The gut microbiome in autoimmunity: Sex matters

Abstract

Autoimmune diseases like rheumatoid arthritis are multifactorial in nature, requiring both genetic and environmental factors for onset. Increased predisposition of females to a wide range of autoimmune diseases points to a gender bias in the multifactorial etiology of these disorders. However, the existing evidence to date has not provided any conclusive mechanism of gender-bias beyond the role of hormones and sex chromosomes. The gut microbiome, which impacts the innate and adaptive branches of immunity, not only influences the development of autoimmune disorders but may interact with sex-hormones to modulate disease progression and sex-bias. Here, we review the current information on gender bias in autoimmunity and discuss the potential of microbiome-derived biomarkers to help unravel the complex interplay between genes, environment and hormones in rheumatoid arthritis.

Keywords: Autoimmunity; Gender-bias; Microbiome; Sex-hormones.

Figure 1. Influence of sex-hormones on the gut microbial composition and immune response

Environment and genetic factors have a significant effect on gut microbial composition and modulate the abundance of specific taxa within the microbial ecosystem. Gender-bias in - gut microbiome profiles is caused, in part, by the sex hormones, estradiol and testosterone, which may influence gut microbial composition directly (a) or indirectly (b) by shaping the gut mucosal immune environment. β-estradiol promotes differentiation of conventional dendritic cells (DCs) into IL-12, IFNγ-producing DCs which activates pathways for pro-inflammatory cytokines IL-6 and IL-8 and polarization of T cells into Th1/Th17 (red dots) rather than anti-inflammatory cytokines (green dots). Estradiol also enhances the survival of B cells and polyclonal B-cell activation, which could be related to increased autoantibody production. In females, there is an increased expression of genes involved in Toll-like receptor pathways. The pro-inflammatory immune environment compromises gut permeability, causing translocation of gut commensals in to the lamina propria where they can amplify pro- inflammatory responses. In males (right panel), testosterone has a suppressive effect on T cell proliferation, resulting in attenuated immune responses and a balanced immune system. DCs maintain a tolerant environment by generating Th1/Th17 as well as T regulatory cells by production of IL-4, IL-10, IL-22 and CCL20. Testosterone is associated with decreased expression of genes involved in Toll-like receptors pathways and antigen presentation so that integrity of the intestinal barrier is not compromised. Thus sex-hormones modulate local immune response by involving cells of the adaptive immune system which leads to changes in systemic immune responses contributing to pathology.

Figure 2. Genetic factors, sex hormones and environment modulate the outcome of gut microbial composition and disease phenotype

In genetically susceptible individuals, a dysbiotic gut microbiome exacerbates a detrimental diet-microbe-host co-metabolism resulting in an unbalanced or pro-inflammatory mucosal immune environment conducive to autoimmunity. A protective phenotype in healthy individuals is maintained by both genomic and dietary control of a homeostatic colonic ecosystem. Sex hormones can modulate the local immune environment. The impact of estrogen on various immune cells contributes to a hyperactive immune environment while androgens (testosterone) maintain an anti-inflammatory mucosal immune environment. Thus, dietary interventions have the potential to modulate the microbiome composition in susceptible individuals and change disease outcome, especially in affected females.