The gut microbiome in autoimmunity: Sex matters

Highlights

• Interaction between environmental and genetic factors with gut microbiota influences gut immunity.

• Sex hormones influence autoimmunity via gut microbial composition.

• Modulation of gut microbial composition may provide a novel target for treatment of autoimmune diseases.

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.

Introduction

Autoimmune diseases are characterized by alterations in normal immune function, resulting in hyperactive immune response against self proteins and tissues. Even though the etiology of autoimmune disorders is unknown, extensive clinical research over the past decade has pointed to genetic and environmental factors that interact to trigger disease. The genetic basis of autoimmunity is associated with a complex array of risk loci, the most important being those located in the Major Histocompatibility Complex (MHC), conferring susceptibility or resistance to disease [1]. Different disease outcomes in genetically identical individuals [2] imply that environmental triggers such as diet [3], infections and smoking exacerbate autoimmunity [4], [5], [6]. Although, in these studies, environment-derived antigens have been reported to increase (inflammatory reactions), mechanistic insight into how autoimmunity arises remains largely obscure.

Recent advances in “omic”-based approaches (metagenomics, metabolomics and proteomics) and bioinformatics have facilitated our understanding of the mechanisms of a broad range of diseases and have allowed us to identify potential biomarkers for diagnosis and therapeutic intervention [7]. One particular area of research receiving increasing attention over the past 5 years has focused on using omic-based techniques to study how the gut microbiome, the collection of bacteria, viruses, fungi and protozoa lining the gastrointestinal mucosa, significantly impacts health and disease [8], [9], [10]. These vastly diverse microbial communities not only play a vital role in nutrient synthesis and energy harvest from foods but also tightly regulate the innate and adaptive branches of immunity [11], [12], [13], [14], [15], [16]. Recent research about the role of gut microbes in adaptive immune response has substantially changed our understanding of how genes, environmental factors and our “second genome” (the gut microbiome) interact to influence autoimmunity.

In this review we focus on the sex-bias of autoimmune disorders that, although well documented, still lacks mechanistic insight with regard to genetic and gut microbial interactions. Studies in humans and mouse models have revealed that females are 2–10 times more susceptible than males into a wide range of autoimmune disorders, including rheumatoid arthritis (RA), Multiple Sclerosis (MS), systemic lupus erythematosus (SLE), myasthenia gravis (MG), Sjogren's syndrome and Hashimoto's thyroiditis [17], [18]. Yet, recent evidence is just beginning to emerge linking sex-specific microbial clades during disease progression, and pointing to complex interactions between gut microbes, genetic factors, environment and sex hormones. This review does not intend to discuss the current knowledge on the genetic or environmental triggers of autoimmune disorders and gender-bias, which have been elegantly reviewed elsewhere [19], [20], [21], [22]. Here, we review the current literature relating gut microbes to the sex-based differences observed in various autoimmune disorders and discuss how diverse experimental platforms contribute to developing useful biomarkers for disease progression and for therapeutics.