Abstract Maternal obesity has been epidemiologically linked to an increased risk of sporadic colorectal cancer (CRC) in offspring, the third most prevalent cancer worldwide. This association underscores the lasting influence of early-life exposures on long-term health and disease susceptibility. Intestinal stem cells (ISCs), the long-lived cells that sustain epithelial renewal and often serve as the origin of intestinal cancers, are thought to play a central role in mediating this elevated cancer risk. However, how maternal obesity shapes the early-life programming and maturation of ISCs in their offspring remains poorly understood. Using mouse models of diet-induced obesity, we show that offspring exposed to a maternal high-fat Western diet (HFD) during pre- and postnatal development exhibit increased colonic proliferation, enhanced stem cell self-renewal, and a hypermetabolic state that persists into adulthood, even after dietary normalization. Alongside changes in stem cell properties, we observe a significant shift in epithelial cell composition, characterized by an increase in cells of secretory lineage at the expense of absorptive enterocytes, and these changes endure into adult life. Additionally, these changes are accompanied by an increased tumor burden in the loss of Apc heterozygosity model. Our data indicate that IL-17a, a pro-inflammatory cytokine, is critical in mediating these changes. Specifically, receptor IL-17RA/C expression is significantly upregulated in ISCs and secretory cells in maternal HFD-exposed offspring. Administration of IL-17a to intestinal organoids demonstrates sufficiency by mimicking the maternal obesogenic phenotype, indicating that immune-epithelial interactions influence ISC function and may be a driver of durable molecular patterning. These findings emphasize the long-term consequences of maternal HFD exposure on intestinal stem cell activity and epithelial composition, and possibly contribute to a higher risk of CRC in offspring later in life. Citation Format: Gourab Lahiri, Karla Mullen, Yesenia B. Millan, Swathi Sankar, Dominic R. Saiz, Thomas H. McDermott, Madeline Blatt, Abhigyan Shukla, Khashayarsha Khazaie, Miyeko D. Mana. Maternal obesity reprograms intestinal stem cells to elevate colorectal cancer risk in offspring abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 841.
Lahiri et al. (Fri,) studied this question.