Nutrient sensing by the intestinal epithelium orchestrates mucosal antimicrobial defense via translational control of Hes1

Metabolic programs and host defense are highly integrated to ensure proper immune responses during stress. Central to these responses, mTOR regulates immune functions by sensing and integrating environmental cues, yet how these systems are coordinated at the intestinal surface remains undefined. We show that the antimicrobial peptide α-defensin is functionally sustained during nutrient deprivation due to regulation of defensin-processing enzyme MMP7 by microbiota- and host-derived factors. Unlike other antimicrobial peptides, the MMP7-α-defensin axis remains active during nutrient fluctuations, providing essential protection against enteric pathogens. Sustained Mmp7 expression requires the microbiota and is mediated by de-repression of the transcription activator Atoh1 upon attenuation of the transcriptional repressor Hes1 in intestinal epithelial cells. Hes1 levels are regulated via mTOR and controlled translationally, constituting a metabolism-translation-transcription loop. Disrupting this loop by supplying nutrients paradoxically compromises anti-bacterial defense. Together, these results uncover a regulatory circuit that couples host nutrient status to epithelial anti-microbial immunity. Mice were fasted for 0 hr (also called fed), 48 hrs or 72 hrs. Ileum mRNA profiles of fed and fasted mice were generated by deep sequencing. NOTE: the 'Fed RNA' sample, prepared and sequenced together with 'Fasted_48 hrs RNA', is the control sample of 'Fasted_48 hrs RNA'. The 'Fed' sample, prepared and sequenced together with 'Fasted_72 hrs', is the control sample for the 'Fasted_72 hrs' sample.