Table 2.
Gut and oral bacterial species associated with autoimmune disorders.
| Disease Group | Autoimmune Disorder | Bacterial Species | Classification | Tissue Localization | Disease Association | Target Cell Type | Mechanisms [Refs] | Clinical Associations [Refs] | Animal Studies [Refs] |
|---|---|---|---|---|---|---|---|---|---|
| Gut Axis | Inflammatory Bowel Disease (IBD) | Roseburia sp, Eubacterium sp.Ruminococcaceae spp., Lachnos piraceae spp., Faecalibacterium prausnitzii, | Commensal | Gut | Protective | DC and Treg | Bacteria produce SCFA playing a major role in modulation of inflammation, regulation of immune responses and maintenance of barrier integrity in the gut. Also promote expansion of Tregs and skew dendritic cells to prime IL-10 secreting T cells (22, 23, 24). | Decreased levels in IBD patients (62). | CD4+CD25+FoxP3+ T cell numbers increased in the lamina propria of mice treated with R. hominis. Treatment with the R. hominis bacterium provided protection against dextran sodium sulfate (DSS)-induced colitis (23). |
| Escherichia coli | Commensal | Gut | Pathogenic | Autoantibodies, Th1 and Tregs | Bacterial antigens induce anti-OmpC antibodies, Th1 cells and impaired CD4+IL-10+ cell responses, promoting intestinal inflammation (63–65). | Increased antibody responses against OpmC were associated with IBD severity. Imparied OmpC-specific IL10-producing CD4+ T cell responses were detected in blood of CD patients (63, 65). | Detected activated Th1 CD4+ T cells against E. coli antigens (64). | ||
| Ruminococcus gnavus | Commensal | Gut | Pathogenic | DC | Bacteria secrete a complex glucorhamnan polysaccharide inducing TNFα secretion by DCs through TLR4 signaling (66) | Higher levels of Ruminococcus gnavus detected in IBD patients often co-occurring with increased disease activity (67). | Germ-free mice colonized with an unencapsulated strain of R. gnavus show increased gut inflammation compared to an encapsulated strain, which stimulates a tolerogenic response in vivo (53). | ||
| B. vulgatus; B. sp. 4_3_47FAA;B. sp. 9_1_42FAA; B. sp. 3_1_33FAA; and B. dorei 5_1_36/D4 | Commensal | Gut | Protective | CD8+ | Gut microbial antigen recruits low avidity IGRP206-214/Kd specific CD8+ T cells to the gut, which then promote the killing of gut microbial mimic-loaded dendritic cells, precluding the activation of other T cell effectors (53). | Bacteroides integrase reactive CD8+ T cells present in PBMC of type 1 diabetic and Crohn´s disease patients (53). | Low avidity autoreactive IGRP 206-214/Kd-specific CD8+ T cells suppress experimental colitis (53). | ||
| Bacteriodes fragilis | Commensal | Gut | Protective | iNKT | Bacteria produce lipid antigens controlling homeostatic iNKT cell proliferation and activation, preserving gut integrity (34). | Higher B. fragilis prevalence associates with Crohn's disease exacerbations (69). | Treatment of mice with Bacteroides fragilis glycosphingolipids reduces colonic iNKT cell numbers and confers protection against oxazolone-induced colitis (34). | ||
| Autoimmune Gastritis (AIG) | Helicobacter pylori | Commensal | Gut | Pathogenic | Th1 | Bacterial antigens activate pro-inflammatory Th1 CD4+ T cells that recognize H+,K+–adenosine triphosphatase host proteins (55). | Identification of H+,K+–ATPase-specific CD4+ T cells that crossreact with Helycobacter pylori in AIG patients (55). | ||
| Brain/Optical - Gut Axis | Multiple Sclerosis (MS | Segmented filamentous bacteria (SFB) | Commensal | Gut | Pathogenic | Th1/Th17 and Treg | Bacteria promote Th17 pro-inflammatory responses (14, 15). | Detected increased levels of Firmicutes species in Relapsing vs. Non-relapsing - Remitting MS patients (70). | SFB colonized germ-free mice develop spontaneous EAE (71). |
| Bacteriodes fragilis | Commensal | Gut | Pathogenic | DC and Treg | Promotes induction of tolerogenic CD103+ DC and expansion of IL-10 FoxP3+ CD39+ CD4 Treg cells trough PSA-TLR2 signaling (31, 32). | Reduced levels of Bacteroides species have been detected in a small cohort of pediatric MS patients (72). Disease modifying therapy increased Bacteriodes content (73). | EAE protection mediated by oral PSA administration (31, 32). | ||
| Prevotella histicola | Commensal | Gut | Protective | DC, Treg and macrophages | Bacteria inhibit pro-inflammatory Th1 and Th17 cells and increase frequencies of CD4+FoxP3+ regulatory T cells, tolerogenic DC and suppressive macrophages (74). | Intestinal Th17 cell frequency is inversely related to the relative abundance of Prevotella strains in the human small intestine of MS patients (70). | Inhibits EAE in mice treated with the commensal bacteria (74). | ||
| Lactobacillus and Bifidobacterium spp. | Commensal | Gut | Protective | Treg | Bacteria promote Tregs, Th1/Th17 supporting autoreactive responses (75, 76). | In a randomized, double-blind, placebo-controlled trial, oral administration of commensals improved MS disease (77). | Bacterial administration in EAE mice show therapeutic activity (75, 76). | ||
| Escherichia coli | Commensal | Gut | Protective/Pathogenic | CD4+ and Treg | E.coli Nissle 1917 trigers the recruitment of anti-inflammatory, IL10-producing MOG-specific CD4+ T cells to the CNS (78). Bacterial molecular mimicry (56). | E.coli Nissle 1917 reduced the severity of EAE induced by immunization with the MOG 35 - 55 peptide (78). E.coli peptide activates and drives EAE in Ob TCR-DR2b mice (56). | |||
| Akkermansia spp. | Commensal | Gut | Pathogenic | CD4+ and Treg | Bacteria mimics guanosine diphosphate-L-fucose synthase sequence (79), and also induce impaired Treg responses (48). | Identification of cerebrospinal fluid-infiltrating cells in MS commensal levels also associate with MS disease (48). | Akkermansia association with MS was reported in a twin study where mice colonized with patient stool samples harbored Tregs producing lower levels of IL-10 (48). | ||
| Erysipelotrichaceae family and Lactobacillus reuteri | Commensal | Gut | Pathogenic | Th17 | Bacterial peptides mimic MOG40 - 48 epitope and induces Th17 polarization (58). | Co-colonization with both strains increased EAE severity (58). | |||
| Autoimmune uveitis | Undefined microbiota | Commensal | Gut | Pathogenic | Th1/Th17 | Bacteria mimics IRBP autoantigen (80) and also induce Th1/Th17 T cells (81). | R161H mouse model, which expresses the R161 TCR, recognize residues 161–180 of IRBP, a major uveitogenic epitope in B10.RIII mice. These cells can be activated by ommensal microbiota. In addition, germ-free C57BL/6 mice were resistant to experimental autoimmune uveitis (80). | ||
| Endocrine/Exocrine -Gut Axis | Primary Biliary Cholangitis (PBC) | E. coli | Commensal | Gut | Pathogenic | CD4+ | Bacteria mimic host PDC-E2 molecule (54). | Frequency of PDC-E2 163 - 176 reactive CD4+ T cells is significantly increased in peripheral blood of PBC patients as compared to healthy subjects (82). | CD4+CD25+FoxP3+ T cell numbers increased in the lamina propria of mice treated with R. hominis . Treatment with the R. hominis bacterium provided protection against dextran sodium sulfate (DSS)-induced colitis (23). |
| Type 1 Diabetes (T1D) | Ruminococcus gnavus | Commensal | Gut | Protective | CD8+ Treg | Bacteria induce CD8+CD122+ regulatory T cells (83). | Compared to healthy individuals, T1D patients have fewer CD8+ Treg cells in association with a lower prevalence of Ruminococcus (83). | Ruminococcus spp. are more abundant in parasite infected mice and seem to be responsible for the induction of CD8+ Treg cells and suppression of streptozotocin (STZ)-induced diabetes (83). | |
| F. prausnitzii | Commensal | Gut | Protective | DC and Treg | Produce SCFA, playing a major role in modulation of inflammation, regulation of immune responses, and maintenance of barrier integrity in the gut. Also promotes expansion of Tregs and skews dendritic cells to prime IL-10 producing T cells (22, 23, 28). | Decreased levels are detected in children with T1D-associated autoantibody seropositivity (84). | |||
| Systemic-Gut Axis | Systemic Lupus Erythematosus (SLE) | Enterococcus gallinarum | Pathobiont | Gut | Pathogenic | Th1/TFH and Antibodies | Bacteria induce Th17 and TFH responses supporting autoantibody responses (59). | Bacteria was found in liver biopsies of SLE patients, but not in healthy controls (59). | Antibiotic treatment decreases mortality in SLE mice by suppressing growth of E. gallinarum in tissues, as well as decreasing pathogenic autoantibodies and autoreactive T cells (59). |
| Bacteroides thetaiotaomicron | Commensal | Gut | Pathogenic | CD4+ and Antibodies | Bacteria mimic Ro60T, induce specific T and B cell responses (85). | Commensal-reactive T cell clones from SLE patients cross-react with human and bacterial Ro60 protein (85). | Monocolonization of germ-free mice with B. thetaiotaomicron triggers T and B cell responses against hRo60 (85). | ||
| Anti-Phospholipid Syndrome (APS) | Roseburia intestinalis | Commensal | Gut | Pathogenic | CD4+ and Antibodies | Bacteria mimics β2GP1 autoantigen (51). | CD4+ T cells that crossreact with commensal bacterial are detected in blood of APS patients (51). | ||
| Rheumatoid Arthritis (RA) | Segmented filamentous bacteria (SFB) | Commensal | Gut | Pathogenic | Th17 and Antibodies | Bacteria induce Th17 and antibody responses [86].Activation of auto-reactive/SFB epitope cross-reactive T cells expressing two TCRs (61). | Monocolonization with SFB triggers arthritis in germ-free K/BxN mice (86). SFB expand dual T cell receptor (TCR) - expressing Th17 cells recognizing both an SFB epitope and autoantigen in a model of autoimmune arthritis (61). | ||
| Porphyromonas gingivalis | Pathobiont | Gut | Pathogenic | Th17 and Antibodies | Bacteria induce specific antibodies and Th17 cell responses by TLR-2 signaling (87, 88). Also increase the antigen repertoire by protein citrullination (89). | Patients with RA have significantly higher titers of anti-P. gingivalis antibodies as compared to controls, albeit without any correlation with disease severity (88). | Periodontitis induced by bacteria significantly aggravated the severity of collagen-induced arthritis in mice (87). | ||
| Aggregatibacter actinomycetemcomitans | Commensal/Pathobiont | Gut | Pathogenic | Antibodies | Bacteria induce hypercitrullination in host neutrophils via pore- forming LtxA signaling, promoting autoantibody formation (60). | Exposure to Ltxa Aa strains was confirmed in patients with RA and was associated with increased titers of anti-citrullinated protein antibodies and rheumatoid factor (60). | Inhibits EAE in mice treated with the commensal bacteria (74). | ||
| Prevotella copri | Commensal | Gut | Pathogenic | Th17 | Bacterial molecules mimic RPL23A, and also induce Th17 cell responses (90). | Patients with early RA disease harbored intestinal microbiota dominated by P. copri (90). | SKG mice harboring microbiota from RA patients had an increased number of intestinal Th17 cells and developed severe arthritis after zymosan treatment. In addition, naive SKG mouse T cells co-cultured with P. copri -challenged dendritic cells produced IL-17 in response to RPL23A antigen and rapidly induced arthritis in mice (90). | ||
| Collinsella | Commensal | Gut | Pathogenic | Th17 | Collinsella correlated strongly with high levels of alpha- aminoadipic acid and asparagine as well as production of the proinflammatory cytokine IL-17A in RA patients (91). | A role for Collinsella in altering gut permeability and disease severity was confirmed in experimental arthritis (91). | |||
| Skin-Gut Axis | Psoriasis | Helicobacter pylori | Commensal/Pathobiont | Gut | Pathogenic | Th1/Th2 and Treg | Bacteria induce intestinal permeability, increasing antigen translocation across gut mucosa (92). The enterotoxin secreted by H. pylori polarizes Th1/Th2 responses and also decreases Treg cell frequencies (93). | H. pylori infection associates with progression of psoriatic disease (94). |
SCFA, short-chain fatty acids; Treg, regulatory T cell; OpmC, outer membrane porine C; TLR4, toll-like receptor 4; PBMC, peripheral blood mononuclear cell; iNKT, invariant natural killer T-cells; EAE, experimental autoimmune encephalomyelitis; DC, dendritic cells; PSA, polysaccharides A; CNS, central nervous system; MOG, myelin oligodendrocyte glycoprotein; IRBP, interphotoreceptor retinoid-binding protein; TCR, T cell receptor; PDC-E2, pyruvate dehydrogenase complex E2; Ro60T, RNA binding protein; β2GP1, Beta-2 glycoprotein I; RPL23A, arthritis-related autoantigen ribosomal protein L23a; Spp., specie; LtxA, toxin leukotoxin A.