Maternal Obesity Programs Intestinal Stem Cells and Epithelial Composition in Offspring, Driving Long-term Colorectal Cancer Susceptibility

Maternal obesity has been epidemiologically linked to an increased risk of sporadic colorectal cancer (CRC) in offspring, the third most prevalent cancer globally. This correlation underscores the profound influence of early-life exposures on long-term health and disease susceptibility. Intestinal stem cells (ISCs), the long-lived cells in the colon that often serve as the origin of intestinal cancers, are believed to play a crucial role in mediating this increased cancer risk. However, the effects of a maternal obesogenic environment on developing and maturing ISCs remain poorly understood. Using mouse models of diet-induced obesity, we show that offspring exposed to a maternal high-fat 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 observed 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 were accompanied by an increased tumour burden in the loss of heterozygosity model. Our data indicate that the IL-17 cytokine pathway 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 leads to enhanced stem cell numbers and regeneration, increased differentiation into secretory cell types and reduced absorptive cell markers, thereby mimicking the maternal obesogenic phenotype and strongly indicating that immune-epithelial interaction influences 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.