严重营养不良（SM）儿童的肠道显示出与增加感染和死亡率相关的结构和功能改变。SM破坏了色氨酸-酪氨酸途径，可能影响SIRT1和mTORC1介导的自噬和线粒体稳态等过程。我们使用小鼠和器官样模型研究了这些调节紊乱对营养不良肠病和维持自噬活性和线粒体健康的保护能力的影响。通过喂养雄性断奶C57BL/6小鼠低蛋白饮食（LPD）14天来诱导SM。小鼠被分别治疗NAD+前体尼克酰胺；mTORC1抑制剂雷帕霉素；SIRT1激活剂白藜芦醇；或SIRT1抑制剂EX-527。通过限制氨基酸提供诱导肠道器官样体营养不良病变。检查了营养不良肠病的特征和路径，包括细胞间隙通透性、营养物吸收和自噬、线粒体和活性氧物质（ROS）异常。LPD饲喂和随后的低色氨酸可用性导致绒毛萎缩、营养物吸收不良和肠道屏障功能障碍。在LPD饲喂小鼠中，尼克酰胺补充与SIRT1介导的线粒体自噬活化连接，减少了损伤的线粒体，并改善了肠道屏障功能。mTORC1的抑制减少了肠道屏障功能障碍和营养物吸收不良。通过器官样模型验证和扩展了这些发现，证明解决线粒体ROS问题可以解决屏障功能障碍。营养不良肠病由SIRT1和mTORC1途径的失调引起，导致自噬、线粒体稳态和ROS的紊乱。尼克酰胺补充是否能够改善SM儿童的营养不良肠病应该在临床试验中进行探索。本研究获得了比尔和梅琳达·盖茨基金会、西极研究所、加拿大卫生研究机构和格罗宁根大学医学中心的支持。版权所有 © 2023 作者们。由Elsevier B.V.出版。保留所有权利。

The intestine of children with severe malnutrition (SM) shows structural and functional changes that are linked to increased infection and mortality. SM dysregulates the tryptophan-kynurenine pathway, which may impact processes such as SIRT1- and mTORC1-mediated autophagy and mitochondrial homeostasis. Using a mouse and organoid model of SM, we studied the repercussions of these dysregulations on malnutrition enteropathy and the protective capacity of maintaining autophagy activity and mitochondrial health.SM was induced through feeding male weanling C57BL/6 mice a low protein diet (LPD) for 14-days. Mice were either treated with the NAD+-precursor, nicotinamide; an mTORC1-inhibitor, rapamycin; a SIRT1-activator, resveratrol; or SIRT1-inhibitor, EX-527. Malnutrition enteropathy was induced in enteric organoids through amino-acid deprivation. Features of and pathways to malnutrition enteropathy were examined, including paracellular permeability, nutrient absorption, and autophagic, mitochondrial, and reactive-oxygen-species (ROS) abnormalities.LPD-feeding and ensuing low-tryptophan availability led to villus atrophy, nutrient malabsorption, and intestinal barrier dysfunction. In LPD-fed mice, nicotinamide-supplementation was linked to SIRT1-mediated activation of mitophagy, which reduced damaged mitochondria, and improved intestinal barrier function. Inhibition of mTORC1 reduced intestinal barrier dysfunction and nutrient malabsorption. Findings were validated and extended using an organoid model, demonstrating that resolution of mitochondrial ROS resolved barrier dysfunction.Malnutrition enteropathy arises from a dysregulation of the SIRT1 and mTORC1 pathways, leading to disrupted autophagy, mitochondrial homeostasis, and ROS. Whether nicotinamide-supplementation in children with SM could ameliorate malnutrition enteropathy should be explored in clinical trials.This work was supported by the Bill and Melinda Gates Foundation, the Sickkids Research Institute, the Canadian Institutes of Health Research, and the University Medical Center Groningen.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.