Microbial dysbiosis in the gut drives systemic autoimmune diseases

Abstract

Trillions of microbes survive and thrive inside the human body. These tiny creatures are crucial to the development and maturation of our immune system and to maintain gut immune homeostasis. Microbial dysbiosis is the main driver of local inflammatory and autoimmune diseases such as colitis and inflammatory bowel diseases. Dysbiosis in the gut can also drive systemic autoimmune diseases such as type 1 diabetes, rheumatic arthritis, and multiple sclerosis. Gut microbes directly interact with the immune system by multiple mechanisms including modulation of the host microRNAs affecting gene expression at the post-transcriptional level or production of microbial metabolites that interact with cellular receptors such as TLRs and GPCRs. This interaction modulates crucial immune functions such as differentiation of lymphocytes, production of interleukins, or controlling the leakage of inflammatory molecules from the gut to the systemic circulation. In this review, we compile and analyze data to gain insights into the underpinning mechanisms mediating systemic autoimmune diseases. Understanding how gut microbes can trigger or protect from systemic autoimmune diseases is crucial to (1) tackle these diseases through diet or lifestyle modification, (2) develop new microbiome-based therapeutics such as prebiotics or probiotics, (3) identify diagnostic biomarkers to predict disease risk, and (4) observe and intervene with microbial population change with the flare-up of autoimmune responses. Considering the microbiome signature as a crucial player in systemic autoimmune diseases might hold a promise to turn these untreatable diseases into manageable or preventable ones.

Keywords: MS; SLE; T1D; arthrities; autoimmune diseases; dysbiosis; microbiome.

Figure 1

Microbial dysbiosis drives systemic inflammation by targeting the mucosal barrier. The illustration represents that, during microbial dysbiosis, the gut barrier is leaky, which results in diffusion of microbial metabolites such as lipopolysaccharides into the circulation, causing systemic inflammation. However, healthy microbiome has a balanced microbial composition including potential anti-inflammatory microbes such as Akkermansia muciniphilia and Faecalibacterium prausnitzii. These microbes or their metabolites activate TLRs leading to overexpression of tight junction proteins and prevent gut leakage. This leakage is thought to drive systemic inflammatory and autoimmune diseases such as insulin resistance and obesity.

Figure 2

The integral role of the balanced gut microbes in maintaining glucose level and suppressing hyperglycemia. The illustration shows the fundamental role of some representative gut microbes in glucose metabolism. The onset of T1D is characterized by a change in microbial composition characterized by decrease in specific taxa such as Bifidobacterium, Lactobacilli, Bacteroides, Faecalibacterium, and Akkermansia—while other taxa such as Fusobacterium is enriched. Bifidobacterium increases glucose uptake in heart, muscle, and liver tissues and stimulates glucagon synthesis. Lactobacilli stimulates cellular receptors involved in translocation of glucose, production of phosphatidyl inositol-3-phosphate, production of insulin receptor substrate, and suppression of hyperglycemia. Bacteroides and Faecalibacterium produce butyrate, which binds to GPCR, activating the production of GLP-1 hormone, which is involved in insulin synthesis, secretion, and sensitivity. Lactobacilli and Akkermansia have an inhibitory effect on alpha-glucosidase enzyme, which helps in the breakdown of complex carbohydrate, raising sugar level. Lactobacilli and Bifidobacterium increase bile salt hydrolyses, leading to GLP-1 hormone stimulation. If this microbial role is disturbed, inflammation and autoimmune diseases arise.

Figure 3

Microbial dysbiosis is a potential factor driving multiple sclerosis. In this illustration, we show how the change in population dynamic of gut microbes suppresses or drives multiple sclerosis. The increase in proinflammatory bacteria induces differentiation of Th1/Th17, which travel systemically to the brain and recruit more proinflammatory cells producing inflammatory cytokines. In contrast, the decrease in proinflammatory bacteria induces differentiation of Treg cells and production of anti-inflammatory cytokines, which balance or counteract Th1/Th17. Interestingly, once MS is developed, a significant decrease in anti-inflammatory community is observed, but the exact signaling mechanism is unknown.

Figure 4

The influence of Prevotella species in preventing or mediating RA. The figure illustrates the role of P. histicola in upregulating the tight junctions, which prevent leakage of proinflammatory metabolites and subsequently prevents inflammation (right side). On the contrary, P. copri stimulates differentiation of Th17, leading to upregulation of proinflammatory cytokines’ production and systemic inflammation.