Early-life acquisition of Lactobacillaceae protects against experimental cholera

Abstract

Cholera causes severe diarrheal illness in young children, but the mechanisms underlying age-dependent susceptibility remain unclear. Experimental cholera in neonatal mice recapitulates age-dependent susceptibility: suckling mice are susceptible to Vibrio cholerae colonization and cholera toxin (CT)-dependent disease, whereas adult mice are not readily colonized and do not develop cholera-like disease. Here, we define a developmental window in which susceptibility declines sharply over the first two postnatal weeks. Maternal antibiotic exposure disrupted vertical transmission of maternal microbiota to offspring and altered distal small intestinal microbiota assembly, extending the window of susceptibility to CT-dependent V. cholerae colonization and disease. Pups born to antibiotic-treated dams exhibited reduced Lactobacillaceae and increased Enterobacteriaceae, and reintroduction of an endogenous Lactobacillus isolate restored offspring lactobacilli levels and reestablished resistance to experimental cholera at two weeks of age. Consistent with a direct protective role, increasing lactobacilli in susceptible neonatal mice reduced experimental cholera burden, and cultures of the endogenous Lactobacillus isolate as well as spent culture media acidified the in vitro growth environment and rapidly eliminated recoverable V. cholerae. Together, these findings identify vertical transmission of maternal microbiota to offspring and lactobacilli-associated antagonism as determinants of early-life resistance to cholera.