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Background: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder in which impaired intestinal barrier integrity contributes to immune activation, visceral hypersensitivity, and disrupted gut–brain communication. Peppermint oil, rich in l-menthol, is clinically effective for IBS symptom relief; however, its role in improving intestinal barrier function remains unclear. In addition, rapid absorption raises questions about whether sufficient intestinal luminal exposure is maintained for barrier protection.
Methods: An IBS-D rat model was established using water-avoidance stress combined with chronic unpredictable stress. The effects of oral l-menthol were evaluated by measuring visceral sensitivity and intestinal barrier function. Pharmacokinetic analyses quantified luminal and systemic exposure to l-menthol and its metabolites in rats. In humans, plasma l-menthol metabolites were measured after oral administration of an l-menthol–containing herbal formulation (Lianhua Qingwen). In vitro studies investigated l-menthol metabolism and transport mechanisms.
Results: Oral l-menthol (28 or 56 mg/kg, twice daily for 7 days) significantly alleviated visceral hypersensitivity and improved bowel function in IBS-D rats. It restored barrier integrity, as indicated by reduced FITC-dextran permeability and decreased plasma diamine oxidase and D-lactate levels. Tight junction proteins (ZO-1, claudin-1, occludin) were upregulated, while pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) were suppressed. L-menthol also modulated neurotransmitters (5-HT, SP, VIP) and reshaped gut microbiota, increasing Bifidobacterium and Lactobacillus. Pharmacokinetic data showed extensive first-pass glucuronidation followed by microbial deconjugation, sustaining high luminal exposure.
Conclusion: L-menthol improves intestinal barrier function, reduces inflammation, and modulates gut microbiota, thereby alleviating IBS-D symptoms. Sustained luminal exposure via metabolic recycling supports its therapeutic potential.