Neurotensin Regulates Proliferation and Stem Cell Function in the Small Intestine in a Nutrient-Dependent Manner

Area of Science:

• Gastroenterology
• Cell Biology
• Nutritional Science

Background:

• Intestinal stem cells (ISCs) are vital for gut health and highly sensitive to nutrient availability.
• Neurotensin (NT), a gut peptide released upon fat ingestion, influences intestinal mucosa growth.
• NT's role in ISC function, particularly during nutritional stress, remains largely unexplored.

Purpose of the Study:

• To investigate the role of Neurotensin (NT) in regulating intestinal stem cell (ISC) function under varying nutrient conditions.
• To elucidate the signaling pathways activated by NT in ISCs during nutrient-rich and nutrient-deprived states.

Main Methods:

• Utilized Lgr5-EGFP NT knockout and wild-type mice, subjected to ad libitum feeding or fasting.
• Employed gene expression analysis, FACS, Western blot, immunohistochemistry, and organoid culture to assess ISC function.
• Investigated NT's role in Drosophila midgut enteroendocrine cells under different dietary conditions.

Main Results:

• Loss of NT impaired ISC proliferation and function, dependent on nutrient status.
• NT stimulated ERK1/2 signaling and cell-cycle genes in nutrient-rich conditions.
• NT activated WNT/β-catenin signaling and ISC-specific genes during nutrient depletion, preserving ISC function and Lgr5 expression.

Conclusions:

• Neurotensin plays a critical, evolutionarily conserved role in maintaining intestinal stem cells during nutritional stress.
• NT signaling is essential for adapting ISC function to nutrient availability, preventing ISC loss during fasting.