as described in any of the preceding clauses, the administration of the postbiotic composition of the present invention is daily for at least two weeks, preferably at least three weeks, more preferably at least four weeks, even more preferably at least five weeks, even more preferably at least six weeks, even more preferably at least seven weeks, even more preferably at least eight weeks, or at least nine weeks, at least ten weeks, at least eleven weeks, or at least twelve weeks.

[0213] 54. A composition for use as described in any of the preceding clauses, administered in an amount ranging from 100 mg to 700 mg per dose, once to six times per day, for at least two weeks.

[0214] 55. A composition for use as described in any of the preceding clauses, administered in an amount ranging from 150 mg to 650 mg per dose, once to five times a day, for at least three weeks.

[0215] 56. A composition for use as described in any of the preceding clauses, administered in a single dose of 200 mg to 600 mg, two to four times a day, for at least four weeks.

[0216] 57. A composition for use as described in any of the preceding clauses, administered in doses ranging from 250 mg to 550 mg, two to four times per day for at least five weeks.

[0217] 58. A composition for use as described in any of the preceding clauses, administered in doses ranging from 300 mg to 500 mg, two to four times per day for at least six weeks.

[0218] 59. A composition for use as described in any of the preceding clauses, administered in an amount ranging from 300 mg to 500 mg per dose, two to four times a day, for at least seven weeks.

[0219] 60. A composition for use as described in any of the preceding clauses, administered in doses ranging from 300 mg to 500 mg, two to four times a day for at least eight weeks.

[0220] 61. A composition for use as described in any of the preceding clauses, administered at a dose of 400 mg three times a day for at least 8 weeks.

[0221] 62. A composition for use as described in any of the preceding clauses, which is used before, concurrently with, or after treatment of a patient with chemotherapy or radiotherapy.

[0222] 63. A composition for use as described in any of the preceding clauses, wherein the dosage of the composition varies at each administration during the day.

[0223] 64. A method for obtaining a post-administration biocomposition for use in the treatment of a solid tumor in a patient, as described in any of Clauses 1 to 63, comprising: - Cultivate the selected microbial species; - The selected microbial species are filtered or centrifuged and processed until sufficient biomass is obtained; - Dissolution by freezing and thawing cycles, followed by ultrasonic treatment of the resulting biomass.

[0224] 65. A method for obtaining a dried powder product by drying the biomass of bacterial lysate by spray drying or freeze-drying in the process described in the preceding clause.

[0225] 66. A pharmaceutical composition comprising a composition described in any of Clauses 1 to 63 and a pharmaceutically acceptable excipient, for use in the treatment of solid tumors.

[0226] 67. A food supplement comprising any of the compositions described in Clauses 1 to 63.

[0227] 68. A composition according to any of the preceding clauses 1 to 67, wherein the cancer is PD-1 / PDL1 positive, and in particular the colon cancer and / or lung cancer is PD-1 / PDL1 positive.

[0228] Therefore, the main advantages arising from the compositions covered by the present invention are as follows: - To complement and / or support the physiological functions of the human and animal microbiome; - To restore changes that cause abnormalities in the gut microbiota (dysbiosis) and affect oxidative stress, inflammation, and antitumor processes; - Due to its oral administration nature, this composition and its remarkable effects make it a highly advantageous option compared to current cancer treatments; - This composition contains lysates of microorganisms and, i.e., does not contain live organisms, thus avoiding the potential dangers associated with biological colonization and exhibiting no toxicity associated with conventional drugs, making it a safe alternative.

[0229] The terms “include,” “essentially constitute,” and “consist of” are interchangeable with any of the other terms. The term “a” may refer to one or more elements being modified (e.g., “a reactant” may mean one or more reactants) unless the context makes it clear whether it is singular or plural. In this specification, the term “approximately” refers to a value within 10% of the underlying parameter (i.e., a range of ±10%) (e.g., a weight of “approximately 100 grams” includes a range from 90 grams to 110 grams). When the term “approximately” is used at the beginning of a list of values, it modifies each value (e.g., “approximately 1, 2, and 3” refers to “approximately 1, approximately 2, and approximately 3”). When describing a list of values, the list includes all intermediate and decimal values ​​(e.g., a list of values ​​“80%, 85%, or 90%” includes 86% of the intermediate value and 86.4% of the decimal value). When the word "greater than or equal to" follows a list of values, "greater than or equal to" applies to each value listed (for example, the list "80%, 90%, 95% or more" refers to "80% or more, 90% or more, or 95% or more"). When describing a list of values, the list includes all ranges between any two values ​​listed (for example, the list "80%, 90%, or 95%" includes the ranges "80% to 90%", "80% to 95%", and "90% to 95%"). Examples of this technique's application are shown below.

[0230] Preferred Embodiments of the Invention To better understand the present invention and to facilitate its practical implementation, preferred embodiments of the invention are described in detail as part of this specification.

[0231] Example 1 - Immunomodulatory activity of microbial lysates in THP-1 cells the purpose: The purpose of this study is to investigate the in vitro immunomodulatory capacity of microbial lysates by regulating cytokine secretion in THP-1 cells.

[0232] Materials and methods: Composition of postbiotic invention: A postbiotic using lysates obtained from strains / species of 14 genera including Lactobacillus, Bifidobacterium, Bacillus, Saccharomyces, and Streptococcus as the main component was used. The composition of the extract is as shown in Table 2, and is expressed as a weight percentage relative to the total weight of the lysate in the composition.

[0233] [Table 2]

[0234] Macrophage culture: Macrophages were obtained from the THP-1 cell line (human monocyte cell line, ATCC® TIB-202). These cells were stored in the Gaika cell bank, and it was confirmed that there was no mycoplasma contamination immediately after thawing. The cells were suspension-cultured in a humid atmosphere of 37°C and 5% CO2. Before the experiment, they were cultured in RPMI medium + 10% FBSi + 50 μM β-mercaptoethanol for at least 2 weeks. The cells were passaged before reaching 80% confluence (cell concentration / volume).

[0235] Twenty-four hours before the immunomodulatory activity test, a cell suspension of 1×10 5 cells / mL was prepared. To differentiate monocytes into macrophages, 1×10 4 cells / well were dispensed into 96-well plates in the presence of 0.31 μg / mL PMA. The plates were cultured at 37°C and 5% CO2 for 24 hours.

[0236] Immunomodulatory activity test: In the immunomodulatory studies, THP-1 PMA-differentiated cells treated with postbiotic compositions at different concentrations, as shown in Table 2, were cultured for 24 hours in the presence of lipopolysaccharide (LPS, 20 μg / mL), an inflammatory stimulant. Non-inflammatory cells (cells exposed to unstimulated culture medium) were used as negative controls. The supernatant was collected after 24 hours. The levels of cytokines IL-8, TNF-α, IL-6, and IL-18 were quantified using ELISA detection kits according to the manufacturer's instructions (Human IL-8 ELISA Kit, in vitrogen: KHC0082; Human IL-6 ELISA Kit, in vitrogen: KHC0062; Human IL-18 ELISA Kit, MBL: 7620; Human TNF-alpha ELISA Kit, in vitrogen: 10008932).

[0237] Cytotoxicity test: To investigate the cytotoxicity of the product, a viability test was conducted using the MTT method. MTT (yellow tetrazolium salt) is reduced to purple formazan in living cells, and viability is measured by evaluating the metabolic activity of the cells. Cells cultured in a 96-well plate were treated with eight concentrations of the test product for 24 hours (37°C, 5% CO2). In parallel, eight concentrations of a positive control (sodium dodecyl sulfate (SDS)) were also tested to confirm the validity of the study. After 24 hours of culture with postbiotics or the positive control, the cells were washed with PBS, stained with MTT solution, and cultured at 37°C for 2 hours. After this culture period, the stain was removed, and 100 μl / well of DMSO was added to solubilize the colored precipitate. Absorbance at 540 nm was measured using a spectrophotometer plate reader. The percentage of cell viability was calculated compared to a negative control, which was not exposed to any product. Cell viability (%) = AbT / AbC×100 AbT = Absorbance at 540 nm after 72 hours of treatment AbC = Absorbance at 540 nm after 72 hours without treatment (negative control)

[0238] result Mycoplasma test The results obtained from the mycoplasma test are shown in the following table:

[0239] Table 3. Ratio of MycoAlerts obtained from each cell line

[0240] [Table 3]

[0241] The ratio obtained with the MycoAlert® mycoplasma detection kit (Lonza LT07-318) was less than 0.9, indicating the absence of mycoplasma contamination.

[0242] Cytotoxicity test The cytotoxic effects of the compounds were tested in vitro using the THP-1 cell line via the MTT assay. Therefore, the compounds under investigation were analyzed at eight concentrations: 500 μg / mL, 250 μg / mL, 125 μg / mL, 62.5 μg / mL, 31.25 μg / mL, 15.63 μg / mL, 7.81 μg / mL, and 3.91 μg / mL. In parallel, different concentrations of sodium dodecyl sulfate (SDS) were used as positive controls (not shown).

[0243] Figure 1 shows 15.63 Concentrations of μg / mL, 7.81 μg / mL, and 3.91 μg / mL were shown not to affect THP-1 cell viability, and these concentrations were selected for immunomodulatory studies.

[0244] immunomodulatory activity THP-1 cells differentiated into macrophages were simultaneously exposed to different concentrations of LPS-induced inflammatory stimuli and postbiotics for 24 hours based on the results of the cytotoxicity test. After exposure, the supernatant was collected and analyzed. The immunomodulatory effect was evaluated by quantifying the secretion levels of IL-6, IL-8, IL-18, and TNF-α. The obtained results are shown in Figure 2. An increase in the levels of cytokines IL-8 and IL-6 was induced at all concentrations tested. The results indicate that in macrophages treated with both LPS and postbiotics, they are secreted at higher values than macrophages stimulated with LPS alone. The levels of IL-8 and IL-6 produced after 24 hours maintained high values at all concentrations tested.

[0245] The secretion of TNF-α and IL-18 was also analyzed, and the results are summarized in Figure 2. In this case, the levels were similar at all concentrations tested, but in both cases, lower secretion amounts were observed compared to when LPS was administered alone.

[0246] Conclusion This study showed that under the described conditions, the postbiotic composition of the present invention exhibited immunomodulatory activity at all concentrations tested (15.63 μg / mL, 7.81 μg / mL, 3.91 μg / mL). LPS stimulation increased the production of IL-6, IL-8, TNF-α, and IL-18 in THP-1 cells. When treating the inflamed cells with this composition together, the secretion levels of IL-18 and TNF-α decreased compared to cells treated with LPS alone. On the other hand, in cells treated with this composition together, the secretion of IL-8 and IL-6 increased and the response was enhanced compared to treatment with LPS alone.

[0247] The results of this study suggest that the composition of the present invention activates the innate immune response of THP-1 macrophages by regulating inflammatory mediators, resulting in an immunomodulatory effect.

[0248] Example 2: Evaluation of the Angiogenic Effect of Postbiotics in Zebrafish

[0249] The formation of new blood vessels is necessary during embryonic development and in pathological conditions such as tumor growth. Angiogenesis is a cellular process in which already formed blood vessels branch and invade tissue in response to normal or pathological stimuli. Many processes and regulatory factors that control embryonic angiogenesis are also common to tumor-induced angiogenesis. Zebrafish have a complex circulatory system similar to that of mammals and have been proven effective as a model for detecting the anti-angiogenic and pro-angiogenic effects of compounds. The existence of transgenic zebrafish that express green fluorescent protein (GFP) under specific promoters in the vascular system allows for direct observation of vascular development and abnormalities under a fluorescence microscope.

[0250] The purpose of this study was to evaluate the effects of microbial molecules on angiogenesis in zebrafish embryos. Therefore, a dose-range exploration (DRF) study was first conducted to assess toxicity, and then the effects of the active ingredient on intersegmental angiogenesis (ISV) were investigated.

[0251] Research design This study used transgenic zebrafish (Danio rerio) expressing GFP protein intravascularly under the Flk1 promoter. The original strain was wild-type AB. 140 embryos provided by BIOBIDE were used. Adult zebrafish were reared and managed according to the standard procedure (ZFIN). The analyte compounds were the compositions of the postbiotic invention (IGEN-1806) shown in Table 2, which were stored at 4°C and then resuspended in DMSO. The positive control was MedChem. The selective vascular endothelial growth factor receptor (VEGFR) inhibitor KRN633 (DMSO solvent) manufactured by Express was used.

[0252] 1. Dosage Range Search (DRF): Five concentrations (0.1, 1, 10, 100, 1000) Ten embryos (5 per well) were cultured at 28.5°C for 2 days under each condition using mg / l. Embryos were treated 24±1 times after hpf fertilization (hpf). Lethality, morphological changes, and signs of angiogenesis / neovascularization were assessed in 48 and 72 samples. The embryos were evaluated using hpf. The control group consisted of untreated embryos in E3 + 0.5% DMSO medium. Synchronized embryos were kept in an incubator at 28.5°C until they reached 24±1 hpf. Lysates were dissolved in DMSO at a concentration of 200 μg / l and stored at 2-8°C. Dilutions (0.1, 1, 10, 100, 1000 mg / l) were prepared from these lysates.

[0253] After approximately 23 hpf, the chorionic membranes of healthy fertilized embryos were placed in 24-well plates (5 embryos per well) in 995 μl of E3 medium. Next, 5 μl of postbiotic or DMSO was added to the control group, and the plates were cultured at 28.5°C. Embryos were analyzed under a stereomicroscope after 48 hpf and 72 hpf. The incidence of mortality, obvious morphological abnormalities (impact on craniofacial structure, trunk, and tail), edema, and the presence or absence of other abnormalities were recorded. Fluorescence stereomicroscopy was also performed at the same developmental stage. Signs of neovascularization (ectopic proliferation) were identified by ISV (48 After hpf (high-pass follicle feeding), the embryos were visually confirmed in anesthetized embryos (0.03 mg / ml) with tricaine for proper analysis.

[0254] In the control group, the experiment was considered valid if the number of embryos (n) that were free of morphological abnormalities and had normal ISV development was 8 or more (n=80%).

[0255] The active ingredient is considered non-toxic at the analyzed dose if the number of affected embryos (death or malformation) is less than 20% of the total number of embryos treated.

[0256] 2. Angiogenesis inhibition test: Based on the preceding DRF analysis, six concentrations were selected (700, 1000, 1200, 1500, 1700, 2000). Ten embryos (5 per well) were cultured at 28.5°C for 2 days under each condition using mg / l. The positive control group consisted of embryos treated with 50 nM KRN633 in E3 medium (0.5% DMSO). Embryos were treated at 24 hpf. The incubation time was 48 hours at 28.5°C. The control group consisted of E3 The study consisted of untreated embryos in 1% DMSO medium. ISV formation was evaluated at 48 hpf and 72 hpf. Embryo production methods are described in the DRF procedure.

[0257] The embryos were deshelled, dispersed, and processed as described in the DRF procedure. After incubation at 28.5°C for 24 hours, they were 48 hpf embryos were removed from the exposure medium and anesthetized with 0.03% trichine. After anesthesia took effect, the presence or absence of abnormalities in ISV development was observed. Fluorescence images were taken of each group of embryos using a fluorescence stereomicroscope. Subsequently, image analysis was performed to quantify the total number of ISVs present in the embryonic trunk (from the most swollen part of the yolk to the tail end) and the number of complete ISVs (those that reached the DLAV (dorsal longitudinal anastomotic vessel) without interruption). Since no defects in ISV germination were observed or clearly detected in 48 hpf embryos, the embryos were washed with E3 medium to remove trichine, returned to the exposure medium, and cultured for a further 24 hours at 28.5°C. Vascular development in the hpf stage was confirmed. At this stage, the circulatory status through the ISV and the integrity of the ISV and DLV (ventral longitudinal anastomotic vessels) were examined. The number of embryos exhibiting characteristic vascular phenotypes in each experimental group was quantified.

[0258] The experiment was considered valid if the proportion of embryos showing normally developing ISVs in the control group exceeded 80%. Furthermore, the induction of statistically significant ISV deficiency in positive control embryos was also considered for verification.

[0259] Considering that the postbiotic composition of the present invention plays a role in angiogenesis, the value of any of the parameters quantified in the analysis of internodal angiogenesis at any point in time analyzed during the study must be significantly different (p<0.05) compared to the control embryo.

[0260] Results of the dose range exploration trial Table 4 shows the results of treating zebrafish embryos to evaluate the impact on angiogenesis. The numbers in each table indicate the number of embryos showing no obvious change, affected embryos, and dead embryos, respectively.

[0261] Table 4. Summary of unaffected, affected, and dead embryos (i.e., (8 / 2 / 0)) after treatment with five doses of the composition of the invention.

[0262] [Table 4]

[0263] Under most conditions, embryonic morphology was unaffected. However, one fish treated with 100 mg / l showed yolk opacity and yolk edema at 48 hpf, and the same fish also showed abnormal body length and cardiac edema at 72 hpf. Another fish with the same dose showed only cardiac edema at 72 hpf. In addition to this morphological analysis, observation of the embryos with a fluorescence stereomicroscope revealed that the ISV (medial thalamus) and DLAV (lateral thalamus) were properly formed at all concentrations and stages analyzed (see Figure 3).

[0264] Based on these results, the concentrations selected for the next stage of the study were 700, 1000, 1200, 1500, 1700, and 2000 mg / l.

[0265] Results of angiogenesis inhibition assay Analysis at 48hpf We analyzed the potential for postbiotic-induced angiogenesis impairment and took photographs of each group. Fish were collected from all experimental groups to quantify ISVs. The raw data for total and complete blood vessel counts, mean, standard deviation (SD), standard error of the mean (SEM), statistical analysis results, and representative images are shown in the table below and in the graphs and figures attached to this document.

[0266] [Table 5]

[0267] [Table 6]

[0268] The results of the statistical analysis are shown in the table below:

[0269] Table 7. Mean, standard deviation (SD), standard error (SEM), and statistical analysis results of ISV results at 48hpf. ns: No significant difference; *: p<0.05, **: p<0.01; ***: p<0.001

[0270] [Table 7]

[0271] These results indicate that the composition of the present invention is 1700 and 2000 This indicates a change in the number of complete ISVs at 48 hpf in mg / l.

[0272] Furthermore, it was confirmed that the total number of ISVs significantly increased even at 1500 mg / ml (p<0.05).

[0273] Analysis at 72hpf Since some defects were observed in ISV development at 48 hpf, the completeness of ISVs and DLAVs was confirmed at 72 hpf. Few embryos survived this stage, especially those exposed to the highest concentration (2000 mg / l). The number of ISVs and complete ISVs in each experimental group were quantified, and the results are shown in the table and Figure 6 below.

[0274] [Table 8]

[0275] [Table 9]

[0276] The results of the statistical analysis are shown in the table below:

[0277] Table 10. Mean, standard deviation (SD), standard error (SEM), and statistical analysis of ISV results at 72hpf for treated embryos and controls. ns: No significant difference; *: p<0.05, **: p<0.01; : p<0.001.

[0278] [Table 10]

[0279] These results indicate that, in embryos at 72 hpf, the composition of the present invention did not affect ISV development at any of the concentrations tested, both in terms of the number of ISVs and the number of complete ISVs.

[0280] conclusion The purpose of this study was to clarify the potential of the present invention's composition to be anti-angiogenic or angiogenic in zebrafish embryos. After analyzing toxicity and vascular effects affecting angiogenesis at 24 and 48 hours post-treatment, the number and integrity of ISVs were analyzed. The results showed that the postbiotic mixture did not induce a clear anti-angiogenic effect in zebrafish embryos at 72 hpf under the conditions of use. However, at 48 hpf, a moderate increase in the number of complete ISVs was observed compared to the control group, and this was particularly pronounced at higher doses. This suggests that angiogenesis may be slightly induced only in the early stages of development.

[0281] In solid tumors, proliferation and metastasis are achieved through excessive angiogenesis. This results in the formation of blood vessels with abnormal structures and irregular perfusion. This alters the distribution of nutrients and oxygen, as well as the delivery of chemotherapy drugs, reducing the therapeutic effect on tumor tissue. Therefore, in recent years, it has been suggested that using angiogenesis promoters could induce the formation of new, healthy blood vessels throughout the tumor microenvironment and potentially repair abnormal vessels. Recent studies have shown that stimulating angiogenesis makes tumors more sensitive to chemotherapy, and that the combination of verapamil and sirengitide increases intratumoral vascular density, dilation, patency, and perfusion. This increases tumor oxygenation, enabling efficient and effective delivery of the chemotherapy drug gemcitabine. Therefore, promoting angiogenesis may be a potential treatment for cancer, particularly colorectal and lung cancer.

[0282] The composition of the present invention has the ability to induce angiogenesis only in the early stages of development, thereby improving the reach of drugs and nutrients, delaying the formation process by limiting hypoxia, and inhibiting the tumorigenesis process.

[0283] Example 3: Effects of the postbiotic composition of the present invention on the PD1-PDL1 signaling pathway

[0284] To determine whether the mechanism of action of the postbiotic composition of the present invention is related to the inhibition of PD-1 signaling, an in vitro test was performed using a PD-1 / PD-L1 blocking bioassay (Promega). PD-1 (Programmed Cell Death Protein 1) is a receptor expressed on activated T cells that negatively regulates the immune response by binding to its PD-L1 (or PD-L2) ligand. This suppresses T cell activity, allowing cancer cells to evade immune system control. To evaluate the potential of the postbiotic composition of the present invention as a PD-1 signaling inhibitor in the cellular environment, the following in vitro model was used:

[0285] a) PD-1 effector cells: Jurkat T cells expressing human PD-1 and luciferase reporters driven by NFAT (activated T cell response element) (NFAT-RE). b) PD-L1 aAPC / CHO-K1 cells: CHO-K1 cells expressing human PD-L1 and modified cell surface proteins designed to activate allogeneic TCRs in an antigen-independent manner.

[0286] When two types of cells are co-cultured, the PD-1 / PD-L1 interaction inhibits TCR signaling and NFAT-RE-mediated luminescence. Adding either an anti-PD-1 antibody or an anti-PD-L1 antibody inhibits the PD-1 / PD-L1 interaction, releasing the inhibitory signal. This results in TCR activation and NFAT-RE-mediated luminescence, which can be detected and quantified by a luminometer after the addition of a luciferase substrate.

[0287] Different concentrations of the postbiotic compositions of the present invention (1 mg / ml, 0, 1 mg / ml, 0.01 mg / ml) were evaluated and compared to a control consisting of 100 μg / ml atezolizumab. PD-L1 aAPC / CHO-K1 cells and PD-1 effector cells were cultured for 6 hours with either the postbiotic compositions of the present invention or atezolizumab. The assay was performed according to the manufacturer's instructions, and luminescence was evaluated using an IVIS® SpectrumCT imaging system. As shown in Figure 7, the postbiotic compositions of the present invention partially inhibited the PD-1 / PD-L1 interaction, resulting in luminescence.

[0288] Example 4: Administration of the postbiotic composition of the present invention as a means of regulating the microbiome in terminally ill cancer patients

[0289] the purpose: This study analyzes whether the compositions described herein can readjust the composition and physiological function of the microbiome in terminally ill cancer patients, including those with colon and lung cancer, and whether this readjustment leads to clinical improvement, an increase in quality of life (QOL), and cachexia typically associated with these patients.

[0290] Research design: This is a prospective observational study involving 34 terminally ill patients with different types of cancer (Table 11). The theoretical life expectancy for each stage and treatment is less than 6 months. Patient background data, disease onset, diagnosis, and treatment received will be collected.

[0291] The eligibility criteria included patients aged 18 years or older, regardless of gender, with cancer of any site, in an advanced metastatic stage, with a theoretical life expectancy of less than 6 months, and receiving any type of aggressive treatment. Patients with non-advanced disease, those whose quality of life could not be assessed, those receiving other types of nutritional supplements or special nutrition, and children under 18 years of age were excluded. All patients were administered 400 mg of the inventive composition three times daily (1200 mg per day, three doses) for at least 8 weeks. Quality of life was verified by EORTC. The QLQ-C30 questionnaire was used to measure and evaluate chemotherapy side effects, loss of appetite, weight gain / loss, and fatigue. Patients completed the questionnaire before the start of treatment and weekly thereafter, and submitted it at their next appointment. The composition of the present invention consisted of three 10g pouches, each containing 400mg of the lysed microbial composition of the present invention. The remainder consisted of 5.44g whey, 200mg calcium, 26.67mg vitamin C, 24mg bromelain, 32.5mg papain, 0.367mg vitamin B1, 0.33mg copper, 66.67μg vitamin B9, 280mg fructooligosaccharides, 238mg inulin, and L-carnitine. 173mg, L-Glutamine 135mg, L-Arginine 102mg, Resveratrol 2.5mg, Vitamin E 4mg, Vitamin B3 5.33mg, Vitamin B5 2mg, Vitamin A 266.67μg, Vitamin B2 0.467mg, Vitamin B6 0.467mg, Vitamin H 16.67 μg, Vitamin D3 1.67 μg, Vitamin B12 0.83 μg, potassium 260 mg, Magnesium 125 mg, Sodium 86.67 mg, Zinc These are excipients and additives such as 3.33 mg of iodine, 0.67 mg of manganese, 13.33 ug of chromium, 50 ug of iodine, and 18.33 ug of selenium.

[0292] Pour the contents of one packet (10g) into a glass, add water (approximately 150ml), and stir until completely dissolved. Each patient took it three times a day, immediately before meals. Specifically, it was taken about 20 minutes before each main meal (breakfast, lunch, and dinner).

[0293] [Table 11]

[0294] result: 80% of patients, including those who presented with cachexia at the start of the study, showed stabilization or increase in weight compared to baseline.

[0295] In 56% of patients receiving chemotherapy, gastrointestinal side effects (nausea, vomiting, diarrhea) were reduced or eliminated. Asthenia was one of the parameters that showed the most improvement throughout the study. Although not included in the study parameters, 71% of treated patients had a life expectancy that was higher than expected for their stage of the disease. Partial or complete radiological response to the lesions was observed in 23% of patients.

[0296] For statistical evaluation, the McNemar test was used for paired data with continuity correction applied. For this purpose, patient improvement was considered to have been observed when the standard error of the mean (SEM) exceeded Cronbach's alpha value. Table 12 summarizes the significance data for each scale. All scales were confirmed to be statistically significant.

[0297] [Table 12]

[0298] Treatment was associated with statistically significant improvements in all questionnaire scales except for cognitive function (CO), dyspnea (DY), and constipation / diarrhea (FC) binary classification. The scales showing the highest significance levels were the physical (PF) and role (RF) scales, as well as the symptoms of fatigue (AF) and loss of appetite (PA).

[0299] During the study period, 97% of patients showed significant improvement in quality of life (above Cronbach's alpha) compared to their baseline status before the study began. This was observed in some functional assessment scales or symptom items of the questionnaire. The mean improvement was 34 points, which is considered a very significant improvement according to the EORTC-QLQ-C30 questionnaire validation clinical trial (https: / / qol.eortc.org / questionnaire / eortc-qlq-c30 / ). To determine if a patient had improved in each functional scale or symptom, SEM and Cronbach's alpha were estimated, and improvement was recognized if the score exceeded the alpha value for that scale.

[0300] Furthermore, 62% of patients showed an improvement of 33 points in their overall assessment of the questionnaire, which is also considered a significant improvement.

[0301] The symptom and function scales with the highest improvement rates among patients were fatigue (76%), sleep disturbances (56%), and appetite (53%), which were associated with significant improvements in physical (56%) and emotional (56%) scales. Dyspnea, on the other hand, improved in 26% of patients, and this group showed the highest improvement rate in the entire study, with an average score of 56 points (minimum 33 points, maximum 100 points). The other two symptoms showing improvement rates of 50 points or more were diarrhea and constipation. Nausea and vomiting improved in more than one-third of patients (38%), with a significant improvement of approximately 30 points on average.

[0302] All of these figures were higher at week 12 in patients who continued treatment and voluntarily submitted questionnaires after the study ended at 8 weeks.

[0303] The magnitude of change in each scale included in the questionnaire was estimated using effect size (ES), standardized mean response (SMR), minimum importance difference (MID), or minimum clinical importance difference (MCID).

[0304] Effect size (ES) was calculated by dividing the difference in mean response values ​​observed before and after drug intervention (8 weeks of administration) by the standard deviation observed at baseline. Standardized mean response (SMR) was calculated by dividing the mean change between the first and last visits by the standard deviation of that change. The baseline values ​​for SMR as a measure of effect (the well-known Cohen threshold) are as follows: 1. Insignificant effect: SMR < 0.20 2. Small effect: SMR > 0.20 < 0.50 3. Moderate effect: SMR > 0.5 < 0.8 4. Significant effect: SMR > 0.80

[0305] As can be seen from the table, except for cognitive and social functions in the functional scale and diarrhea and dyspnea in the symptom scale, the magnitude of the effect is moderate or large in all scales. As described above, this is related to the significance level of each scale. Although the data at the 12-week point have not been evaluated in this study, it should be noted that the effect becomes larger in most scales. This indicates that it can be predicted that the longer the treatment period, the greater the impact of the effect. As is clear from the results, since almost no side effects are observed even when the present composition is administered for a long period (three times a day for at least 12 weeks), the present invention is extremely safe.

[0306]

Table 13

[0307] To calculate the minimal important difference, the standard error of the mean (SEM) was calculated and the reliability of the scale was estimated using Cronbach's alpha coefficient. Based on the difference between the SEM and the baseline score and the final score of each scale, it was classified into three groups: improvement (d > SEM), no change (d = ±SEM), and deterioration (d < SEM) (see Table 14).

[0308]

Table 14

[0309] Conclusion: Treatment with the postbiotic composition of the present invention shows a statistically significant association (p < 0.01 to p < 0.005) with improvement in the quality of life (EORTC questionnaire QLQ-C30) of patients with advanced cancer including colorectal cancer and / or lung cancer. The magnitude of the effect is important or very important in most of the scales analyzed. The most significantly improved symptoms are fatigue, appetite, pain, and sleep disorder. Although dyspnea and diarrhea did not show a significant association, they were the symptoms with the greatest magnitude of the effect on treatment. Treatment with the composition of the present invention improved the tolerance of chemotherapy and enabled the re-administration of chemotherapy to patients who had discontinued treatment due to its toxicity.

[0310] In conclusion, the present invention demonstrates that the disclosed postbiotic composition, administered to patients with terminal cancer including terminal colorectal cancer and / or lung cancer, is associated with improvements in quality of life, resistance to chemotherapy, asthenia, and cachexia. These beneficial effects mean an extension of the patient's life expectancy.

Claims

1. A postbiotic composition for oral administration, comprising the following amounts of probiotic microbial lysates in weight percentage of the total weight of microbial lysates in the composition: - 15% to 17% bacterial lysates of Bacillus licheniformis, Bacillus mesentericus, Bacillus subtilis, Bacillus clausii, and Bacillus coagulans, where the weight percentages of Bacillus licheniformis, Bacillus pumilus, and Bacillus subtilis are the same; and the weight percentages of Bacillus clausii and Bacillus coagulans are higher, and these are approximately the same. - 4.6% to 6% bacterial lysate of Bifidobacterium lactis; - Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus reuteri The bacterial lysates of Lactobacillus fermentum, Lactobacillus reuteri, Lactobacillus rhamnosus, and Lactobacillus bulgaricus accounted for 20.5% to 21.8%, where the weight percentage of Lactobacillus casei was higher than that of Lactobacillus acidophilus, the weight percentage of Lactobacillus acidophilus was higher than that of Lactobacillus bulgaricus, and the weight percentage of Lactobacillus bulgaricus was higher than that of Lactobacillus fermentum and Lactobacillus reuteri. It surpasses *Lactobacillus reuteri* and *Lactobacillus rhamnosus*, and the weight percentages of these three strains are similar; - 54% to 56% yeast lysate of Saccharomyces cerevisiae; - Streptococcus thermophilus bacterial lysates: 2.8% to 3.2% Postbiotic compositions for use in the treatment of solid tumors.

2. A postbiotic composition for use according to claim 1, comprising, in weight percentage of the total weight of the lysates of the microorganisms in the composition, the following amounts of probiotic microbial lysates: - 15% to 17% bacterial lysates of Bacillus licheniformis, Bacillus mesentericus, Bacillus subtilis, Bacillus clausii, and Bacillus coagulans, where the weight percentages of Bacillus licheniformis, Bacillus pumilus, and Bacillus subtilis are the same; the weight percentage of Bacillus clausii is 0.3% and the weight percentage of Bacillus coagulans is 0.3%. - 4.6% to 6% bacterial lysate of Bifidobacterium lactis; - Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus reuteri The bacterial lysates of Lactobacillus reuteri, Lactobacillus rhamnosus, and Lactobacillus bulgaricus accounted for 20.5% to 21.8%, where the weight percentage of Lactobacillus casei was higher than that of Lactobacillus acidophilus, the weight percentage of Lactobacillus acidophilus was higher than that of Lactobacillus bulgaricus, and the weight percentage of Lactobacillus bulgaricus was higher than that of Lactobacillus fermentum Lactobacillus It surpasses *Lactobacillus reuteri* and *Lactobacillus rhamnosus*, and the weight percentages of these three strains are similar; - 54% to 56% yeast lysate of Saccharomyces cerevisiae; - Streptococcus thermophilus bacterial lysates: 2.8% to 3.2% Postbiotic composition.

3. A postbiotic composition for use according to any of the preceding claims, comprising, in weight percentage of the total weight of microbial lysates of the composition, the following amounts of probiotic microbial lysates: - Bacterial lysates of Bacillus licheniformis, Bacillus mesentericus, Bacillus subtilis, Bacillus clausii, and Bacillus coagulans, where the weight percentages of Bacillus licheniformis, Bacillus pumilus, and Bacillus subtilis are the same; the weight percentage of Bacillus licheniformis is 5%, the weight percentage of Bacillus mesentericus is 5%, and the weight percentage of Bacillus subtilis is 5%. The weight percentage of Bacillus subtilis is 5%, the weight percentage of Bacillus clausii is 0.3%, and the weight percentage of Bacillus coagulans is 0.3%. - 4.6% to 6% bacterial lysate of Bifidobacterium lactis; - Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus reuteri The bacterial lysates of Lactobacillus reuteri, Lactobacillus rhamnosus, and Lactobacillus bulgaricus accounted for 20.5% to 21.8%, where the weight percentage of Lactobacillus casei was higher than that of Lactobacillus acidophilus, the weight percentage of Lactobacillus acidophilus was higher than that of Lactobacillus bulgaricus, and the weight percentage of Lactobacillus bulgaricus was higher than that of Lactobacillus fermentum and Lactobacillus reuteri. It surpasses *Lactobacillus reuteri* and *Lactobacillus rhamnosus*, and the weight percentages of these three strains are similar; - 54% to 56% yeast lysate of Saccharomyces cerevisiae; - Streptococcus thermophilus bacterial lysates: 2.8% to 3.2% Postbiotic composition.

4. A postbiotic composition for use according to claim 1, comprising, in weight percentage of the total weight of microbial lysates of the composition, the following amounts of probiotic microbial lysates: - 4% to 6% bacterial lysates of Bacillus licheniformis, - 4% to 6% bacterial lysates of Bacillus mesentericus, - 4% to 6% bacterial lysates of Bacillus subtilis, - Bacillus clausii bacterial lysates 0.1% to 0.5% - 0.1% to 0.5% bacterial lysate of Bacillus coagulans, Here, the total amount of bacterial lysates from Bacillus genera species is between 15% and 17% by weight. - 4.6% to 6% bacterial lysate of Bifidobacterium lactis; - 4% to 6% bacterial lysate of Lactobacillus casei; - 2.7% to 4.7% bacterial lysate of Lactobacillus acidophilus; - 2.6% to 4.6% bacterial lysate of Lactobacillus bulgaricus; - 2% to 4% bacterial lysate of Lactobacillus fermentum; - 2% to 4% bacterial lysate of Lactobacillus reuteri; - 2% to 4% bacterial lysate of Lactobacillus rhamnosus; Here, the total amount of bacterial lysates from Bacillus species is between 20.5% and 21.8% by weight. - 54% to 56% yeast lysate of Saccharomyces cerevisiae. - 2.8% to 3.2% of bacterial lysates from Streptococcus thermophilus; Postbiotic composition.

5. A postbiotic composition for use according to any of the preceding claims, comprising, in weight percentage of the total weight of microbial lysates of the composition, the following amounts of probiotic microbial lysates: - 5% bacterial lysate of Bacillus licheniformis; - 5% bacterial lysate of Bacillus mesentericus; - 5% bacterial lysate of Bacillus subtilis; - 0.3% bacterial lysate of Bacillus clausii; - 0.3% bacterial lysate of Bacillus coagulans; - 5% bacterial lysate of Bifidobacterium lactis; - 5% bacterial lysate of Lactobacillus casei; - 3.7% bacterial lysate of Lactobacillus acidophilus; - 3.6% bacterial lysate of Lactobacillus bulgaricus; - 3% bacterial lysate of Lactobacillus fermentum; — 3% bacterial lysate of Lactobacillus reuteri; - 3% bacterial lysate of Lactobacillus rhamnosus; - 55% lysate of Saccharomyces cerevisiae; - 3% bacterial lysate of Streptococcus thermophilus; Postbiotic composition.

6. A postbiotic composition for use according to any of the prior claims, wherein the solid tumor is selected from colorectal cancer and / or lung cancer.

7. A postbiotic composition for use according to any one of the preceding claims 1 to 5, wherein the solid tumor is selected from prostate cancer, breast cancer, central nervous system (CNS) cancer, pancreatic cancer, esophageal cancer, uterine cancer, lymphoma, pheochromocytoma and / or sarcoma.

8. A postbiotic composition for use according to any of the preceding claims, which does not contain bacterial lysates of the genera Akkermansia, Enterococcus, and Escherichia.

9. A postbiotic composition for use according to any of the preceding claims, comprising one or more of the following additives: resveratrol, astaxanthin, bromelain, papain, fermented rice starch, corn starch, and FOS.

10. A postbiotic composition for use according to any of the prior claims, wherein the treatment of the solid tumor includes improving the patient's quality of life.

11. A postbiotic composition according to a prior claim, wherein the improvement in quality of life relates to one or more of the following symptoms: anxiety, fatigue, nausea, vomiting, pain, sleep disturbance, stress, asthenia, appetite, pain, shortness of breath, and diarrhea.

12. A postbiotic composition for use according to any of the prior claims, wherein the patient is a terminally ill cancer patient.

13. A postbiotic composition for use according to any of the preceding claims, wherein the composition is administered in an amount of 100 mg to 700 mg per dose, once to six times per day for at least two weeks.

14. A postbiotic composition according to any of the preceding claims, wherein the treatment is administered before, concurrently with, or after treatment of a patient with chemotherapy or radiotherapy.

15. A pharmaceutical composition comprising an effective pharmacological amount of the composition according to any one of claims 1 to 14 and a pharmaceutically acceptable excipient for use in the treatment of solid tumors.

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