Sex-dependent effects of a glutamine supplementation on metabolic disorders, intestinal barrier function and gut microbiota in mice with diet-induced obesity.

Abstract

RationaleObesity is often associated with sex-dependent metabolic complications, in which altered intestinal barrier function and gut microbiota contribute. Glutamine (Gln) supplementation previously showed beneficial effects on gut barrier function and glycemic control. We thus aimed to characterize in mice the sex-dependent effects of a Gln supplementation during high fat diet induced obesity. MethodsMale and female C57BL/6 mice received a standard (SD) or high fat diet (HFD; 60% kcal from fat) during 14 weeks (W14). From W12, mice received or not Gln in drinking water (2g/kg/day; n=12/group). Body composition, glucose tolerance, insulin sensitivity, intestinal permeability, colonic expression of 44 genes encoding factors involved in inflammatory response and gut barrier function, cecal microbiota and inflammatory/endocrine adipose response have been assessed. Data were analyzed using t-test or Mann-Whitney test (HFD effect), and two-way ANOVA (HFD x Gln) followed by Bonferroni post-tests. ResultsIn both male and female mice, Gln supplementation failed to improve body weight and body composition. However, Gln reduced glucose intolerance in HFD males (AUC reduced by 14.57%, p<0.05) that was associated to a partial restoration of plasma resistin and insulin and to a trend for a limitation of adipose inflammatory response. In males, Gln did not affect gut microbiota composition and colonic response. To the opposite, in females fed HFD, Gln supplementation led to gut microbiota changes (increase of Bacteroidota and Pseudomonadota phyla; increase of Muribaculaceae and Tannerellaceae families), increased colonic inflammatory markers (TNF, IL-1{beta}, TLR4, Myd88, Irf3) that were associated to increased inflammatory response in subcutaneous adipose tissue and increased HOMA-IR. ConclusionsHigh fat diet mice exhibit sex-dependent response to glutamine supplementation with protective effects in males and harmful effects in females. The role of gut microbiota should be deeply deciphered in further investigations.