Mini-Review: Gut-Microbiota and the Sex-Bias in Autoimmunity - Lessons Learnt From Animal Models.

It is well appreciated that there is a female preponderance in the development of most autoimmune diseases. Thought to be due to a complex interplay between sex chromosome complement and sex-hormones, however, the exact mechanisms underlying this sex-bias remain unknown. In recent years, there has been a focus on understanding the central pathogenic role of the bacteria that live in the gut, or the gut-microbiota, in the development of autoimmunity. In this review, we discuss evidence from animal models demonstrating that the gut-microbiota is sexually dimorphic, that there is a bidirectional relationship between the production of sex-hormones and the gut-microbiota, and that this sexual dimorphism within the gut-microbiota may influence the sex-bias observed in autoimmune disease development. Collectively, these data underline the importance of considering sex as a variable when investigating biological pathways that contribute to autoimmune disease risk.

Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease.

BACKGROUND: Evidence suggests an important role for gut-microbiota dysbiosis in the development of rheumatoid arthritis (RA). The link between changes in gut bacteria and the development of joint inflammation is missing. Here, we address whether there are changes to the gut environment and how they contribute to arthritis pathogenesis. METHODS: We analyzed changes in markers of gut permeability, damage, and inflammation in peripheral blood and serum of RA patients. Serum, intestines, and lymphoid organs isolated from K/BxN mice with spontaneous arthritis or from wild-type, genetically modified interleukin (IL)-10R-/-or claudin-8-/-mice with induced arthritis were analyzed by immunofluorescence/histology, ELISA, and flow cytometry. FINDINGS: RA patients display increased levels of serum markers of gut permeability and damage and cellular gut-homing markers, both parameters positively correlating with disease severity. Arthritic mice display increased gut permeability from early stages of disease, as well as bacterial translocation, inflammatory gut damage, increases in interferon γ (IFNγ)+and decreases in IL-10+intestinal-infiltrating leukocyte frequency, and reduced intestinal epithelial IL-10R expression. Mechanistically, both arthritogenic bacteria and leukocytes are required to disrupt gut-barrier integrity. We show that exposing intestinal organoids to IFNγ reduces IL-10R expression by epithelial cells and that mice lacking epithelial IL-10R display increased intestinal permeability and exacerbated arthritis. Claudin-8-/-mice with constitutively increased gut permeability also develop worse joint disease. Treatment of mice with AT-1001, a molecule that prevents development of gut permeability, ameliorates arthritis. CONCLUSIONS: We suggest that breakdown of gut-barrier integrity contributes to arthritis development and propose restoration of gut-barrier homeostasis as a new therapeutic approach for RA. FUNDING: Funded by Versus Arthritis (21140 and 21257) and UKRI/MRC (MR/T000910/1).

Regulatory B Cells in Experimental Mouse Models of Arthritis.

Regulatory B cells (Breg) have been shown to have a role in the suppression of a wide variety of immune responses, yet they are deficient or defective in autoimmune diseases such as rheumatoid arthritis. For the study of autoimmune inflammation, experimental models of arthritis have acted as a valuable tool in understanding the development of Bregs and their role in maintaining immune homeostasis. In this chapter, we will focus on the study of transitional-2 marginal zone precursor (T2-MZP) Bregs in the context of two experimental arthritis models: antigen-induced arthritis (AIA) and collagen-induced arthritis (CIA). We will specifically focus on how to induce arthritis, as well as on methods for the isolation and functional study of Bregs both in vitro and in vivo.

Microbiota-Derived Metabolites Suppress Arthritis by Amplifying Aryl-Hydrocarbon Receptor Activation in Regulatory B Cells.

The differentiation of IL-10-producing regulatory B cells (Bregs) in response to gut-microbiota-derived signals supports the maintenance of tolerance. However, whether microbiota-derived metabolites can modulate Breg suppressive function remains unknown. Here, we demonstrate that rheumatoid arthritis (RA) patients and arthritic mice have a reduction in microbial-derived short-chain fatty acids (SCFAs) compared to healthy controls and that in mice, supplementation with the SCFA butyrate reduces arthritis severity. Butyrate supplementation suppresses arthritis in a Breg-dependent manner by increasing the level of the serotonin-derived metabolite 5-Hydroxyindole-3-acetic acid (5-HIAA), which activates the aryl-hydrocarbon receptor (AhR), a newly discovered transcriptional marker for Breg function. Thus, butyrate supplementation via AhR activation controls a molecular program that supports Breg function while inhibiting germinal center (GC) B cell and plasmablast differentiation. Our study demonstrates that butyrate supplementation may serve as a viable therapy for the amelioration of systemic autoimmune disorders.