Colon to Rectum

Cell. 2026;189(9):2714-2730.e20

Rispal J, Garcia JR, Palikuqi B, Vegesna M, Vaka D, Kang SW, Trentesaux C, Du J, Realini NR, Spencer PN, Gardner JM, Hausmann A, Kattah MG, Lau KS, Boffelli D, Klein OD

Microbiome-produced nicotinic acid controls colon regional identity and injury susceptibility

The regionalized structure of the intestinal epithelium is critical for its function, and the risk for certain diseases has a regional bias. However, how regionalization is established and how it influences disease susceptibility remain poorly understood. Here, we investigated the role of the gut microbiome—the regionalized community of microorganisms in the intestinal lumen—in promoting regionalization of the colon. We found that the proximo-distal identity of colonocytes along the organ’s length is disrupted in mice lacking a microbiome and that the proximal colonic microbiome produces high levels of nicotinic acid, which induces Pparα expression to establish proximal colonocyte identity. Furthermore, we report that microbiome-driven proximal identity confers protection against tissue injury in the mouse. Finally, we determined that the human colon is regionalized and loses its proximal identity during certain disease states.

DOI:  10.1016/j.cell.2026.02.007