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

Mol Nutr Food Res. 2024 May;68(9):e2300704. doi: 10.1002/mnfr.202300704. Epub 2024 Apr 24.


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.

Keywords: 5‐fluorouracil; glutamine; intestinal mucositis; microbiota.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / adverse effects
  • Dysbiosis / chemically induced
  • Dysbiosis / drug therapy
  • Fluorouracil* / adverse effects
  • Gastrointestinal Microbiome* / drug effects
  • Glutamine* / pharmacology
  • Heme Oxygenase-1 / metabolism
  • Intestinal Mucosa* / drug effects
  • Intestinal Mucosa* / metabolism
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mucositis* / chemically induced
  • Mucositis* / drug therapy
  • Mucositis* / metabolism
  • NF-E2-Related Factor 2 / metabolism
  • NF-kappa B / metabolism
  • Oxidative Stress / drug effects
  • TOR Serine-Threonine Kinases / metabolism
  • Toll-Like Receptor 4 / metabolism


  • Fluorouracil
  • Glutamine
  • Toll-Like Receptor 4
  • NF-E2-Related Factor 2
  • NF-kappa B
  • TOR Serine-Threonine Kinases
  • Antimetabolites, Antineoplastic
  • Nfe2l2 protein, mouse
  • Heme Oxygenase-1
  • Tlr4 protein, mouse