There is increasing recognition of the role the microbiome plays in states of health and disease. and/or direct effects on immune responses. has an inhibitory effect on Th17 cells, segmented filamentous bacteria (SFB) have a well-documented ability to promote a Th17 response (17C19). This response is dependent on SFB adherence to intestinal epithelial cells (20) via cell wall glycopolymers which are common to gram-positive bacteria (21); however adherent gram-negative bacteria are also capable of inducing Th17 responses (20). Furthermore, coinfection with SFB and generated Th17 and Th1 cells, respectively, demonstrating an important concept that individual bacteria can elicit specific immune cell responses (22). Colonic Tregs are also capable of undergoing expansion in response to certain bacterial species. For example, a cocktail of Clostridial strains isolated from healthy human fecal Tandospirone samples reduced features of TNBS-associated colitis and allergic diarrhea models via Treg upregulation (23, 24). In the intestines, B cells primarily localize to the lamina propria (LP). LP B cells were found to express and DNA polymerase, characteristics of pro-B cells, which suggests that B cell development may occur in the gut (25). Interestingly, colonized germ free mice (by weaning with specific pathogen free mice for 7 days) had significantly increased and genus is the most prevalent in the gut (32). Polysaccharide A (PsA), a component of the cell wall, has been widely studied. PsA induces IL-10 production by intestinal T cells, possibly via Tandospirone ligation of TLR2 on plasmacytoid dendritic cells (33). Induction of regulatory T cells (Treg) was shown to be dependent on IL-10-producing B cells, and protected against herpes encephalitis (29). Corresponding with this immunoregulatory response, PsA inhibits Th17 cell expansion, while a modified that lacks PsA loses the ability to induce IL-10 production and becomes proinflammatory (34, 35). As discussed, the literature supports that microbiota promote both humoral immunity (B cell development and proinflammatory T cell responses) as well as immune regulation (regulatory B and T cells). In MS, multiple studies have shown that disease improves with B cell depletion (rituximab, anti-CD20), yet is exacerbated by neutralization of a B cell growth factor (atacicept, TACI-Ig) [reviewed in (36)]. It can be inferred from these data that there are disease-promoting and disease-fighting B cell subsets, and that it is possible that these specific cell subsets are differentially influenced by microbial influences. Metabolites produced by intestinal bacteria (e.g., short chain fatty acids, lipids, vitamins) also play an important role in immune modulation [reviewed by (37, 38)]. Short chain fatty acids (SCFA; e.g., butyrate, acetate, propionate) are byproducts of dietary fiber fermentation in the large intestine. In general, the Bacteroidetes phylum primarily produce acetate and propionate, TGFB1 whereas the Firmicutes phylum mainly produce butyrate (39), though this is a simplification. Butyrate and propionate, but not acetate, were shown to promote extrathymic Treg differentiation (40, 41). Tandospirone Additionally, butyrate leads to a downregulation of LPS-induced proinflammatory cytokine production (i.e., NO, IL-6, IL-12) by intestinal macrophages (42), further supporting butyrate as an anti-inflammatory metabolite. There is also increasing data suggesting that SCFAs help maintain blood-brain barrier integrity (43) which is believed to contribute to neurologic conditions including MS that are being increasingly associated with the gut [reviewed in (38)]. Secondary bile acids (i.e., deoxycholic acid and lithocholic acid) are converted from primary bile acids by colonic bacteria. Activation of bile acid activated receptors by secondary bile acids triggers an anti-inflammatory response characterized by increases in gene expression, and suppression of NF-kB mediated expression of proinflammatory cytokines (and (phylum: Bacteroidetes), and (phylum: Firmicutes), and an increased representation of (phylum: Actinobacteria) and (phylum: Firmicutes) genera in MS patients with and without ongoing therapy (Table 1). Table 1 Overview of identified bacteria of significant enrichment or depletion in autoimmune human gut microbiome studies compared to healthy gut microbiota. ??????Bifidobacterium (55)Bacteroidetes??????(56)Euryarchaeota??????(57)Firmicutes??????(57)??????(56)??????(56)??????(55)Proteobacteria??????(56)??????(56)??????(58) Verrucomicrobia??????????????????(66)??????(67)??????(67)??????Firmicutes??????(67)??????(67)??????(67)Actinobacteria??????(72)??????(72)Bacteroidetes??????(72)??????(73)??????(73)??????(73)Firmicutes??????(73)??????(73)Proteobacteria??????(72)DepletionActinobacteria??????(56)??????(56)Bacteroidetes??????(57)??????(55, 57)??????(57)??????(56)??????Firmicutes??????(55)??????(55)??????(56)Proteobacteria??????(56)Firmicutes??????Bacteroidetes??????(76)Actinobacteria??????(67)Bacteroidetes??????spp. (67)Firmicutes??????(67)Proteobacteria??????spp. (67)??????(67)Firmicutes??????(72)??????(72)??????(73)??????(73)??????(73)??????(73)(phylum: Proteobacteria), and (phylum: Firmicutes), and (phylum: Bacteroidetes); whereas healthy controls showed Tandospirone enrichment with and (phylum: Actinobacteria), (phylum: Firmicutes) and (phylum: Bacteriodetes) (56) (Table 1). In contrast, an American study reported enrichment of (phylum: Euryarchaeota), (phylum: Verrucomicrobia), and (phylum: Firmicutes), and a reductions of (phylum: Bacteroidetes), (phylum: Bacteroidetes), (phylum: Actinobacteria), (phylum: Actinobacteria), (phylum: Bacteroidetes), and (phylum: Proteobacteria) in untreated MS patients compared to healthy controls (57) (Table 1). In this study it was shown that and were associated with the expression of proinflammatory genes, while associated with anti-inflammatory gene expression.