Microbiome-produced nicotinic acid controls colon regional identity and injury susceptibility (Bulk-RNAseq)

The gut epithelium exhibits regional specialization critical for its function and susceptibility to disease, as gut diseases localize to specific regions of the organ. However, how regionalization is established and its influence on disease susceptibility remain poorly understood. Here, we investigate the role of the gut microbiome—which comprises all microorganisms residing in the gut lumen and is itself regionalized—in regulating regionalization of the colon. We demonstrate that the regional identity of colonocytes is disrupted in mice lacking a microbiome. Mechanistically, we show that the proximal colonic microbiome produces high levels of nicotinic acid, which induces Pparα expression to establish proximal colonocyte identity. Furthermore, we find that microbiome-driven proximal identity confers protection against tissue injury in the mouse. Finally, we show that colon regionalization and the loss of proximal identity during disease are also present in human.