Immunity-modulating strain of lactobacillus rhamnosus

Abstract

An ingestible composition comprising Lactobacillus rhamnosus strain LMGP-33100 for use in modulating the immune system of a patient.

Description

[0001] IMMUNITY MODULATING STRAIN OF LACTOBACILLUS RHAMNOSUS

[0002] Technical field

[0003] The present invention relates to the use of the strain Lactobacillus rhamnosus LMGP-33100 for the modulation of the immune system, this strain being administered by ingestion.

[0004] Prior art

[0005] Symbiosis between a mammalian host and intestinal microbes occurs through a finely regulated system that can induce the destruction of a pathogen or conversely the tolerance of commensals. Indeed, continuous crosstalk between environmental signals and the immune system is essential to maintain local tissue homeostasis, and alterations in these signals (e.g., nutritional deficiencies or alterations in microbial composition; dysbiosis) can alter the composition and functionality of immune cells, leading, for example, to the development of allergies and an increased risk of infections.

[0006] For its normal development and behavior, the immune system thus critically depends on a wide range of microbial metabolites. This includes metabolites produced by bacteria from food components, metabolites produced by the host and biochemically modified by intestinal bacteria, and metabolites that are synthesized de novo by intestinal microbes. Among the metabolites produced by the microbiota / probiotics, organic acids such as short-chain fatty acids (SCFAs) or branched-chain SCFAs, but also specific bile acid derivatives are continuously produced by intestinal bacteria. In addition to their direct role in de novo nutrient production, SCFAs can bind to and activate specific G-protein-coupled receptors (FFAR2 and FFAR3, also called GPR43 and 41), which are receptors expressed in different cell types (e.g.,Immune cells such as Treg cells, endocrine cells and adipocytes). Thus, SCFAs produced by the intestinal microbiota are considered as messengers capable of modulating host immunity and metabolism.

[0007] In other words, several publications focus on the interactions between the intestinal microbiome and the immune system.

[0008] Among these, WO 2006 / 007526 describes the LGG strain of Lactobacillus rhamnosus, and its usefulness in the prevention or treatment of respiratory infections in infants potentially in synergy with bifidobacteria.

[0009] Unfortunately, although these documents describe the merits of their technology, there remains value in actively and simply enhancing a patient's immune response by providing selected microorganisms to the patient.

[0010] Brief summary of the invention

[0011] An ingestible composition comprising the strain Lactobacillus rhamnosus LMGP-33100 for use in modulating a patient's immune system, once ingested.

[0012] Preferably this ingestible composition comprises at least 10 7 CFU of Lactobacillus rhamnosus LMGP-33100 strain and / or a therapeutically effective content of Lactobacillus rhamnosus LMGP-33100 strain.

[0013] Preferably, this ingestible composition is administered at least once a day, preferably for at least 7 consecutive days.

[0014] Preferably, the Lactobacillus rhamnosus strain (LMGP- 33100) of this ingestible composition is encapsulated in a filler structure, preferably said filler structure comprising a polysaccharide, advantageously selected from the group consisting of alginate, chitosan, pectin, pullulan, carrageenan, agar or a combination thereof and / or encapsulated in an outer coating comprising alginate, chitosan, pectin, gelatin, pullulan, carrageenan, agar or a combination thereof.Preferably, the modulation of the immune system of this ingestible composition is the activation of the Th1 response in the patient, preferably following a viral infection and / or following a respiratory tract infection, and / or the activation of cellular immunity in the patient, preferably following a viral infection and / or following a respiratory tract infection, and / or the increased maturation of dendritic cells, and / or CD1 1 + immune cells, following an infection, preferably following a viral infection and / or following a respiratory tract infection.

[0015] Advantageously, the ingestible composition of the present invention is for the prevention of a viral infection and / or a respiratory tract infection in a patient.

[0016] Preferably, the ingestible composition of the present invention is not administered to a pregnant mammal, preferably not being administered to a pregnant woman.

[0017] Preferably, the ingestible composition of the present invention does not alter the intestinal microbiota of the patient.

[0018] Detailed description of an embodiment of the invention

[0019] The inventors found that administering the Lactobacillus rhamnosus LMGP-33100 strain to a patient does not alter their gut microbiome in any measurable or significant way. However, the inventors noted that the patient responds much better to infections, particularly viral infections and / or respiratory tract infections: the microbiota strengthened by the Lactobacillus rhamnosus LMGP-33100 strain becomes an initiator of good immunity.

[0020] The deposit under the Budapest Treaty of the strain LMGP-33100 was made on April 27, 2023 by Superbiotics SRL. Thus, a first aspect of the present invention relates to an ingestible composition comprising the strain Lactobacillus rhamnosus LMGP-33100 for its use in modulating the immune system of a patient, once ingested.

[0021] Preferably at least 10 7 CFU of the strain Lactobacillus rhamnosus LMGP-33100 is present in the composition for administration, preferably at least 10 8 CFU, or at least 10 9 CFU and / or an effective therapeutic content of the Lactobacillus rhamnosus LMGP-33100 strain. Indeed, depending on the patient's weight, the quantity should be adapted.

[0022] Preferably, this composition is administered at least once a day, preferably for at least 7 consecutive days, preferably for at least 30 consecutive days.

[0023] This allows the strain of the invention to exert its effect at the level of the intestine.

[0024] Advantageously, the Lactobacillus rhamnosus LMGP- 33100 strain is encapsulated in a filler structure, preferably comprising a polysaccharide, advantageously selected from the group consisting of alginate, chitosan, pectin, pullulan, carrageenan, agar or a combination thereof and / or is encapsulated in an outer coating comprising alginate, chitosan, pectin, gelatin, pullulan, carrageenan, agar or a combination thereof.

[0025] This ensures the proper conditioning of the strain and protects it as it passes through the patient's digestive tract.

[0026] Advantageously, the strain according to the invention ensures (reinforces) the activation of the Thl response in the patient, and / or the activation of cellular immunity, preferably following a viral infection and / or following a respiratory tract infection.

[0027] Preferably, the strain according to the invention accelerates and / or increases the maturation (allows accelerated and / or increased maturation) of dendritic cells following an infection, preferably following a viral infection and / or following a respiratory tract infection. For example, after a viral and / or respiratory tract infection, the proportion of CD45+CD64-Lin-MHC2+CD1 1 C+CD26+XCR1 +SIRPa- cells is greater (for example compared to CD1 1 + cells) following oral administration of the strain according to the invention. This proportion is estimated for example at the level of a sample from the patient, for example at the level of the spleen, preferably by biopsy, and / or the lung (biopsy, or even a sample of mucus or bronchoalveolar fluid).

[0028] Advantageously, the strain according to the invention is for the prevention of a viral infection and / or a respiratory tract infection in a patient.

[0029] According to an alternative, the strain according to the invention is not administered to a pregnant mammal, preferably is not administered to a pregnant woman.

[0030] Advantageously, the administration of the strain according to the invention to a patient does not alter their intestinal microbiota.

[0031] This is preferably measured using the criteria of alpha diversity (Shannon index and / or Faith's phylogenetic diversity and / or Pielou's evenness and / or ASV (amplicon sequence variant)) and / or beta diversity (e.g. Jaccard distance, preferably the percentage of bacteria that is not common to both conditions) and / or by verifying in a patient that the strain according to the invention is not present among the 10 most abundant strains of the intestinal microbiota (quantitative PCR or fluorescence or by CFU).

[0032] Other features and advantages of the present invention will be drawn from the following non-limiting description, and with reference to the drawings and examples. Examples.-

[0033] It is understood that the present invention is in no way limited to the embodiments described above and that many modifications may be made thereto without departing from the scope of the appended claims.

[0034] Example 1:

[0035] No measurable effect on the diversity of a mammal's microbiota.

[0036] A content of 10 8 CFU of encapsulated Lactobacillus rhamnosus LMGP-33100, or placebo, was administered orally to a cohort of 10- to 12-week-old C57BL / 6 mice for 15 days.

[0037] The inventors then compared microbiota diversity between treatment conditions vs. placebo, using alpha diversity (Pielou equilibrium, Faith phylogenetic diversity, and ASV) and beta diversity (Jaccard distance) criteria. Under these conditions, diversity indices were not altered, despite repeated supplementation with a specific bacterium capable of multiplying in the intestine.

[0038] Example 2: effect on viral and / or pulmonary load

[0039] Mice treated for 9 days as in Example 1 (test vs. placebo) were then inoculated nasally, under anesthesia, with 0.25 PFU of the Influenza HI NI virus (PR8 strain) while maintaining the administration of either the placebo or the protective bacterial strain, and the viral load was measured 3, 6 and 9 days after infection.

[0040] The inventors measured a significant decrease in viral load in the test condition, compared to the placebo.

[0041] Example 3: Effect on the immune system

[0042] By analyzing the cells and tissues of the mice of Example 2, the inventors noticed that the maturation of antigen-presenting cells, such as dendritic cells, for example the content of CD45+CD64-Lin-MHC2+CD1 lc+CD26+XCRl +SIRPa- dendritic cells was higher under the test conditions, compared to the placebo, both in the lungs and in the lymph nodes.

[0043] Similarly, the cytotoxic activity of the immune system is increased by administering the bacteria according to the invention (production of gamma interferon at the level of the pulmonary infection, percentage of pulmonary CD8 cells producing gamma interferon, recruitment of macrophages or NK cells).

[0044]

[0045] BUDAPEST TREATY ON THE INTERNATIONAL RECOGNITION OF THE DEPOSIT OF MICRO-ORGANISMS FOR THE PURPOSES OF PATENT PROCEDURE

Claims

CLAIMS 1. An ingestible composition comprising the strain Lactobaciiius rhamnosus LMGP-33100 for use in modulating a patient's immune system, once ingested.

2. The ingestible composition for use according to claim 1 comprising at least 10 7 CFU of Lactobacillus rhamnosus LMGP-33100 strain and / or a therapeutically effective content of Lactobacillus rhamnosus LMGP-33100 strain.

3. The ingestible composition for use according to claim 1 or 2 being administered at least once a day, preferably for at least 7 consecutive days.

4. The ingestible composition for use according to any one of the preceding claims, wherein the Lactobacillus rhamnosus strain LMGP-33100 is encapsulated in a filler structure, preferably said filler structure comprising a polysaccharide, advantageously selected from the group consisting of alginate, chitosan, pectin, pullulan, carrageenan, agar or a combination thereof and / or encapsulated in an outer coating comprising alginate, chitosan, pectin, gelatin, pullulan, carrageenan, agar or a combination thereof.

5. The ingestible composition for use according to any one of the preceding claims, wherein the modulation of the immune system is the activation of the Th1 response in the patient, preferably following a viral infection and / or following a respiratory tract infection.

6. The ingestible composition for use according to any one of the preceding claims, wherein the modulation of the immune system is the activation of cellular immunity in the patient, preferably following a viral infection and / or following a respiratory tract infection.

7. The ingestible composition for use according to any one of the preceding claims, wherein the modulation of the immune system is the increased maturation of dendritic cells, and / or CD1 1 + immune cells, following an infection, preferably following a viral infection and / or following a respiratory tract infection.

8. The ingestible composition for use according to any one of the preceding claims 1 to 4, being for the prevention of a viral infection and / or a respiratory tract infection in a patient.

9. The ingestible composition for use according to any one of the preceding claims, not being administered to a pregnant mammal, preferably not being administered to a pregnant woman.

10. The ingestible composition for use according to any one of the preceding claims, not altering the intestinal microbiota of the patient.

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