Knockout of caspase recruitment domain-containing protein 9 (Card9), an IBD susceptibility gene, exacerbates colitis in mice by impairing microbial production of ligands critical for immune regulation that act via the aryl hydrocarbon receptor (AHR), according to a new study.
Whether dysbiosis is a cause or consequence of IBD is unclear. CARD9 plays a part in the innate immune response to fungi and promotes recovery from colitis by activating IL-22 production, but certain CARD9 polymorphisms favour IBD pathogenesis. In addition, Card9-knockout (Card9−/−) mice have increased vulnerability to colitis.
Card9−/− mice have a defective activation of the IL-22 pathway
Harry Sokol and colleagues investigated how Card9 and the gut microbiota might interact to affect IBD pathogenesis. In Card9−/− mice, the researchers detected impeded recovery from induced colitis in addition to altered gene expression in the colon. “Card9−/− mice have a defective activation of the IL-22 pathway,” explains Sokol. “We then compared the faecal microbiota of wild-type and Card9−/− mice and observed several differences both at the bacterial and fungal level”.
To isolate the effect of the altered microbiota on intestinal inflammation, the team colonized germ-free, wild-type mice with microbiota from Card9−/− mice and found that increased susceptibility to colitis and reduced IL-22 production was recapitulated in these animals. AHR activation can modulate IL-22 production, and microbiota-mediated metabolism of tryptophan is a crucial step in generating AHR ligands. Interestingly, the researchers observed impaired tryptophan metabolism in microbiota from Card9−/− mice. Furthermore, AHR agonist treatment or supplementation with tryptophan-metabolizing Lactobacillus strains rescued susceptibility to colitis in Card9−/− mice. Sokol and colleagues also found reduced AHR activation in patients with IBD compared with healthy individuals, a defect exacerbated in those with disease-associated CARD9 polymorphisms.
“The next steps would be to try to correct this impaired microbiota function,” concludes Sokol.
References
Lamas, B. et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat. Med. http://dx.doi.org/10.1038/nm.4102 (2016)
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Ridler, C. Dysbiosis underlies CARD9 risk alleles in colitis. Nat Rev Gastroenterol Hepatol 13, 316 (2016). https://doi.org/10.1038/nrgastro.2016.82
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DOI: https://doi.org/10.1038/nrgastro.2016.82
