Bacteria use two-component quorum-sensing systems to communicate with each other and their hosts. Catecholamines are host stress signals that participate in this dialogue and drive bacterial growth and virulence. Evidence from a preclinical model of inflammatory bowel disease (IBD) revealed that Enterobacteriaceae and pathways linked to catecholamine-mediated bacterial virulence are enriched in active disease. Here we targeted the bacterial adrenergic sensor, quorum-sensing Escherichia coli regulator C (QseC) of the QseBC two-component system. Genetically inactivating qseC in a pathogenic, IBD-associated E. coli strain (LF82) reduced its virulence and ability to colonize a murine host. Furthermore, biochemically inhibiting QseC attenuated disease in multiple preclinical IBD models. This report demonstrates that QseC signaling influences IBD pathogenesis and identifies QseC blockade as a therapeutic strategy for colitis-associated bacteria.

Abstract

Hosts and their microbes have established a sophisticated communication system over many millennia. Within mammalian hosts, this dynamic cross-talk is essential for maintaining intestinal homeostasis. In a genetically susceptible host, dysbiosis of the gut microbiome and dysregulated immune responses are central to the development of inflammatory bowel disease (IBD). Previous surveys of stool from the T-bet−/−Rag2−/− IBD mouse model revealed microbial features that discriminate between health and disease states. Enterobacteriaceae expansion and increased gene abundances for benzoate degradation, two-component systems, and bacterial motility proteins pointed to the potential involvement of a catecholamine-mediated bacterial signaling axis in colitis pathogenesis. Enterobacteriaceae sense and respond to microbiota-generated signals and host-derived catecholamines through the two-component quorum-sensing Escherichia coli regulators B and C (QseBC) system. On signal detection, QseC activates a cascade to induce virulence gene expression. Although a single pathogen has not been identified as a causative agent in IBD, adherent-invasive Escherichia coli (AIEC) have been implicated. Flagellar expression is necessary for the IBD-associated AIEC strain LF82 to establish colonization. Thus, we hypothesized that qseC inactivation could reduce LF82’s virulence, and found that an absence of qseC leads to down-regulated flagellar expression and motility in vitro and reduced colonization in vivo. We extend these findings on the potential of QseC-based IBD therapeutics to three preclinical IBD models, wherein we observe that QseC blockade can effectively modulate colitogenic microbiotas to reduce intestinal inflammation. Collectively, our data support a role for QseC-mediated bacterial signaling in IBD pathogenesis and indicate that QseC inhibition may be a useful microbiota-targeted approach for disease management.