L‐Glutamine Substantially Improves 5‐Fluorouracil‐Induced Intestinal Mucositis by Modulating Gut Microbiota and Maintaining the Integrity of the Gut Barrier in Mice

Scope This study investigates the potential of glutamine to mitigate intestinal mucositis and dysbiosis caused by the chemotherapeutic agent 5‐fluorouracil (5‐FU). Methods and results Over twelve days, Institute of Cancer Research (ICR) mice are given low (0.5 mg kg−1) or high (2 mg kg−1) doses of L‐Glutamine daily, with 5‐FU (50 mg kg−1) administered between days six and nine. Mice receiving only 5‐FU exhibited weight loss, diarrhea, abnormal cell growth, and colonic inflammation, correlated with decreased mucin proteins, increased endotoxins, reduced fecal short‐chain fatty acids, and altered gut microbiota. Glutamine supplementation counteracted these effects by inhibiting the Toll‐like receptor 4/nuclear factor kappa B (TLR4/NF‐κB) pathway, modulating nuclear factor erythroid 2‐related factor 2/heme oxygenase 1 (Nrf2/HO‐1) oxidative stress proteins, and increasing mammalian target of rapamycin (mTOR) levels, thereby enhancing microbial diversity and protecting intestinal mucosa. Conclusions These findings underscore glutamine's potential in preventing 5‐FU‐induced mucositis by modulating gut microbiota and inflammation pathways. The disruption of the mucosal layer by 5‐FU (5‐fluorouracil) treatment leads to microbiota dysbiosis. Glutamine possesses the potential to protect against 5‐FU‐induced microbiota dysbiosis and prevents the activation of the TLR4/NF‐κB pathway. Administration of high‐dose glutamine effectively alleviates 5‐FU‐induced mucositis by enhancing the Nrf2/HO‐1 pathway and promoting mTOR expression.