Monosodium glutamate‐mediated Ca 2+ ‐dependent intestinal epithelial ion transports in health and IBS ‐D in male mice

Abstract Despite the ubiquitous use of monosodium glutamate (MSG) as a food additive, its specific effects on intestinal health and disease remain largely unclear. Here we found mucosal application of MSG induced an upward intestinal short‐circuit current ( I sc ) in the murine ileum, which was significantly reduced by extracellular Cl − , Na + , and Ca 2+ removal. Mechanistically, MSG‐induced I sc was significantly attenuated by pharmacological inhibition of key transporters (NCX, SGLT1, NKA) and secretory channels (CaCC, CFTR, IK Ca ). Furthermore, disrupting intracellular Ca 2+ homeostasis via endoplasmic reticulum (ER) chelation or blockade of IP 3 R, RyR, SOCE/CRAC, and VGCC significantly suppressed both the ileal I sc and MSG‐stimulated Ca 2+ signaling in IECs. Importantly, MSG triggered a simultaneous elevation in intracellular Ca 2+ and a reduction in Na + , which were abolished by the blockers of NCX and SGLT1. In vivo, MSG‐induced Ca 2+ ‐dependent ion transports were significantly reduced in irritable bowel syndrome with diarrhea (IBS‐D) mice. Our findings indicate that MSG drives Ca 2+ ‐dependent intestinal ion transports through a complex network orchestrated by SGLT1 and NCX under healthy state, which is markedly attenuated in IBS‐D. This study provides novel insights into the gastrointestinal impact of dietary MSG in both health and bowel disease.