Microbiota: Linking Genetics and Inflammatory Disease

Humans and the microbiota living in an on human surfaces (microbiota) have co-evolved over thousands of years, affecting each other’s development in unknown ways. While microbes have traditionally been viewed as having a commensal or parasitic relationship with their hosts, a surge in microbiota research is showing how important microbiota is for human health (1,2). Colonization of human mucosal surfaces by microorganisms in neonates is essential for educating the naïve immune system and developing adaptive immune responses. However, abnormal microbial composition (termed dysbiosis), especially within the gastrointestinal tract, may play direct or indirect roles with the development of numerous inflammatory diseases like inflammatory bowel disease (IBD), rheumatoid arthritis (RA), asthma, multiple sclerosis and more diseases (3). Since microbiota composition is associated with genetic and environmental factors, further research is needed to determine how intestinal microbes influence the local and systemic inflammatory reactions This research may help bridge the gap in our understanding of induction of these chronic inflammatory diseases. 

Intestinal microbial composition may depend on mucosal enzymes, which are related to genetic factors identified as risk loci in some inflammatory diseases. For instance, NOD2, which has been identified as a risk locus for IBD, stimulates an immune response when recognizing muramyl dipeptide in bacteria cell walls and can influence the intestinal microbiota composition (4,5). While the specific composition of intestinal microbiobes varies greatly between individuals, IBD patients often have characteristic changes in gut microbiota: decrease in Firmicutes, increases in Bacteroidetes and Enterobacteriaceae taxa (E. coli especially), and an overall decrease in biodiversity (6). Other genetic factors, such as Human Leukocyte Antigen (HLA) genes Toll-Like Receptor (TLR) genes, have been shown to influence intestinal microbial composition, while also being linked with chronic inflammatory diseases like coeliac disease (7-9). 

Thus, the presence of intestinal dysbiosis in inflammatory disease patients, the ability of genetic factors to shape intestinal microbial composition, and the correlation of these genetic factors to inflammatory diseases suggests that a person’s microbiota, shaped by genetics and other factors (diet, antibiotic use, mode of delivery), can be a driving force for chronic inflammatory diseases. The contribution of microbiota to inflammatory disease pathogenesis has been confirmed using animal models of disease, and not just for inflammatory diseases affecting gastrointestinal tissues (4).

The K/BxN mouse model of autoimmune arthritis is a spontaneously developing inflammatory arthritis model that has many similarities to human RA. Under specific pathogen free (SPF) conditions, K/BxN mice develop a severe arthritis caused by autoantibody reaction to glucose-6-phosphate isomerase (GPI). However, under germ free (GF) conditions, K/BxN mice have an attenuated form of arthritis and lower levels of anti-GPI antibodies (10). When these GF mice were then colonized with segmented filamentous bacteria (SFB) via oral gavage and transferred to SPF conditions, the mice rapidly developed arthritis and exhibited higher anti-GPI antibody levels than their strictly GF counterparts. Another model or RA, the Collagen-Induced Arthritis model, has shown compositional changes in the gut microbes of mice during the pre-clinical arthritis stage, suggesting that these microbial changes may be important for arthritis progression in this model (11).

Correlations between intestinal dysbiosis and autoimmune diseases like RA has led to an increased focus on how modulating intestinal microbobes can be used as a therapeutic for inflammatory diseases. Advances in genome sequencing allow researchers to draw correlations between microbial composition and diseases states while using gnotobiological techniques and disease models are vital tools for teasing apart the contributions of individual microbes. However, to gain a more complete picture of how a particular microbe may influence inflammatory responses, it is important to characterize the immune systems response to the pathogen of interest.

To help further this line of research, Chondrex, Inc. has recently launched a line of Human Anti-Bacteria Antibody Assay Kits & Mouse Bacteria Antibody Assay Kits. These kits are designed to characterize and quantify the immune response to common environmental pathogens such as E. coli, Lactobacillus casei, Porphyromonas gingivalis, and Lipopolysaccharide (LPS). We also provide Cytokine Detection Kits and Chemokine Detection Kits that can be used to determine the inflammatory profiles of human and mouse samples. Please contact us at support@chondrex.com for more information about these kits.

References

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2. Y. K. Lee, S. K. Mazmanian, Has the Microbiota Played a Critical Role in the Evolution of the Adaptive Immune System?. Science 330, 1768-1773 (2010). DOI: 10.1126/science.1195568
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