Microbiota-derived small molecule genotoxins: host interactions and ecological impact in the gut ecosystem

Abstract

The human intestinal tract is densely colonized by a microbial community that is subject to intense competition. Bacteria in this complex habitat seek to outcompete their neighbors for nutrients and eliminate competitors with antibacterial toxins. Antagonism can be mediated by diverse effectors including toxic proteins and small molecule inhibitors that are released extracellularly or delivered by specialized secretion systems to targeted cells. Two prototypical microbiota-derived enterotoxins, colibactin and tilimycin, and the newly discovered family of indolimines represent an expanding group of non-proteinaceous small molecules which specifically target DNA. In addition to cell killing, they generate mutations and genome instability in intoxicated microbes and host cells alike. They have been studied in detail because of their direct toxicity to human cells and important etiological roles in intestinal pathologies. Increasing evidence, however, reveals that these commensal genotoxins are also mediators of interbacterial antagonism, which impacts gut microbial ecology. In this review, we illustrate the functional versatility of commensal genotoxins in the gut ecosystem.

Keywords

• Bacterial antagonism
• DNA damage
• secondary metabolites
• colorectal cancer
• inflammatory bowel disease
• colibactin