Crosstalk Between Gut Microbiota and Innate Immunity and Its Implication in Autoimmune Diseases

Abstract

The emerging concept of microbiota contributing to local mucosal homeostasis has fueled investigation into its specific role in immunology. Gut microbiota is mostly responsible for maintaining the balance between host defense and immune tolerance. Dysbiosis of gut microbiota has been shown to be related to various alterations of the immune system. This review focuses on the reciprocal relationship between gut microbiota and innate immunity compartment, with emphasis on gut-associated lymphoid tissue, innate lymphoid cells, and phagocytes. From a clinical perspective, the review gives a possible explanation of how the "gut microbiota-innate immunity" axis might contribute to the pathogenesis of autoimmune diseases like rheumatoid arthritis, spondyloarthritis, and systemic lupus erythematosus.

Keywords: gut microbiota; innate immunity; innate lymphoid cells; rheumatoid arthritis; spondyloarthritis; systemic lupus erythematosus.

Figure 1

The interplay between innate immune cells and gut microbiota. (A) At steady state, CX₃CR1+ dendritic cell (DC) forms dendrites for phagocytosis, while CD103+ DC migrates to Peyer's patches or mesenteric lymph nodes to present antigens to naïve T cells. (B) Upon activation by commensals, DC secretes interleukin (IL)-12, IL-15, and interferon (IFN) to prime conventional NK (cNK) cells. Short-chain fatty acids (SCFAs) as metabolic by-products upregulate H3K4me3 in DC and promote the production of IL-6, IL-12, IFN, and tumor necrosis factor (TNF), which is another strategy to condition cNK cells. Conditioned cNK cells have proper cytotoxicity and cytokine secretion capability to exert the anti-microbial or anti-viral function. (C) Intestinal epithelial cell (IEC) in response to commensal bacteria produces IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) to activate ILC2. (D) Major histocompatibility complex class II (MHC II) expressing ILC3 is capable of presenting commensal antigens to CD4+ T cells, limiting their self-reactivity. The priming of ILC3 also relies on microbiota signals in an ID2-dependent manner. Primed ILC3 secretes IL-22 and joins the defense against pathogens: driving the antimicrobial peptide production such as REGIIIβ and REGIIIγ, and fucosylation of surface proteins on IEC. (E) TLR2 is crucial in maintaining the integrity of IEC. Deficiency may increase the susceptibility of intestinal inflammation. Invasive pathogens, in this case, invade into lamina propria layer. Phagocytes exert host defense function via phagocytosis and cytokine production such as IL-6 and IL-23. (F) Translocation of commensal bacteria Enterococcus gallinarum from gut to liver enhance the Th17 response and worsen manifestations of autoimmune diseases.