Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 308, Issue 10, Pages G831-G839Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00422.2014
Keywords
intestinal organoids; L-glutamine; L-alanyl-L-glutamine; ERK; mammalian target of rapamycin
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Funding
- Fogarty International Center/National Institutes of Health [K02 TW-08767]
- North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Foundation/Nestle Nutrition Young Investigator Award
- National Council for Scientific and Technological Development (CNPq) Science Without Borders award
- National Institutes of Health [R01 DK-092306, R01 CA-142826]
- University of Cincinnati Medical Scientist Training Program
- National Institute of Diabetes and Digestive and Kidney Diseases [P30 DK-078392]
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L-Glutamine (Gln) is a key metabolic fuel for intestinal epithelial cell proliferation and survival and may be conditionally essential for gut homeostasis during catabolic states. We show that L-alanyl-L-glutamine (Ala-Gln), a stable Gln dipeptide, protects mice against jejunal crypt depletion in the setting of dietary protein and fat deficiency. Separately, we show that murine crypt cultures (enteroids) derived from the jejunum require Gln or Ala-Gln for maximal expansion. Once expanded, enteroids deprived of Gln display a gradual atrophy of cryptlike domains, with decreased epithelial proliferation, but stable proportions of Paneth and goblet cell differentiation, at 24 h. Replenishment of enteroid medium with Gln selectively activates mammalian target of rapamycin (mTOR) signaling pathways, rescues proliferation, and promotes crypt regeneration. Gln deprivation beyond 48 h leads to destabilization of enteroids but persistence of EGFP-Lgr5-positive intestinal stem cells with the capacity to regenerate enteroids upon Gln rescue. Collectively, these findings indicate that Gln deprivation induces a reversible quiescence of intestinal stem cells and provides new insights into nutritional regulation of intestinal epithelial homeostasis.
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