Stress reactions such as trauma, burns and severe infections can lead to intestinal mucosal damage. A variety of peptides can promote intestinal mucosal growth and repair after injury, but their effects lack specificity and act on both intestinal mucosa and other tissue cells. Glucagon-like peptide 2 (GLP-2) is a peptide hormone synthesized by intestinal L endocrine cells and released with food, which achieves its biological activity through G protein-coupled receptor-mediated signaling. GLP-2 is a single-chain peptide composed of 33 amino acid residues, with a molecular weight of 3900 daltons. GLP-2 is synthesized and released by intestinal L endocrine cells and is regulated by feeding, neurological and endocrine factors, with the most important stimulation of the secretory activity by eating foods containing carbohydrates and fats [2]. In normal adults, the most significant increase in the concentration of GLP-2 in the blood circulation occurs within 15 minutes and 1 hour after a meal.The main form of GLP-2 present in the intestinal mucosal tissue and blood circulation is the intact GLP-2, GLP-2(1-33), which has a biological half-life of about 7 minutes in the human blood circulation and is metabolized mainly by renal excretion and by dipeptidyl peptidase 4 on the intestinal brush border ( Its metabolism is mainly through renal excretion and hydrolysis of the first two residues of the amino terminus by dipeptidyl peptidase-4 (DPP-4) on the intestinal brush border to form the inactive GLP-2(2-33). The intestinal epithelial growth of rats fed GLP-2 analogs lacking the DDP-4 site of action was significantly better than that of rats fed natural GLP-2, and the clearance of GLP-2 in the blood of bilaterally nephrectomized rats was significantly lower than that of non-nephrectomized rats, whereas GLP-2(2-33) has recently been shown to be a competitive antagonist of the GLP-2 receptor (GLP-2R), inhibiting GLP- 2and nutritionally induced intestinal mucosal growth [3]. These suggest that the biological activity of GLP-2 is regulated by the triad of DDP-4 hydrolysis, antagonism of its degradation products and renal clearance. II. Protective effects of GLP-2 on intestinal mucosa The effects of GLP-2 on the intestine include [4]: specific stimulation of intestinal mucosal growth and enhanced regeneration of intestinal mucosa after injury; inhibition of apoptosis of intestinal mucosal epithelial cells and crypt cells; enhancement of glucose transport on the basolateral side of intestinal epithelial cells and glucose transporter-2 (GLUT2 The effect of GLP-2 on intestinal mucosa is basically independent of age and sex, and it has obvious effect on intestinal digestion and absorption by sedation, intramuscular injection, subcutaneous injection and intraperitoneal injection. GLP-2 can increase the weight and nutrient absorption of the small intestine of rats, and the microscopic observation of GLP-2-treated small intestinal mucosa shows a significant increase in the number of microvilli, which are associated with the promotion of small intestinal crypt cell proliferation, making the crypt volume increase and the villi increase. GLP-2 significantly promoted RNA and protein synthesis in mouse intestinal mucosa, significantly increased the activity of maltase, sucrase, lactase, Y-glutamyl transpeptidase, dipeptidase and other marker enzymes of mature intestinal mucosal epithelial cells, and also promoted the differentiation of intestinal mucosal epithelial cells. GLP-2 also increased the net glucose uptake flux per unit mucosal surface area in the residual small intestine of short-gut rats by more than 50%, probably by stimulating the gene expression of sodium-dependent glucose transporter 1 (SGLT1) and GLUT2 proteins in intestinal mucosal cells, thereby increasing the glucose uptake efficiency of the intestinal epithelium. Glucose uptake by the intestinal epithelium was improved. The intestinal mucosal growth of mice was significantly slowed down after stopping the administration of exogenous GLP-2, indicating that the effect of GLP-2 to enhance intestinal mucosal nutrient uptake and thus promote intestinal mucosal growth is reversible. [5] Various factors such as stress can lead to alterations in intestinal mucosal barrier function such as loosening of epithelial junctions, increased ion and mucus secretion, and intestinal bacterial translocation [6].GLP-2 can significantly improve intestinal mucosal barrier function by decreasing ion and small molecule transport and inhibiting trans-cellular uptake of large molecules through trans-cellular channels and paracellular pathways within a few hours after administration. In [7] rats injected subcutaneously with GLP-2 and its analogues, changes in transmembrane flow of Na+ flow, Cr-EDTA and large molecules horseradish peroxidase (HRP) were reflected to improve permeability by increasing intestinal epithelial cell junctional tightness and to decrease the amount of large molecules entering intestinal epithelial cells.This effect of GLP-2 may be related to its increase in mucosal thickness and villi height. 2. regulation of GLP-2 on intestinal injury repair In addition to its nutritional and growth-promoting effects on normal intestinal mucosa, GLP-2 also accelerates regenerative repair after intestinal mucosal injury. gLP-2 significantly promotes the adaptive proliferative response of mucosa in residual intestinal segments after major small bowel resection, resulting in significant increases in intestinal tube diameter, crypt depth, villi height, and intestinal mucosal DNA and protein content [8]. Jeppesen et al [9] administered 400 μg GLP-2 subcutaneously twice/day for 35 days to eight patients with short bowel syndrome who had resected terminal ileum and colon; the results showed that GLP-2 improved energy, water and nitrogen absorption, increased body weight and 24-hour creatinine clearance, and increased gastric half-volume emptying time without changes in small intestine transit time, and most patients had increased intestinal mucosal crypt depth and villi height were increased; thus, it is proposed that GLP-2 improves nutritional status and residual intestinal absorption compensation in patients with short bowel syndrome with unreserved terminal ileum and colon with reduced postprandial GLP-2 secretion. Studies using a dextran sulfate-induced mouse model of acute colitis found that GLP-2 stimulated crypt cell proliferation, increased villi height, reduced inflammatory response and histological damage in the colon, decreased inflammatory cytokine IL-1 expression, and increased mucosal integrity. Studies using an animal model of enteritis in mice induced by the NSAID anti-inflammatory drug anti-inflammatory pain revealed that GLP-2 significantly increased animal survival, reduced the incidence of intestinal mucosal ulcers, accelerated the healing rate of intestinal mucosal damage, reduced the expression level of inflammatory cytokines and the incidence of bacteremia and the positive rate of bacterial culture in liver and spleen tissues, promoted the proliferation of intestinal epithelial cells, inhibited intestinal cell apoptosis, and significantly increased the integrity of the intestinal mucosa. Prasad et al [10] showed that treatment of rats with GLP-2 analogs for ischemia-reperfusion of the superior mesenteric artery significantly reduced mortality and increased intestinal mucosal DNA and protein content. The long-acting analogue of GLP-2, Teduglutide [12], also showed significant effects in the treatment of burn and acute necrotizing pancreatitis models in rats, enhancing the mechanical and immune barrier function of the intestinal mucosa and significantly reducing the incidence of bacterial translocation.A study by Burrin et al [13] suggested that GLP-2 mainly exhibits anti-apoptotic effects when used at low doses and at high doses The study by Burrin et al [13] suggested that GLP-2 mainly exhibits anti-apoptotic effect at low dose and stimulates the proliferation of corresponding cells at high dose. III. Mechanism of action of GLP-2 The GLP-2 receptor (GLP-2R) is a member of the B-type glucagon-glucagon-like G protein-coupled receptor superfamily, and its expression is highly tissue-specific. Immunohistochemistry and in situ hybridization techniques have demonstrated that GLP-2R is expressed in human enteroendocrine cells, murine enteric neurons, and subepithelial myofibroblasts in rats, mice, and marmosets [14,15].The lack of GLP-2R expression on enterocytes suggests that its proproliferative and cytoprotective effects may be indirect. Intracellular signaling of GLP-2 is achieved through the specific GLP-2R-mediated cyclic adenosine monophosphate (cAMP) pathway, which activates adenylate cyclase, causing an increase in intracellular cAMP, activating protein kinase A (PKA), and then possibly promoting gene transcription of cAMP-responsive elements via the intracellular Ca2+ and/or inositol triphosphate pathways.GLP-2 can be regulated by Phosphorylated extracellular signal-regulated kinase (MEK) phosphorylates the threonine and tyrosine residues of two isoforms of mitogen-activated protein kinase (MAPK) in Caco-2 cells cultured in vitro from human intestinal mucosal epithelial cells, resulting in increased activity and significantly promoting Caco-2 cell proliferation. This effect could be blocked by specific tyrosine protein kinase inhibitor (Genistein), phosphatidylinositol 3-kinase (PI3-K) inhibitor (LY294002), and mitogen-activated protein kinase (MAPK) inhibitor (PD098059), respectively. On the other hand, GLP-2R signaling activation inhibited actinomycin-induced apoptosis of BHK-GLP-2R cells, which was associated with its inhibition of cysteine-aspartate-specific protease-3 (caspase-3) enzyme activity and reduction of poly ADP ribose polymerase division. And GLP-2 reduced actinomycin-induced caspase-3 splitting irrespective of the presence or absence of the PKA inhibitor H289. After actinomycinone administration, GLP-2 also increased cell survival in the presence of two kinase inhibitors, namely phosphatidylinositol-3-kinase (PI3-K) inhibitor LY294002 and mitogen-activated protein kinase (MAPK) inhibitor PD98054. This indicates that the intracellular signaling of GLP-2 is not entirely dependent on PI3-K and MAPK pathways. This shows that the signaling channels involved in the mechanism of GLP-2 action on the intestine are complex, including both cAMP-dependent protein kinase pathway, tyrosine kinase pathway, PI3-K and MAPK pathway, and the exact molecular mechanism of GLP-2 action has not been fully elucidated yet. The clinical application prospect of GLP-2 The human trials on the enteroprotective effect of GLP-2 are still in the initial stage and limited to the therapeutic study of patients with short bowel syndrome. It is clear that GLP-2 has a pro-nutrient absorption effect, but whether it has the effect of reducing intestinal damage and promoting intestinal repair remains to be confirmed in further clinical trials. Although no adverse effects of GLP-2 have been found during treatment, it is difficult to conclude whether GLP-2 stimulates the growth of intestinal tumors, considering that the biological effects of GLP-2 were found in studies of glucagon induced tumors in animals, and nude mice with subcutaneous glucagon showed significant pro-growth of intestinal mucosa. As far as the treatment of short bowel syndrome is concerned, the effectiveness of GLP-2 needs to be confirmed in a large-scale population-based randomized controlled study, and the optimal dose, route of administration, duration of treatment and timing of application of GLP-2 treatment need to be studied in more depth. It is believed that its special enteroprotective effects have important clinical applications in the prevention and treatment of malabsorption, inflammatory bowel disease, and stress-related gastrointestinal mucosal barrier damage.