Stress limits the beneficial effects of glutamine in male ob/ob mice

Tiffay, A.; Lefebvre, C.; Breemeersch, C.-E.; Dreux, V.; Bole-Feysot, C.; Guerin, C.; Maximin, E.; Monnoye, M.; Dechelotte, P.; Douard, V.; Goichon, A.; Coeffier, M.

doi:10.64898/2026.07.21.739777

bioRxiv · 10.64898/2026.07.21.739777

Stress limits the beneficial effects of glutamine in male ob/ob mice

Tiffay, A.·Lefebvre, C.·Breemeersch, C.-E.·Dreux, V.·Bole-Feysot, C.·Guerin, C.·Maximin, E.·Monnoye, M.·Dechelotte, P.·Douard, V.·Goichon, A.·Coeffier, M.

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Abstract

IntroductionObesity is a major health issue associated with metabolic and psychological comorbidities, as well as an increased prevalence of disorders of gut-brain interaction (DGBI). Obesity and DGBI share common mechanisms such as inflammation, gut barrier dysfunction, and alterations of gut microbiota, which are all known to be regulated by stress. Glutamine (Gln), which is essential to maintain intestinal integrity and immune response, may counteract these alterations. This study aimed to evaluate the effects of oral Gln supplementation on stress-induced response in obese mice. MethodsSeven-week-old male leptin-deficient ob/ob mice were assigned to four groups: control, chronic restraint stress (CRS), Gln-supplemented, or both CRS and Gln-supplemented. Gln was administered in drinking water for two weeks, and CRS was performed during the final 4 days. Metabolic parameters, intestinal permeability, inflammatory markers, gene and protein expression, and gut microbiota composition were assessed. ResultsStress increased plasma corticosterone levels but had a limited effect on metabolic parameters. In obese mice without stress, Gln supplementation reduced body weight gain, improved body composition and reduced inflammation in the visceral adipose tissue. These effects were lost under stress conditions, with an increase in fasting glycaemia. Stress reduced occludin protein levels, while Gln exerted context-dependent effects, decreasing gene expression of Tjp3, Cldn15 and Ccl2 in unstressed mice but increasing gene expression of multiple tight junction (Tjp2, Tjp3, Cldn12, Cgn, F11r, Marveld2) and inflammatory markers (Tlr2, Myd88, Irf3) under stress. Interestingly, in unstressed obese mice, Gln altered the composition of the gut microbiota, with changes in key bacterial taxa (Thermodesulfobacteriota and Clostridiaceae). This was associated with decreased levels of cecal short-chain fatty acids and increased levels of branched-chain fatty acids. ConclusionIn conclusion, Gln improves metabolic and adipose inflammatory parameters in genetically obese mice. However, these benefits are no longer observed when mice are under stress conditions. Since, Gln has been found to increase fasting glycaemia and colonic inflammation, in association with alterations of gut microbiota.

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Tiffay, A., Lefebvre, C., Breemeersch, C.-E., Dreux, V., Bole-Feysot, C., Guerin, C., Maximin, E., Monnoye, M., Dechelotte, P., Douard, V., Goichon, A., Coeffier, M.. 2026-07-24. Stress limits the beneficial effects of glutamine in male ob/ob mice. https://doi.org/10.64898/2026.07.21.739777

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