The role of gut microbiota in immune homeostasis and autoimmunity

Abstract

Keeping a delicate balance in the immune system by eliminating invading pathogens, while still maintaining self-tolerance to avoid autoimmunity, is critical for the body's health. The gut microbiota that resides in the gastrointestinal tract provides essential health benefits to its host, particularly by regulating immune homeostasis. Moreover, it has recently become obvious that alterations of these gut microbial communities can cause immune dysregulation, leading to autoimmune disorders. Here we review the advances in our understanding of how the gut microbiota regulates innate and adaptive immune homeostasis, which in turn can affect the development of not only intestinal but also systemic autoimmune diseases. Exploring the interaction of gut microbes and the host immune system will not only allow us to understand the pathogenesis of autoimmune diseases but will also provide us new foundations for the design of novel immuno- or microbe-based therapies.

Figure 1. Commensal bacteria induce CD4⁺T cell differentiation. Naïve CD4⁺T cells can differentiate into four major cell types: Th1, Th2, Tregs and Th17. The differentiation of each lineage requires the induction of a transcription factor that is unique to each lineage. Once differentiated, each lineage secretes a special (set of) cytokine, as shown in the figure. Th1 cells play an important role in eliminating intracellular pathogens while Th2 function to control parasitic infection. The primary role of Th17 is to control infection and Tregs is to regulate immune response. The type of bacteria species that has been shown to induce a particular T cell differentiation pathway is indicated in the figure.

Figure 2. An autoimmune arthritis model that demonstrates the link between gut microbiota and an extraintestinal disease. The K/BxN arthritis model was used to demonstrate how the gut microbiota can influence a non-gut-associated disease. K/BxN mice express a transgene-encoded T-cell receptor that reacts to a self-peptide. Colonization of SFB on the gut induces the differentiation of Th17 cells (step 1 and 2), which subsequently exit the gut and migrate into the peripheral lymphoid tissue. The gut-origin of Th17 cells can be identified by their expression of the α4β7 receptor, imprinted on these T cells by intestinal-mucosa-associated DCs (step 3). IL-17, in turn, acts directly on B cells to provide help in the differentiation of germinal center B cells and the production of autoantibody in spleen (step 4). The autoantibody then circulates into its target organ joints, which ultimately leads to the development of disease.