Alanine Catabolism of Paneth Cells Maintains Intestinal Stem Cell Function During Dietary Restriction

Paneth cell niche promotes the function of intestinal stem cells (ISCs) during reduced food intake, but how ISC activity can be boosted when availability of resources is simultaneously reduced remains unknown. Here, we show that the increase in ISC function upon dietary restriction (DR) is dependent on the mitochondrial alanine transaminase Gpt2 in Paneth cells. Metabolic tracing of Alanine directly showed that during DR, the Paneth cell niche catabolizes increased amounts of alanine to produce lactate, which is transported to ISCs to fuel their TCA cycle. Correspondingly, inhibition of lactate import to stem cells abolished the DR induced capacity of Paneth cells to support ISC function. DR resulted in deacetylation of Gpt2 in a Sirtuin3 dependent manner, providing a possible mechanism for Gpt2 regulation. Taken together, our results reveal an important role of the metabolic niche in tissue adaptation, where alanine utilization by the Paneth cells supports stem cells during nutritional challenges.