Maternal obesity induces developmental programming of Intestinal stem cells through an IL-17A/PPAR immune-epithelial axis

Lahiri, G.; Barrera Millan, Y.; Sankar, S.; Mullen, K.; Hartley McDermott, T.; Saiz, D. R.; Farnsworth, F.; Torel, M.; Blatt, M.; Roginski, A. C.; Shukla, A.; Florsheim, E. B.; Bartelle, B. B.; Gounari, F.; Khazaie, K.; Mana, M. D.

doi:10.64898/2026.03.15.711939

bioRxiv · 10.64898/2026.03.15.711939

Maternal obesity induces developmental programming of Intestinal stem cells through an IL-17A/PPAR immune-epithelial axis

Lahiri, G.·Barrera Millan, Y.·Sankar, S.·Mullen, K.·Hartley McDermott, T.·Saiz, D. R.·Farnsworth, F.·Torel, M.·Blatt, M.·Roginski, A. C.·Shukla, A.·Florsheim, E. B.·Bartelle, B. B.·Gounari, F.·Khazaie, K.·Mana, M. D.

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Abstract

Maternal obesity is associated with increased risk of sporadic colorectal cancer (CRC) in offspring, suggesting that early-life environmental exposures durably shape disease susceptibility. Intestinal stem cells (ISCs), long-lived drivers of epithelial renewal and tumor initiation, are well poised to mediate this effect; however, how maternal obesity influences ISC programming during development remains poorly understood. Using mouse models of diet-induced obesity, we show that exposure to a maternal high-fat Western diet (mHFD) during pre- and postnatal development stably programs colonic ISCs. Offspring exhibit increased ISC proliferation, enhanced self-renewal, a hypermetabolic state, and altered epithelial lineage composition that persists into adulthood despite dietary normalization. These changes are accompanied by increased tumor burden following loss of Apc heterozygosity. Mechanistically, we identify the pro-inflammatory cytokine IL-17A as a key extrinsic driver and PPARd/a nuclear receptors as intrinsic mediators of the mHFD phenotype, revealing an immune-epithelial axis that programs ISC function during early life. Together, our findings demonstrate that maternal metabolic environments durably enhance stem cell fitness, providing a mechanistic link between developmental exposure and adult disease risk.

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Lahiri, G., Barrera Millan, Y., Sankar, S., Mullen, K., Hartley McDermott, T., Saiz, D. R., Farnsworth, F., Torel, M., Blatt, M., Roginski, A. C., Shukla, A., Florsheim, E. B., Bartelle, B. B., Gounari, F., Khazaie, K., Mana, M. D.. 2026-03-16. Maternal obesity induces developmental programming of Intestinal stem cells through an IL-17A/PPAR immune-epithelial axis. https://doi.org/10.64898/2026.03.15.711939

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