Diarrheal pathogens trigger rapid evolution of the guanylate cyclase-C signaling axis in bats

The pathogenesis of infectious diarrheal diseases is largely attributed to enterotoxins that cause dehydration by disrupting intestinal water absorption. We investigated patterns of genetic variation in mammalian guanylate cyclase-C (GC-C), an intestinal receptor targeted by bacterially encoded heat-stable enterotoxins (STa), to determine how host species adapt in response to diarrheal infections. Our phylogenetic and functional analysis of GC-C supports long-standing evolutionary conflict with diarrheal bacteria in primates and bats, with highly variable susceptibility to STa across species. In bats, we further show that GC-C diversification has sparked compensatory mutations in the endogenous uroguanylin ligand, suggesting an unusual scenario of pathogen-driven evolution of an entire signaling axis. Together, these findings suggest that conflicts with diarrheal pathogens have had far-reaching impacts on the evolution of mammalian gut physiology. [Display omitted] •Intestinal enterotoxin receptor GC-C bears signatures of a host-pathogen arms race•Primate and bat GC-C show species-specific susceptibility to enterotoxin variants•Bats exhibit unique compensatory evolution of the GC-C/uroguanylin signaling axis Studies of evolutionary arms races have primarily focused on interactions between host immune factors and infectious microbes. Carey et al. describe an unusual genetic conflict between diarrheal bacterial pathogens and a core intestinal signaling axis critical for maintaining proper gut physiology, broadening conceptions of the reach of pathogen-driven evolution.