卡路里限制可以增强受伤肠道上皮的再生能力。除其他代谢变化外，卡路里限制还可以激活自噬途径。虽然独立研究将卡路里限制的再生益处归因于mTORC1下调，但尚不清楚自噬本身是否对卡路里限制的再生益处具有必要性。我们使用自噬基因删除的小鼠和器官样本来评估在卡路里限制后自噬对肠上皮再生的贡献。在没有受伤的情况下，肠上皮特异性删除自噬基因Atg7 (Atg7ΔIEC)的小鼠在卡路里限制后体重下降和组织学变化类似于野生型小鼠。相反，在辐射后卡路里限制的Atg7ΔIEC小鼠显示出再生性隐窝的显著减少，相比之下，与卡路里限制的野生型小鼠相比。通过对卡路里受限小鼠组织代谢物的定向分析，发现卡路里限制与野生型小鼠但不是Atg7ΔIEC小鼠的胆固醇酸盐酸（GCA）降低有关。为了评估GCA是否可以直接调节上皮干细胞的自我更新，我们进行了GCA处理的enteroid形成实验。野生型enteroid在GCA处理后表现出降低的形成效率，这表明在卡路里限制期间减少GCA的可用性可能是卡路里限制依赖于上皮自噬的方式中有一种机制，这种机制对上皮干细胞的自我更新具有影响。综上所述，我们的数据支持了肠上皮Atg7对卡路里限制的再生益处的前提，部分原因在于其调节肠道lumen GCA，从而直接影响上皮干细胞的自我更新。

Calorie restriction can enhance the regenerative capacity of the injured intestinal epithelium. Among other metabolic changes, calorie restriction can activate the autophagy pathway. While independent studies have attributed the regenerative benefit of calorie restriction to downregulation of mTORC1, it is not known whether autophagy itself is required for the regenerative benefit of calorie restriction. We used mouse and organoid models with autophagy gene deletion to evaluate the contribution of autophagy to intestinal epithelial regeneration following calorie restriction. In the absence of injury, mice with intestinal epithelial-specific deletion of autophagy gene Atg7 (Atg7ΔIEC) exhibit weight loss and histological changes similar to wildtype mice following calorie restriction. Conversely, calorie restricted Atg7ΔIEC mice displayed a significant reduction in regenerative crypt foci following irradiation compared to calorie restricted wildtype mice. Targeted analyses of tissue metabolites in calorie restricted mice revealed an association between calorie restriction and reduced glycocholic acid (GCA) in wildtype but not Atg7ΔIEC mice. To evaluate whether GCA can directly modulate epithelial stem cell self-renewal, we performed enteroid formation assays with or without GCA. Wildtype enteroids exhibited reduced enteroid formation efficiency in response to GCA treatment, suggesting that reduced availability of GCA during calorie restriction may be one mechanism by which calorie restriction favors epithelial regeneration in a manner dependent upon epithelial autophagy. Taken together, our data support the premise that intestinal epithelial Atg7 is required for the regenerative benefit of calorie restriction, due in part to its role in modulating luminal GCA with direct effects on epithelial stem cell self-renewal.