Metabolic regulation of intestinal homeostasis: molecular and cellular mechanisms and diseases

Abstract

Metabolism serves not only as the organism's energy source but also yields metabolites crucial for maintaining tissue homeostasis and overall health. Intestinal stem cells (ISCs) maintain intestinal homeostasis through continuous self-renewal and differentiation divisions. The intricate relationship between metabolic pathways and intestinal homeostasis underscores their crucial interplay. Metabolic pathways have been shown to directly regulate ISC self-renewal and influence ISC fate decisions under homeostatic conditions, but the cellular and molecular mechanisms remain incompletely understood. Understanding the intricate involvement of various pathways in maintaining intestinal homeostasis holds promise for devising innovative strategies to address intestinal diseases. Here, we provide a comprehensive review of recent advances in the regulation of intestinal homeostasis. We describe the regulation of intestinal homeostasis from multiple perspectives, including the regulation of intestinal epithelial cells, the regulation of the tissue microenvironment, and the key role of nutrient metabolism. We highlight the regulation of intestinal homeostasis and ISC by nutrient metabolism. This review provides a multifaceted perspective on how intestinal homeostasis is regulated and provides ideas for intestinal diseases and repair of intestinal damage.

Keywords: gut microbiota; intestinal homeostasis; intestinal stem cell; metabolite; nutrient metabolism.

FIGURE 1

Epithelial and organoid structures of the small intestine. (A) The small intestinal epithelium is organized in units of crypts (proliferation zone) and villi (differentiation zone). Crypts are located at the bottom of the villi, and at the base of each crypt are wedge‐shaped crypt base columnar cells, also known as intestinal stem cells. (B) Small intestinal organoids can be categorized into fetal organoids and adult organoids according to their origin. Their transcriptomes and morphology display notable differences. BMP, bone morphogenetic protein; WNT, wingless‐related integration site.

FIGURE 2

Regulation of intestinal homeostasis by microenvironment. (A) The intestinal microenvironment comprises stromal cells and gut microbiota. Stromal cells include mesenchymal and immune cells. The mesenchymal cells encompassing fibroblasts, myofibroblasts, pericytes, smooth muscle cells, and mesenchymal stem cells. Paneth cells and crypt myofibroblasts secrete wingless‐related integration site (WNT) and epidermal growth factor (EGF) ligands, which are essential for the growth and maintenance of intestinal stem cells (ISCs). Villus fibroblasts contribute to epithelial differentiation by secreting bone morphogenetic protein (BMP) ligands and the EGF family ligand neuregulin 1 (NRG1). Upon intestinal injury, fibroblasts upregulate the secretion of R‐spondin3 to promote tissue repair. MAP3K2‐regulated intestinal stromal cells (MRISC) are located at the base of colonic crypts. These cells enhance WNT signaling through the upregulation of R‐spondin1. Ptgs2 ⁺ fibroblasts secrete prostaglandin E2, which activates the Yes‐associated protein (YAP) pathway and stimulates epithelial regeneration. After radiation‐induced damage, macrophages accumulate at the injury site, releasing transforming growth factor beta 1 (TGFB1) to facilitate tissue repair. Innate lymphocyte types 3 (ILC3s) activate postinjury and secrete interleukin‐22 (IL‐22) to further support the regenerative process. Smooth muscle cells contribute to intestinal repair by secreting BMP antagonists and matrix metallopeptidase 17 (MMP17), which together enhance YAP signaling. (B) Lactobacillus reuteri produces lactic acid, which activates G‐protein‐coupled receptor 81 (GPR81) receptors on stromal cells, leading to the upregulation of Wnt2 and Wnt3a expression. This activation enhances the WNT/β‐catenin signaling pathway, thereby promoting ISC self‐renewal and organoid proliferation. Furthermore, Lactobacillus reuteri stimulates lamina propria lymphocytes to secrete IL‐22, which activates the signal transducer and activator of transcription 3 (STAT3) pathway and accelerates proliferation of intestinal epithelial cells. Additionally, Lactobacillus reuteri promotes oxytocin secretion through proinsulin signaling mechanisms. Bacteroides fragilis produces 3‐phenylpropionic acid derivatives, which contribute to the maintenance of intestinal barrier integrity by activating the aryl hydrocarbon receptor (AhR) signaling pathway. Clostridium bifermentans enhances lipid absorption by upregulating diacylglycerol O‐acyltransferase 2 (Dgat2) expression, thereby increasing oleic acid uptake and regulating lipid metabolism.

FIGURE 3

Regulation of intestinal stem cells (ISCs) by glucose, fatty acid, and ketone body metabolism. (A) Regulation of the small intestine by key genes and metabolites involved in glucose metabolism. Paneth cells produce lactate through anaerobic glycolysis to fuel the ISCs and promote ISC self‐renewal. (B) Acetyl coenzyme A carboxylase (ACC) and fatty acid synthase (FASN) are essential enzymes in the pathway of fatty acid synthesis, responsible for producing long‐chain fats and their derivatives. Carnitine palmitoyl‐transferase1 alpha (CPT1A) is involved in the transport of fatty acids into mitochondria. A portion of the acetyl‐CoA produced from fatty acid oxidation is redirected to the liver, where it contributes to ketone body metabolism. In the presence of HMG‐CoA synthase 2 (HMGCS2), beta‐hydroxybutyrate (β‐OHB) is generated to promote ISC self‐renewal. HNF4, hepatocyte nuclear factor 4; PPAR, peroxisome proliferator‐activated receptor; PRDM16, PR/SET domain 16.