The Gut Microbiota in Immune-Mediated Inflammatory Diseases

Abstract

The collection of microbes and their genes that exist within and on the human body, collectively known as the microbiome has emerged as a principal factor in human health and disease. Humans and microbes have established a symbiotic association over time, and perturbations in this association have been linked to several immune-mediated inflammatory diseases (IMID) including inflammatory bowel disease, rheumatoid arthritis, and multiple sclerosis. IMID is a term used to describe a group of chronic, highly disabling diseases that affect different organ systems. Though a cornerstone commonality between IMID is the idiopathic nature of disease, a considerable portion of their pathobiology overlaps including epidemiological co-occurrence, genetic susceptibility loci and environmental risk factors. At present, it is clear that persons with an IMID are at an increased risk for developing comorbidities, including additional IMID. Advancements in sequencing technologies and a parallel explosion of 16S rDNA and metagenomics community profiling studies have allowed for the characterization of microbiomes throughout the human body including the gut, in a myriad of human diseases and in health. The main challenge now is to determine if alterations of gut flora are common between IMID or, if particular changes in the gut community are in fact specific to a single disease. Herein, we review and discuss the relationships between the gut microbiota and IMID.

Keywords: chronic immune mediated inflammatory diseases; dysbiosis; metagenome; microbiome; systems microbiology.

FIGURE 1

Role of the gut microbiome in the pathogenesis of IMID. Enterocytes (via recognition of microbe-associated molecular patterns by Toll-like receptors) and M cells (transcytosis) communicate microbial dysbiosis to the mucosal immune system. Gut dysbiosis, in combination with a reduction of SCFA can shift the Treg-Th17 balance toward inflammation through Th17 expansion. Several pro-inflammatory cytokines are released in the lamina propria (LP) including IL-6, IL-17, IL-21, IL-23, and IFN-γ. The inflammatory state enhances intestinal permeability through expression of tight junction proteins including occludins and claudins and may lead to microbial translocation and enhanced antigen exposure in the LP. Activated T cells, B cells and dendritic cells (DC) travel to the mesenteric lymph nodes (MLN) via lymphatic vessels. Antigen presentation by DCs to T cells occurs and B cells differentiate toward plasma cells. Activated B cells, Th17 cells, and antibody-producing plasma cells enter circulation. B cells may be stimulated to differentiate toward autoantibody producing plasma cells if exposed to mimicry antigen in LP or MLN. Increased Th17 cells and presence of autoantibodies are the result of the microbiota induced pro-inflammatory state. Figure adapted from van der Meulen et al. (2016) with permission and modified.