The intestinal microbiota appears to be a key determinant of health and disease. Indeed, microbiota differences are associated with a number of inflammatory diseases, including inflammatory bowel disease (IBD). However, the method by which alterations in the microbiota composition (influenced by genetics, the environment, and diet) contribute to IBD pathogenesis is not well understood.
In a recently published paper in Nature Medicine, a group led by Harry Sokol at INRA studied how host genes affect the composition and function of the gut microbiota, and in turn, the production of metabolites and intestinal inflammation. Lamas et al found that mice lacking caspase recruitment domain family member 9 (CARD9), a susceptibility gene for IBD that is important in microbial signaling, were more susceptible to experimental colitis and showed impaired mucosal healing. CARD9 was critical for the induction of IL-22, a cytokine that is important in host defense at mucosal surfaces and in tissue repair, and in recovery from colitis. When the authors analyzed the microbial composition in the wild-type (genetically normal) and CARD9 deficient mice, they found significant baseline differences. Moreover, the wild-type mice were more resilient to colitis-induced alterations in the microbial composition, suggesting that CARD9 has a role in shaping the gut microbiota composition, which plays a role in controlling experimental colitis.
To dissect the contribution of the altered microbial composition to colitis pathogenesis, the authors performed a number of elegant microbial transfer experiments using germ-free mice. Wild-type germ-free mice that were colonized with microbiota from CARD9 deficient mice had increased susceptibility to colitis, which was associated with decreased levels of IL-22 in the colon. Their findings suggest that the genetic defect itself is not sufficient to induce inflammation; however, microbial alterations resulting from CARD9 deficiency are responsible for defective IL-22 production from local gut immune cells, leading to impaired recovery from colitis.
Aryl hydrocarbon receptor (AHR) ligands promote IL-22 production, and are produced during metabolism of dietary tryptophan by bacteria in the gut or by host cells. Notably, the authors found that bacterial-derived tryptophan products were decreased in CARD9 deficient mice, and in germ-free mice that received CARD9 deficient microbiota.
The authors then sought to determine whether this impaired tryptophan metabolism associated with the CARD9 deficient microbiota actually caused the increased colitis susceptibility and inflammation. Using in vitro assays, they first found that fecal samples from CARD9 deficient mice were defective in the ability to activate AHR. Importantly, the authors demonstrated that defects in AHR signaling in CARD9 deficient mice can be reversed. When CARD9 deficient mice were treated with an AHR agonist or with Lactobacillus strains shown to stimulate AHR in vitro, colitis and IL-22 levels normalized.
These results in animal studies clearly show that genetic defects in innate immunity can lead to functional changes in the microbiota that result in a defect in the ability to produce important microbial metabolites from the diet, which can exacerbate inflammation. However, can these findings be translated to human disease? The researchers addressed this question by testing fecal samples from healthy controls and IBD patients for their ability to activate AHR and for the presence of bacterial derived tryptophan derivatives. Microbiota from fecal samples of IBD patients were impaired in their ability to activate AHR and had decreased levels of bacterial-derived tryptophan metabolites. In particular, this defect was more severe in IBD patients who had a CARD9 mutation.
Together, these findings show how defects in innate immunity can lead to altered microbial metabolism of dietary components, which in turn can affect host immunity and susceptibility to inflammation. These results also highlight the important interactions between host genetics, the function of the intestinal microbiota, and host immunity, and how a defect in one component can have critical consequences on intestinal homeostasis. The importance of studying not only changes in the composition of the microbiota, but also the functional changes in the microbiota is another key message that can be taken from this paper. Importantly, these results provide exciting opportunities for future diagnostics and therapeutics: microbial derived tryptophan derivatives could in the future be used as biomarkers for dysbiosis, and this pathway could be targeted using specific probiotics or agonists.
Lamas B, Richard ML, Leducq V, et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med. 2016; 22(6):598-605. doi: 10.1038/nm.4102.
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