Scientists struggle with elucidating how host and gut microbiome interact for shaping the genetic susceptibility of IBD. In 633 IBD patients, Harry Sokol and colleagues have found associations between genetic variants associated with a higher risk of IBD and the depletion of certain gut bacterial taxa.

Although the underlying mechanisms involved in inflammatory bowel disease (IBD) pathogenesis remain elusive, it is known that certain genes, which are shared by both Crohn’s disease (CD) and ulcerative colitis (UC) patients, may show a predisposition to the development of this disease. Furthermore, the intestinal bacterial and fungal microbiota might also drive disease pathogenesis and progression.

Despite this knowledge, the specific way in which host and gut microbiome interaction shapes the genetic susceptibility of IBD remains unclear.

A new study, led by Prof. Harry Sokol from Saint Antoine Hospital in Paris (France), reveals that the IBD disease risk previously related to genetics is partly mediated by the gut microbiome.

In a sample of 633 IBD patients, the researchers explored the effect of four major genetic variants associated with a higher risk of IBD—NOD2, CARD9, LRRK2, and ATG16L1—and gut bacterial taxa.

By using a covariates for multiphenotype studies’ approach, which looks for gene-bacteria associations, the authors first identified four associations between genetic variants of IBD and the depleted abundance of certain gut bacterial taxa in 182 women and men with either CD or UC:

Roseburia genus and faecis with NOD2.

Bacteroidaceae family and Bacteroides genus with

Faecalibacterium prausnitzii and NOD2.

Firmicutes phyla and CARD9.

The study also confirmed the previously reported decreased levels of F. prausnitzii in IBD patients. Furthermore, the associations between a decreased abundance of Roseburia genus and F. prausnitzii and NOD2 variants were replicated in three independent cohorts consisting of 451 individuals with IBD.

Altogether, these findings support an association between host genetics and the relative abundance of gut bacteria commensals.

By using additional statistical gene-bacteria-IBD causal models and sensitivity analyses, which provide unbiased estimation of genetic effects and accurate control of false-positive rates while maximizing statistical power, the researchers confirmed that, first, the effect of the risk alleles was mediated by gut bacteria levels and, secondly, that the genetic variant influenced both the disease and the bacteria. The association pattern was maintained when considering cofounders such as flare and remission disease status. However, the authors acknowledged that other mechanisms could also act in parallel, mediating IBD allele risk-bacteria and bacteria-IBD associations.

To sum up, this is the first study that provides robust support for the role of host genetics in IBD development through the gut microbiome. Now, further studies elucidating the contribution of other IBD genetic variants are needed.

Reference:

Aschard H, Laville V, Tchetgen ET, et al. Genetic effects on the commensal microbiota in inflammatory bowel disease patients. PLoS Genet. 2019; 15(3):e1008018. doi: 10.1371/journal.pgen.1008018.