Microbiota-derived genotoxic metabolites discovered in patients with inflammatory bowel disease

Functional screening of human gut microbiota reveals a family of small molecule genotoxins called indolimines in patients with inflammatory bowel disease (IBD), according to a new study. According to the findings, these genotoxic metabolites may play a role in the development of colorectal cancer (CRC) – the second leading cause of cancer deaths worldwide. Individuals with IBD are at increased risk of developing CRC. Previous research shows that microbiota-derived genotoxic metabolites, which damage or mutate DNA, likely play a critical role in driving CRC pathogenesis. However, the full spectrum of genotoxic chemicals produced by commensal gut microbes remains poorly defined. To better understand these molecules, Yiyun Cao and colleagues developed a functional screen to systematically evaluate the genotoxicity of a large collection of indigenous microbiota from patients with IBD. Cao et al. report the discovery of a previously unknown family of DNA-damaging genotoxic microbial metabolites they term the indolimines, which are produced by the CRC-associated gut microbe Morganella morganii. The authors demonstrate that, in a mouse model of colon cancer, M. morganii exacerbated tumor growth. However, a non-indolimine-producing mutant strain lacked this observed genotoxicity and did not influence tumorigenesis. According to Cao et al., the findings underscore the diverse impacts that small-molecule metabolites from the microbiome have on host biology and disease. "The study of Cao et al. reveals that the human colon microbiota – already highly implicated in CRC pathogenesis – has a broad-ranging, previously unimagined capacity to produce genotoxins with colon disease-inducing potential," write Jens Puschhof and Cynthia Sears in a related Perspective.