Good Gone Bad: One Toxin Away From Disease for Bacteroides fragilis

Abstract

The human gut is colonized by hundreds of trillions of microorganisms whose acquisition begins during early infancy. Species from the Bacteroides genus are ubiquitous commensals, comprising about thirty percent of the human gut microbiota. Bacteroides fragilis is one of the least abundant Bacteroides species, yet is the most common anaerobe isolated from extraintestinal infections in humans. A subset of B. fragilis strains carry a genetic element that encodes a metalloprotease enterotoxin named Bacteroides fragilis toxin, or BFT. Toxin-bearing strains, or Enterotoxigenic B. fragilis (ETBF) cause acute and chronic intestinal disease in children and adults. Despite this association with disease, around twenty percent of the human population appear to be asymptomatic carriers of ETBF. BFT damages the colonic epithelial barrier by inducing cleavage of the zonula adherens protein E-cadherin and initiating a cell signaling response characterized by inflammation and c-Myc-dependent pro-oncogenic hyperproliferation. As a consequence, mice harboring genetic mutations that predispose to colonic inflammation or tumor formation are uniquely susceptible to toxin-mediated injury. The recent observation of ETBF-bearing biofilms in colon biopsies from humans with colon cancer susceptibility loci strongly suggests that ETBF is a driver of colorectal cancer. This article will address ETBF biology from a host-pathobiont perspective, including clinical data, analysis of molecular mechanisms of disease, and the complex ecological context of the human gut.

Keywords: BFT; Bacteroides fragilis; Fragilysin; Gut microbiota; Metalloprotease.