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

Area of Science:

• Developmental biology
• Cancer research
• Metabolic disease

Background:

• Maternal obesity increases offspring's risk for sporadic colorectal cancer (CRC).
• Early-life environmental factors can durably influence disease susceptibility.
• Intestinal stem cells (ISCs) are crucial for gut renewal and tumor initiation.

Purpose of the Study:

• To investigate how maternal obesity programs intestinal stem cells (ISCs) during development.
• To understand the mechanisms linking maternal diet to offspring's CRC risk.

Main Methods:

• Utilized mouse models of diet-induced obesity.
• Exposed pregnant mice to a high-fat Western diet (mHFD).
• Analyzed colonic ISCs in offspring for proliferation, self-renewal, metabolic state, and lineage composition.

Main Results:

• Maternal HFD stably programmed colonic ISCs in offspring.
• Offspring exhibited increased ISC proliferation, enhanced self-renewal, and a hypermetabolic state.
• These programming effects persisted into adulthood and increased tumor burden after Apc loss.

Conclusions:

• Maternal obesity durably enhances ISC fitness, establishing a link between developmental exposures and adult disease risk.
• Identified IL-17A and PPARd/a nuclear receptors as key mediators of the mHFD phenotype.
• Revealed an immune-epithelial axis programming ISC function during early life.