Gut microbiota mediated T cells regulation and autoimmune diseases

Abstract

Gut microbiota regulates the immune system, the development and progression of autoimmune diseases (AIDs) and overall health. Recent studies have played a crucial part in understanding the specific role of different gut bacterial strains and their metabolites in different AIDs. Microbial signatures in AIDs are revealed by advanced sequencing and metabolomics studies. Microbes such as Faecalibacterium prausnitzii, Akkermansia muciniphila, Anaerostipes caccae, Bacteroides sp., Roseburia sp., Blautia sp., Blautia faecis, Clostridium lavalense, Christensenellaceae sp., Coprococcus sp., Firmicutes sp., Ruminococcaceae sp., Lachnospiraceae sp., Megamonas sp., Monoglobus sp., Streptococcus pneumoniae and Bifidobacterium sp. help maintain immune homeostasis; whereas, Prevotella copri, Ruminococcus gnavus, Lactobacillus salivarius, Enterococcus gallinarum, Elizabeth menigoseptica, Collinsella sp., Escherichia sp., Fusobacterium sp., Enterobacter ludwigii, Enterobacteriaceae sp., Proteobacteria, Porphyromonas gingivalis, Porphyromonas nigrescens, Dorea sp., and Clostridium sp. cause immuno-pathogenesis. A complex web of interactions is revealed by understanding the influence of gut microbiota on immune cells and various T cell subsets such as CD4+ T cells, CD8+ T cells, natural killer T cells, γδ T cells, etc. Certain AIDs, including rheumatoid arthritis, diabetes mellitus, atopic asthma, inflammatory bowel disease and non-alcoholic fatty liver disease exhibit a state of dysbiosis, characterized by alterations in microbial diversity and relative abundance of specific taxa. This review summarizes recent developments in understanding the role of certain microbiota composition in specific AIDs, and the factors affecting specific regulatory T cells through certain microbial metabolites and also focuses the potential application and therapeutic significance of gut microbiota-based interventions as novel adjunctive therapies for AIDs. Further research to determine the precise association of each gut bacterial strain in specific diseases is required.

Keywords: Anaerostipes caccae; Bacteroides sp.; Blautia faecis; Blautia sp.; Christensenellaceae sp.; Clostridium lavalense; Roseburia sp.; muciniphila.

Figure 1

The American Gut project is the largest crowdsourced citizen science project to date. Fecal, oral, skin, and other body site samples collected from thousands of participants represent the largest human microbiome cohort in existence. It is the PRJEB11419 project on NCBI (National Center for Biotechnology Information). In the PRJEB11419 project, a total of 1,053 samples were related to the phenotype of autoimmune diseases. In the GMrepo database, 553 samples were selected from the 1,053 samples for research, and 3,095 species and 1,016 genera were found. In figure, the top 50 species/genera of gut microbiota are selected in descending order based on the median relative abundance. (A) shows 50 species; (B) shows 50 genera. Abundance: mean/median relative abundance of a species/genus in all samples of autoimmune diseases.

Figure 2

Dysbiosis along with dysregulation of T cells leads to certain AIDs. Abbreviations include Type 1 Diabetes Mellitus (T1DM), Type 2 Diabetes Mellitus (T2DM), and Non-Alcoholic Fatty Liver Disease (NAFLD), Inflammatory Bowel Disease (IBD), Rheumatoid Arthritis (RA).

Figure 3

Highlights how gut pathogens and commensal bacteria can influence the gut immunity. Short-chain fatty acids (SCFAs) are involved in controlling immunological responses, including the activation of regulatory T cells (Treg). In pathogenic condition, SCFAs numbers are reduced which results in reduced activation of Treg cells. Furthermore, compromised gut barrier function facilitates the translocation of commensals and pathogens by inducing pro-inflammatory cytokines (IL-1β, IL-6, TNFα, INF-α, and INF-β) via dendritic cells (DC) and plasmacytoid dendritic cells (pDC). The TCR-MHCII contact on DCs activates naive T cells, which thereafter differentiate into diverse T helper cell subsets (Tfh, Th1, and Th17) and contribute to the gut’s immunological environment. Moreover, molecular mimicry is caused when microbial antigens structurally resemble the human autoantigens leading to B cell activation that use the assistance of Tfh cells to produces both protective sIgA and, in dysregulated states, pathogenic autoantibodies. In addition, impaired gut barrier facilitates the transfer of microbial antigens, which can result in immunological cross-reactions where T and B cells may mistakenly target host tissues by activating the T cell subsets and pro-inflammatory cytokines. These interactions highlight how the gut microbiome shapes autoimmune susceptibilities, especially in hosts who are genetically susceptible.

Figure 4

In both pathogenic and homeostatic settings, the microbiota is an essential factor in guiding T-cell differentiation. By using a bacterial product called PSA in a PSA-dependent pathway, B. fragilis promotes the growth of Th1-associated immune responses in germfree mice. Klebsiella and commensal A4 bacteria also induces Th1 cells. The proliferation of regulatory T (Treg) cells is encouraged by B. fragilis. By utilizing innate cells to produce either serum amyloid A (SAA) or adenosine 5′-triphosphate (ATP), SFB trigger a Th17 immune response. SFB also promotes the Tfh and Th2 cell production. Prevotella induces Th17 cells. Bafidobacterium produces SCFA, which stimulates the generation of Treg cells. Clostridium aids in the development of immunotolerance by promoting the production of Treg cells. Furthermore, within a particular tissue environment, systemic T cells can give rise to tissue-specific T cells through the activation of APCs by bacterial antigens.

Figure 5

The gut microbiota associated with six autoimmune diseases (RA, T1DM, T2DM, Asthma, IBD, NAFLD). The LDA scores less than 0 indicate Health enriched taxa, while LDA scores larger than 0 indicate autoimmune diseases enriched taxa. The length of the bar chart represents the significance of differential phenotypes. (A–C) show the top 40 gut microbiota with the highest LDA scores for RA, T2DM, and IBD, respectively. (D) shows the gut microbiota with LDA scores greater than 0 for T1DM, asthma, and NAFLD. Nr. samples: In GMrepo, manually curation was performed for selected NCBI BioProjects in order to group samples according to their corresponding phenotypes to obtain Nr. samples, and identify marker taxa between a pair of phenotypes of interests, e.g., RA vs. Health. The total Nr. sample size involved in figure is Rheumatoid arthritis (RA,N = 233;HC,N = 174), Type 1 diabetes mellitus (T1DM,N = 113;HC,N = 153), Type 2 diabetes mellitus (T2DM,N = 240;HC,N = 264), Asthma (asthma,N = 145;HC,N = 1,451), Inflammatory bowel disease (IBD,N = 241;HC,N = 126), Non-alcoholic fatty liver disease (NAFLD,N = 81;HC,N = 62).