mTORC1 in the Paneth cell niche couples intestinal stem cell function to calorie intake

How adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here, we find that Paneth cells, a key constituent of the mammalian intestinal stem cell (ISC) niche, augment stem cell function in response to calorie restriction (CR). CR acts by reducing mTOR complex 1 (mTORC1) signaling in Paneth cells, and the ISC-enhancing effects of CR can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced mTORC1 activation in Paneth cells during CR abolishes their effects on ISCs. Finally, increased expression in Paneth cells of bone stromal antigen 1 (Bst-1), an ectoenzyme that produces the paracrine factor cyclic ADP ribose (cADPR), mediates the effects of CR and rapamycin on ISC function. Our findings establish that mTORC1 non-cell autonomously regulates stem cell self-renewal, and highlight a significant role of the mammalian intestinal niche in coupling stem cell function to organismal physiology.