The intestinal barrier is a sum of the functions and structures consisting of the intestinal mucosal epithelium, mucus, intestinal flora, secretory immunoglobulins, and digestive juices. It is the first-line defense mechanism that resists nonspecific infections with powerful functions that include physical, endocrine, and immune defenses. Health and physiological homeostasis are greatly dependent on the sturdiness of the intestinal barrier shield, whose dysfunction can contribute to the progression of numerous types of intestinal diseases. Disorders of internal homeostasis may also induce barrier impairment and form vicious cycles during the response to diseases. Therefore, the identification of the underlying mechanisms involved in intestinal barrier function and the development of effective drugs targeting its damage have become popular research topics. Evidence has shown that multiple signaling pathways and corresponding critical molecules are extensively involved in the regulation of the barrier pathophysiological state. Ectopic expression or activation of signaling pathways plays an essential role in the process of shield destruction. Although some drugs, such as molecular or signaling inhibitors, are currently used for the treatment of intestinal diseases, their efficacy cannot meet current medical requirements. In this review, we summarize the current achievements in research on the relationships between the intestinal barrier and signaling pathways. The limitations and future perspectives are also discussed to provide new horizons for targeted therapies for restoring intestinal barrier function that have translational potential.

Background: This study aimed to analyze and compare the short-term and long-term outcomes of proximal gastrectomy (PG) and total gastrectomy (TG) in patients with locally advanced proximal gastric cancer (GC) following neoadjuvant chemotherapy (NACT). Method: A multicenter retrospective cohort study and propensity score matching (PSM) were employed. The authors examined 367 patients with proximal GC who received NACT followed by PG (n=164) or TG (n=203) at two Chinese medical institutions between December 2009 and December 2022. Clinical and pathological parameters, postoperative complications, and 5-year overall survival (OS) and recurrence-free survival (RFS) were compared between the two groups. The dissection status and metastasis rate of each lymph node station were assessed. Results: After PSM, 80 patients were enrolled in both TG and PG group, and baseline characteristics were comparable between the groups (all P>0.05). The TG group had a higher total number of lymph nodes retrieved (P<0.001) and longer operative time (P=0.007) compared to the PG group. The incidence of Clavien–Dindo grade II or higher postoperative complications was similar between the TG group (21.3%, 17/80) and the PG group (17.5%, 14/80) (P=0.689). The 5-year OS rates were 68.4 for the PG group and 66.0% for the TG group (P=0.881), while the 5-year RFS rates were 64.8 and 61.9%, respectively (P=0.571), with no statistically significant differences. Metastasis rates at lymph node stations #4d, #5, #6, and #12a were notably low in the TG group, with values of 2.74, 0.67, 1.33, and 1.74%, respectively. Conclusion: For proximal GC patients following NACT, PG maintains comparable curative potential and oncological efficacy to TG, making it a safe option.