Immunomodulatory compositions comprising microbial entities

Abstract

This disclosure provides for compositions (e.g., pharmaceutical compositions, dietary supplements, medical foods and food stuff), comprising combinations of live microbe populations for the treatment and/or prevention of immune system disorders and conditions related to inflammation, including both pathogen assisted conditions and conditions that are independent of pathogens. Included with the present disclosure are methods for use of the compositions, and methods for selecting microbial entities to formulate the compositions of the disclosure.

1 . A method of improving immune health, comprising administering to a human subject an effective amount of a composition comprising viable microbes, comprising:
 (xvii) a first microbial entity comprising a first bacterial population comprising  Lactobacillus brevis;      (xviii) a second microbial entity comprising a second bacterial population comprising  Lactococcus lactis;      (xix) a third microbial entity comprising a third bacterial population comprising  Bacillus velenzensis ; and   (xx) a fourth microbial entity comprising a fourth bacterial population comprising  Lactobacillus harbinensis.      
     
     
         2 . A method of improving immune health, comprising administering to a human subject an effective amount of a composition comprising:
 (i) a first microbial entity comprising a first bacterial species comprising a 16S rDNA sequence that is at least 97% identical to a 16S rDNA sequence set forth in SEQ ID NO: 43;   (ii) a second microbial entity comprising a second bacterial species comprising a 16S rDNA sequence that is at least 97% identical to a 16S rDNA sequence set forth in SEQ ID NO: 285;   (iii) a third microbial entity comprising a third bacterial species comprising a 16S rDNA sequence that is at least 97% identical to a 16S rDNA sequence set forth in SEQ ID NO: 284; and   (iv) a fourth microbial entity comprising a fourth bacterial species comprising a 16S rDNA sequence that is at least 97% identical to a 16S rDNA sequence set forth in SEQ ID NO: 286.   
     
     
         3 . The method of  claim 1 , wherein the composition comprises a medical food, nutritional supplement or food stuff. 
     
     
         4 . The method of  claim 1 , wherein the composition comprises a pharmaceutical composition. 
     
     
         5 . The method of  claim 2 , wherein the composition comprises a medical food, nutritional supplement or food stuff. 
     
     
         6 . The method of  claim 2 , wherein the composition comprises a pharmaceutical composition. 
     
     
         7 . The method of  claim 1 , wherein the viable microbes are plant-derived or food-derived. 
     
     
         8 . The method of  claim 2 , wherein the viable microbes are plant-derived or food-derived. 
     
     
         9 . The method of  claim 1 , wherein improving immune health comprises reducing inflammation in the human subject. 
     
     
         10 . A method of inhibiting inflammation in a human subject, the method comprising:
 administering to a human subject an effective amount of a composition comprising:
 (i) a first microbial entity comprising a first bacterial species comprising n 16S rDNA sequence that is at least 97% identical to a 16S rDNA sequence set forth in SEQ ID NO: 43 
 (ii) a second microbial entity comprising a second bacterial species comprising n 16S rDNA sequence that is at least 97% identical to an 16S rDNA sequence set forth in SEQ ID NO: 285; 
 (iii) a third microbial entity comprising a third bacterial species comprising n 16S rDNA sequence that is at least 97% identical to an 16S rDNA sequence set forth in SEQ ID NO: 284; and 
 (iv) a fourth microbial entity comprising a fourth bacterial species comprising n 16S rDNA sequence that is at least 97% identical to an 16S rDNA sequence set forth in SEQ ID NO: 286; wherein the human subject has lower circulating levels of at least one anti-inflammatory marker and/or higher circulating levels of at least one inflammation-associated marker; and/or wherein the method results in higher circulating levels of at least one anti-inflammatory marker and/or lower circulating levels of at least one inflammation-associated marker. 
   
     
     
         11 . The method of  claim 2 , wherein the composition is capable of producing neurotransmitters selected from the group consisting of serotonin, gamma-aminobutyric acid (GABA), dopamine, acetylcholine, and combinations thereof. 
     
     
         12 . The method of  claim 2 , wherein the composition is capable of modulating IFNγ, IL-12, TNF-α, IL-17, IL-6, IL-1β, IL-10 or combinations thereof in the human subject. 
     
     
         13 . The method of  claim 2 , wherein at least one microbial entity comprises a first genome; wherein the first genome comprises at least one functional expression sequence at least about 30% identical to a functional expression sequence selected from Table 5 or Table 6. 
     
     
         14 . The method of  claim 2 , wherein at least one microbial entity is capable of producing an enzyme having an amino acid sequence at least 60% identical to an enzyme selected from Table 5 or an enzyme capable of acting on the same substrate as an enzyme having an amino acid sequence at least 60% identical to an enzyme selected from Table 5 or 6. 
     
     
         15 . The method of  claim 2 , wherein at least one microbial entity comprises a genus of bacteria with a metabolic signature or functionality selected from Tables 5 or 7. 
     
     
         16 . The method of  claim 1 , wherein at least one microbial entity comprises one or more features selected from the group consisting of:
 (i) capable of engrafting when administered to a subject,   (ii) capable of having anti-inflammatory activity,   (iii) not capable of inducing pro-inflammatory activity,   (iv) capable of producing a secondary bile acid,   (v) capable of producing a tryptophan metabolite,   (vi) capable of restoring epithelial integrity as determined by a primary epithelial cell monolayer barrier integrity assay,   (vii) capable of being associated with remission of an inflammatory bowel disease,   (viii) capable of producing a short-chain fatty acid,   (ix) capable of inhibiting a histone deacetylase (HDAC) activity,   (x) capable of producing a medium-chain fatty acid,   (xi) capable of expressing catalase activity,   (xii) capable of having alpha-fucosidase activity,   (xiii) capable of inducing Wnt activation,   (xiv) capable of producing a B vitamin,   (xv) capable of modulating host metabolism of endocannabinoid,   (xvi) capable of producing a polyamine and/or modulating a host metabolism of a polyamine,   (xvii) capable of reducing fecal levels of a sphingolipid,   (xviii) capable of modulating host production of kynurenine and/or capable of producing kynurenine,   (xix) capable of reducing fecal calprotectin level,   (xx) not capable of activating a pattern recognition receptor (PRR) pathway, and optionally, a toll-like receptor (TLR) pathway, a NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome pathway, or a C-type lectin receptor pathway and combinations thereof,   (xxi) capable of activating a PRR pathway, and optionally a TLR pathway, a NLRP3 pathway a C-type lectin receptor pathway, and combinations thereof,   (xxii) not capable of producing ursodeoxycholic acid,   (xxiii) capable of not being associated with clinical non-remission of an inflammatory bowel disease,   (xxiv) capable of inhibiting apoptosis of intestinal epithelial cells,   (xxv) capable of inducing an increased anti-inflammatory Interleukin (IL)-10/IL-6 cytokine ratio in macrophages,   (xxvi) capable of not inducing pro-inflammatory IL-6, Tumor Necrosis Factor Alpha (TNFα), IL-1β, IL-23 or IL-12 production or gene expression in macrophages,   (xxvii) capable of downmodulating one or more genes induced in Interferon gamma (IFN-γ) treated colonic organoids,   (xxix) capable of producing IL-18,   (xxx) capable of inducing the activation of antigen presenting cells,   (xxxi) capable of reducing the expression of one or more inhibitory receptors on T cells,   (xxxii) capable of increasing expression of one or more genes/proteins associated with T cell activation and/or function,   (xxxiii) capable of enhancing the ability of CD8+ T cells to kill tumor cells,   (xxxiv) capable of enhancing the efficacy of an immune checkpoint inhibitor therapy, (xxxv) capable of reducing colonic inflammation,   (xxxvi) capable of promoting the recruitment of CD8+ T cells to tumors, and combinations thereof, and   (xxxvii) capable of producing antioxidants, and optionally, flavonoids, terpenoids, acorbate, and combinations thereof.   
     
     
         17 . The method of  claim 13 , wherein the not activating a toll-like receptor pathway comprises no activation of TLR4 or TLR5, and/or wherein the activating a toll-like receptor pathway comprises activation of TLR2. 
     
     
         18 . The method of  claim 13 , wherein the one or more genes induced in IFN-γ treated colonic organoids, is selected from the group consisting of genes associated with inflammatory chemokine signaling, Nuclear Factor Kappa B (NF-κB) signaling, TNF family signaling, type I interferon signaling, type II interferon signaling, TLR signaling, lymphocyte trafficking, Th17 cell differentiation, Th1 differentiation, Th2 differentiation, apoptosis, inflammasomes, autophagy, oxidative stress, major histocompatibility (MHC) class I and II antigen presentation, complement, mTor, nod-like receptor signaling, Phosphatidylinositol-4,5-Bisphosphate 3-Kinase (PI3K) signaling, and combinations thereof. 
     
     
         19 . The method of  claim 16 , wherein the one or more inhibitory receptors on T cells is selected from the group consisting of T Cell Immunoreceptor With Ig And ITIM Domains (TIGIT), T-Cell Immunoglobulin Mucin Family Member 3 (TIM-3), Lymphocyte Activating 3 (LAG-3), and combinations thereof. 
     
     
         20 . The method of  claim 16 , wherein the one or more genes or proteins associated with T cell activation and/or function is selected from the group consisting of CD45RO, CD69, IL-24, TNF-α, perforin, IFN-γ, and combinations thereof. 
     
     
         21 . The method of  claim 2 , wherein at least one microbial entity is capable of producing (a) one or more indole-containing compounds, optionally wherein the indole-containing compound is selected from the group consisting of indole, indole acetic acid (IAA), and indole propionic acid (IPA) and/or (b) bacteriocins and/or antibacterial peptides and/or (c) a biosurfactant that reduces pro-inflammatory cytokines. 
     
     
         22 . The method of  claim 2 , wherein at least one microbial entity metabolizes human produced primary bile acids into secondary bile acids, optionally wherein the primary bile acid is cholic acid, chenodeoxycholic acid, or combinations thereof, and optionally wherein the secondary bile acid inhibits FXR and/or activates TGR5. 
     
     
         23 . The method of  claim 2 , wherein at least one microbial entity produces more omega-3 fatty acids compared to omega-6 fatty acids. 
     
     
         24 . The method of  claim 2 , wherein at least one microbial entity comprises one or more bacteria that are capable of producing a metabolite selected from Table 5 or Table 7. 
     
     
         25 . The method of  claim 2 , wherein the composition further comprises a metabolite selected from Table 5 or Table 7. 
     
     
         26 . The method of  claim 2 , the composition further comprises a prebiotic fiber. 
     
     
         27 . The method of  claim 2 , wherein the inhibition of inflammation in the subject is caused by the production at least one anti-inflammatory metabolite by at least one microbial entity. 
     
     
         28 . The method of  claim 2 , wherein the method reduces the level and/or activity of at least one inflammatory cytokine from Table 8 relative to a level and/or activity of the inflammatory cytokine in the serum of the human subject; or a tissue of the subject, prior to administering the pharmaceutical composition, medical food, or solid food. 
     
     
         29 . The method of  claim 2 , wherein the method comprises treating, preventing or reducing the severity of at least one symptom of an immune system disorder. 
     
     
         30 . The method of  claim 29 , wherein the immune system disorder is selected from the group consisting of allergic rhinitis, allergic conjunctivitis, allergic bronchial asthma, atopic eczema, anaphylaxis, insect sting, drug allergy, food allergy, asthma, eczema, a disorder or condition associated with a pathological Th17 activity, and a rheumatic disease selected from spondyloarthritis, psoriasis and rheumatoid arthritis.