Indoleamine 2,3-dioxygenase (IDO) is known to be involved in immune function and catalyses the degradation of tryptophan. Now, new research published in Nature Medicine demonstrates that this enzyme also has a role in metabolic health, via effects on the gut microbiota.

Representative fluorodeoxyglucose (FDG)-PET images (left) and quantification (right) of tissue FDG uptake in wild-type and Ido1−/− mice fed with a high-fat diet for 14 weeks. White arrows show the FDG uptake in muscle. Reproduced from Laurans, L. et al. Nat. Med. https://doi.org/10.1038/s41591-018-0060-4, Springer Nature Limited.

Increased levels of IDO have been observed in patients with cardiovascular disease and seem to be predictive of poorer outcomes. However, the mechanisms underlying this association are unclear. “As obesity is a major contributor to cardiovascular diseases, we wanted to know the direct effects of IDO in obesity,” explains author Soraya Taleb.

In wild-type mice, the authors showed that IDO activity in the plasma, epididymal white adipose tissue, brown adipose tissue and soleus muscle increased in those receiving a high-fat diet (HFD) compared with those receiving a normal chow diet (NCD). Ido1–/– mice fed a NCD had a similar phenotype to the wild-type mice on this diet. However, knockout mice fed a HFD had a similar weight curve to the wild-type and knockout mice fed a NCD. These HFD-fed knockout mice also had a lower fat mass than wild-type mice on a HFD, as well as lower liver weights, less lipid accumulation in the liver and less macrophage infiltration in the liver. These findings suggest that knockout of IDO protects against the negative effects of a HFD, including weight gain and liver steatosis.

Taleb and her colleagues used 16S ribosomal sequencing to show that Ido1–/– mice fed a HFD had a different gut microbiota composition to knockout mice and wild-type mice fed a NCD. These findings suggest that IDO has a role in determining the composition of the gut microbiota, which is known to be important for metabolic health.

“During our search for the mechanisms involved, we first thought that IDO had effects through kynurenine generation (because IDO converts tryptophan to give rise to the kynurenine pathway), but this was not the case,” explains Taleb. “Instead, we found that IDO, through tryptophan catabolism, indirectly altered the indole and IL-22 pathway (generation of indole depends on tryptophan).” The researchers also demonstrated that these effects were dependent on the gut microbiota.

“In terms of therapy, we know that a specific IDO inhibitor failed to show efficacy in cancer, so we propose re-using this inhibitor in patients with metabolic diseases,” concludes Taleb. Patients with obesity could also be treated with indole metabolites or with indole-producing bacteria, according to Taleb.