Editors' ChoiceMicrobiome

Nature and nurture shape the microbiome

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Science Translational Medicine  11 Jul 2018:
Vol. 10, Issue 449, eaau1974
DOI: 10.1126/scitranslmed.aau1974


Host and microbial tryptophan metabolism work together to regulate gut mucosal barrier function and metabolic disease.

Recent research highlights that environmental factors are more important to gut microbiome ecology than host genetics (i.e., nurture over nature). This concept is distinct from the importance of genetics in shaping microbial functions or the host response to these functions. Here, Laurans et al. demonstrate that host genetics, environment, and microbial ecology interface to regulate tryptophan metabolic pathways and determine negative metabolic outcomes related to diabetes and obesity.

In mammals, the enzyme indoleamine 2,3-dioxygenase (IDO) catalyzes the degradation of tryptophan. Increased IDO activity has been associated with negative outcomes in cancer due to its effects on immune tolerance mediated by regulatory T cells. Increased IDO activity has also been linked to metabolic diseases but through unknown mechanisms. Using Ido1−/− mice, the authors demonstrated that IDO activity is increased by a high-fat diet (HFD), and IDO is necessary for the development of negative metabolic outcomes associated with a HFD including adiposity, hepatic steatosis (accumulation of fat in the liver), insulin resistance, and impaired glucose homeostasis. These negative effects are independent of weight gain and were not seen in mice fed normal chow.

Using a conditional knockout mouse, the authors then observed that the negative effects of IDO activity were not specific to myeloid cells. They hypothesized that the effects of IDO may be local to the gastrointestinal tract, where IDO depletion of tryptophan would inhibit microbial conversion of tryptophan to beneficial indole metabolites. Microbial indole metabolites induce interleukin-22 (IL-22) production, which beneficially regulates intestinal immunity and mucosal barrier functions. The investigators demonstrated that IDO activity was dependent on the microbiome by microbial depletion with antibiotics, as well as cohousing and fecal transfer experiments in mice. Inhibition of IL-22 with an antibody recapitulated the negative metabolic phenotype independent of the microbiome and IDO activity. In humans, changes in fecal tryptophan metabolites as predicted by higher IDO activity correlated with the development of obesity and diabetes.

Overall, the researchers found that the relationship between IDO activity and metabolic outcomes is dependent on a HFD, host IDO genes, and microbial tryptophan metabolism, which in turn regulates IL-22–mediated intestinal barrier function. Although the precise link between IL-22–dependent intestinal barrier functions and negative metabolic outcomes remains to be determined, these studies suggest a novel mechanism whereby metabolic diseases could be treated via microbial tryptophan metabolite enrichment.

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