Monosodium glutamate-mediated Ca2+-dependent intestinal epithelial ion transports in health and IBS-D in male mice

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 CA²⁺ 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 CA²⁺ homeostasis via endoplasmic reticulum (ER) chelation or blockade of IP₃R, RyR, SOCE/CRAC, and VGCC significantly suppressed both the ileal I_sc and MSG-stimulated CA²⁺ signaling in IECs. Importantly, MSG triggered a simultaneous elevation in intracellular CA²⁺ and a reduction in Na⁺, which were abolished by the blockers of NCX and SGLT1. In vivo, MSG-induced CA²⁺-dependent ion transports were significantly reduced in irritable bowel syndrome with diarrhea (IBS-D) mice. Our findings indicate that MSG drives CA²⁺-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.