The Role of the Microbiome in Driving RA-Related Autoimmunity.

Cristopher M Rooney,Paul Emery,Kulveer Mankia

doi:10.3389/fcell.2020.538130

Abstract

Once referred to as “normal commensal flora” the human microbiome plays an integral role between health and disease. The host mucosal surface replete with a multitude of immune cells is a vast arena constantly sensing and responding to antigen presentation and microbial by-products. It is this key role that may allow the microbiome to prime or protect the host from autoimmune disease. Rheumatoid arthritis (RA) is a chronic, disabling inflammatory condition characterized by a complex multifactorial etiology. The presence of certain genetic markers has been proven to increase susceptibility to RA however it does not guarantee disease development. Given low concordance rates demonstrated in monozygotic twin studies there is a clear implication for the involvement of external players in RA pathogenesis. Since the historical description of rheumatoid factor, numerous additional autoantibodies have been described in the sera of RA patients. The presence of anti-cyclic citrullinated protein antibody is now a standard test, and is associated with a more severe disease course. Interestingly these antibodies are detectable in patient’s sera long before the clinical signs of RA occur. The production of autoantibodies is driven by the lack of tolerance of the immune system, and how tolerance is broken is a crucial question for understanding RA development. Here we review current literature on the role of the microbiome in RA development including periodontal, gut and lung mucosa, with particular focus on proposed mechanisms of host microbiome interactions. We discuss the use of Mendelian randomization to assign causality to the microbiome and present considerations for future studies.

Highlights

Complex interactions govern the symbiosis that exists between the human body as the host and our microbiome
This definition would encompass all living organisms at that site, including bacterial, viral, fungal and archaeal populations. This is an important concept as tools for analysis of these complex communities can be divided broadly into functional or taxonomic characterization. The former relies on metagenomic shotgun sequencing and the latter on 16S rRNA sequencing but overlap exists, where hypothesized function can be inferred from 16S rRNA sequencing (Ortiz-Estrada et al, 2019) and metagenomics shotgun sequencing is capable of taxonomic resolution
Newer estimates suggest a more modest ratio of 1:1 of bacterial to human cell biomass (Sender et al, 2016), this this does not take into account genetic potential and subsequent metabolic pathways which still favor the microbiome as having numerical dominance in terms of transcriptional and subsequent functional activity

Summary

INTRODUCTION

Complex interactions govern the symbiosis that exists between the human body as the host and our microbiome. Strictly speaking the term microbiome refers to all microorganisms and the collection of all their genes and genomes within a microbial community associated with a distinct anatomical region (Lederberg and Mccray, 2001) This definition would encompass all living organisms at that site, including bacterial, viral, fungal and archaeal populations. Dynamic temporal microbial changes in this pre-RA phase have been demonstrated using CIA mouse models (Jubair et al, 2018), with an initial decrease in Bacteroidetes and an increase in Lactobacillaceae; by day 35 of the model (early induction of arthritis at day 14) Lactobacillaceae had returned to day 0–7 levels, while Lachnospiraceae significantly increased in abundance. A predominance of Prevotella copri (discussed later in this review) was identified with within the early RA patients, which was corroborated within the mice receiving the RA microbiome following inoculation and associated with increased Th17 cells and arthritis severity (Maeda et al, 2016). This is a unique time point which is unattainable in most disease

Findings

Microbiome Methodology