The mammalian intestine is a natural habitat for trillions of bacteria, including harmless species called commensals and potentially pathogenic species. However, long-term persistence is a challenge for these resident bacteria, which must resist expulsion by waves of peristalsis — the process that pushes the intestinal contents downstream. The ways in which pathogenic bacteria adhere to host cells at sites of infection have been extensively investigated, but little is known about how commensal bacteria cling to mucosal surfaces in the gut. Spaulding et al. (2017) report that uropathogenic Escherichia coli (UPEC), a bacterium that is a commensal in the gut but pathogenic in the bladder, persists in the intestine thanks to filamentous protein complexes called pili that project from the bacterium and promote its adhesion to the gut wall. The authors also identify a sugar derivative that can combat pilus-mediated adhesion.
Fig. 1. Inhibición de la adherencia de Escherichia coli (UPEC) en el intestino mediado por el manósido M4284.
Uropathogenic Escherichia coli (UPEC) strains colonize the gut and are shed in faeces. If, from faeces, they gain access to the area around the urethra, the bacteria can work their way up the urethra, causing urinary-tract infections (UTIs). Preventing the colonization of the gut by these bacteria could therefore be a way to stop UTIs (particularly recurrent infections) from arising.
UPEC isolates encode up to 16 distinct chaperone-usher pathway pili, and each pilus type may enable colonization of a habitat in the host or environment. For example, the type 1 pilus adhesin FimH binds mannose on the bladder surface, and mediates colonization of the bladder. However, little is known about the mechanisms underlying UPEC persistence in the gut.
Using a mouse model, authors show that F17-like and type 1 pili promote intestinal colonization and show distinct binding to epithelial cells distributed along colonic crypts. Phylogenomic and structural analyses reveal that F17-like pili are closely related to pilus types carried by intestinal pathogens, but are restricted to extra-intestinal pathogenic E. coli. Moreover, they show that targeting FimH with M4284, a high-affinity inhibitory mannoside, reduces intestinal colonization of genetically diverse UPEC isolates, while simultaneously treating UTI, without notably disrupting the structural configuration of the gut microbiota. By selectively depleting intestinal UPEC reservoirs, mannosides could markedly reduce the rate of UTIs and recurrent UTIs.
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Fig. 2. Estructura del manósido M4284