Aspartate Alleviates Colonic Epithelial Damage by Regulating Intestinal Stem Cell Proliferation and Differentiation via Mitochondrial Dynamics

Abstract

Scope 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. Methods and results 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. Conclusions The findings indicate that aspartate promotes ISC proliferation and differentiation to alleviate colonic epithelial damage by regulation of mitochondrial metabolism and dynamics.

Oleanolic acid alleviate intestinal inflammation by inhibiting Takeda G-coupled protein receptor (TGR) 5 mediated cell apoptosis

“…33 Stem cells situated at the crypt base are indispensable for epithelial repair and renewal. 34 Consistent with previous research findings, we found that IBD typically results in a decline in both the number and efficacy of functional cells, such as goblet cells and stem cells, 22,27 implying that its therapeutic efficacy is particularly relevant in pathological states of intestinal inflammation or damage.…”

“…The protocols for organoid generation and assessment of budding efficiency were adapted from established literature. 27…”

Modulation of stem cell fate in intestinal homeostasis, injury and repair

“…Targeting p53-dependent stem cell death is the core strategy for intestinal chemo- or radioprotection[ 102 , 104 , 105 ]. The Toll-like receptor 4 signaling pathway[ 106 ], Slit guidance ligand 2 (Slit2)/ Roundabout guidance receptor 1 (Robo1) signaling[ 45 ], gut microbiota[ 90 , 107 ], and dietary components such as green tea derivative (-)-epigallocatechin-3-gallate[ 108 ], aspartate[ 109 ], pectin[ 110 ], and vitamin D[ 111 ] have been shown to mitigate the loss of ISCs and alleviate intestinal injury. The deletion of CREPT suppresses the proliferation and differentiation of ISCs and reduces Lgr5 + cell numbers after X-ray irradiation[ 112 ].…”

Anthocyanin attenuates disturbance of intestinal barrier in high-fat/high-cholesterol diet-challenged mice through regulating the response of T-helper 17 cells

“…As stimulating agents to model intestinal damage, toxic substances targeting the digestive system have been used in a few studies [11] . However, this kind of stimulators may not well represent the real causes of intestinal disfunctions, especially in the daily diet.…”