Wang Dan, Kuang Yanling, Wan Zhicheng, Li Pei, Zhao Jiangchao, Zhu Huiling, Liu Yulan
Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, P. R. China.
Division of Agriculture, Department of Animal Science, University of Arkansas, Fayetteville, AR, 72701, USA.
Mol Nutr Food Res. 2022 Dec;66(24):e2200168. doi: 10.1002/mnfr.202200168. Epub 2022 Oct 30.
Proliferation and differentiation of intestinal stem cells (ISCs) are crucial for functional restoration after injury, which can be regulated by nutritional molecules. Aspartate is implicated in maintaining intestinal barrier after injury, but underlying mechanisms remain elusive. Here, this study seeks to investigate if aspartate alleviates colonic epithelial damage by regulating ISC function, and to elucidate its mechanisms.
Eight-week-old male C57BL/6 mice supplement with or without 1% L-aspartate are subjected to drinking water or 2.5% DSS to induce colitis. In this study, aspartate administration alleviates the severity of colitis, as indicated by reduced body weight loss, colon shortening, and inhibited pro-inflammatory cytokine expression in DSS-challenged mice. Additionally, aspartate promotes colonic epithelial cell proliferation and differentiation after DSS-induced damage in mice. Pretreatment with aspartate not only enhances ISC proliferation but also induces ISC differentiation toward enterocytes and goblet cells, which prevent TNF-α-induced colonoid damage. Mechanistically, aspartate ameliorates DSS/TNF-α-induced perturbation of mitochondrial metabolism and maintains mitochondrial dynamics in colonic epithelium and colonoids. Moreover, aspartate-mediated ISC proliferation and differentiation are primarily dependent on mitochondrial fusion rather than fission.
The findings indicate that aspartate promotes ISC proliferation and differentiation to alleviate colonic epithelial damage by regulation of mitochondrial metabolism and dynamics.
肠道干细胞（ISC）的增殖和分化对于损伤后的功能恢复至关重要，其可受营养分子调控。天冬氨酸与损伤后维持肠道屏障有关，但其潜在机制仍不清楚。在此，本研究旨在探究天冬氨酸是否通过调节ISC功能减轻结肠上皮损伤，并阐明其机制。
8周龄雄性C57BL/6小鼠，分别给予或不给予1% L-天冬氨酸，通过饮用含或不含2.5%葡聚糖硫酸钠（DSS）的水诱导结肠炎。在本研究中，给予天冬氨酸可减轻结肠炎的严重程度，表现为体重减轻减少、结肠缩短减轻以及DSS诱导的小鼠促炎细胞因子表达受到抑制。此外，天冬氨酸可促进DSS诱导损伤后的小鼠结肠上皮细胞增殖和分化。天冬氨酸预处理不仅增强ISC增殖，还诱导ISC向肠上皮细胞和杯状细胞分化，从而防止肿瘤坏死因子-α（TNF-α）诱导的类结肠损伤。机制上，天冬氨酸改善DSS/TNF-α诱导的线粒体代谢紊乱，并维持结肠上皮和类结肠中的线粒体动力学。此外，天冬氨酸介导的ISC增殖和分化主要依赖于线粒体融合而非裂变。
研究结果表明，天冬氨酸通过调节线粒体代谢和动力学促进ISC增殖和分化，以减轻结肠上皮损伤。
