Obesity is associated with metabolic dysfunction, psychological comorbidities and a higher prevalence of disorders of gut–brain interaction. Shared mechanisms across obesity and these gut–brain disorders include systemic and local inflammation, impairment of intestinal barrier function, and alterations of the gut microbiota. These pathophysiological processes are known to be modulated by stress exposure. The amino acid glutamine (Gln) is critical for enterocyte metabolism, maintenance of intestinal integrity and modulation of immune responses, and has been proposed as a nutritional approach to counteract gut barrier disruption and inflammation in metabolic disease. The present study tested whether oral Gln supplementation modifies stress-induced responses in genetically obese mice.
Male leptin-deficient ob/ob mice (age stated in the report) were randomized to four experimental groups: control (no stress, no Gln), chronic restraint stress (CRS) alone, Gln supplementation alone, and combined CRS plus Gln. Glutamine was administered in drinking water for two weeks. CRS was applied during the last 4 days of the protocol. Outcome measures included plasma corticosterone, metabolic parameters (including body weight changes, body composition and fasting glycaemia), assessment of intestinal permeability and tight junction protein expression, inflammatory markers at gene and protein levels, and characterization of gut microbiota composition and cecal metabolite profiles (short-chain and branched-chain fatty acids).
CRS reliably increased plasma corticosterone levels, confirming activation of the stress axis; however, CRS produced only limited effects on the broad metabolic parameters measured in the study. In the absence of stress, oral Gln supplementation improved metabolic outcomes in these genetically obese mice: it reduced body weight gain, produced favorable changes in body composition, and lowered markers of inflammation in visceral adipose tissue. These beneficial effects of Gln were not observed when mice were exposed to CRS. Under stress conditions, Gln supplementation was associated with an increase in fasting glycaemia, indicating a context-dependent reversal of metabolic benefit.
The study found that CRS reduced levels of the intestinal tight junction protein occludin. Effects of Gln on genes related to tight junctions and inflammation varied according to stress exposure. In unstressed ob/ob mice, Gln decreased expression of Tjp3 (a tight junction protein gene), Cldn15 (a claudin family member) and the inflammatory chemokine gene Ccl2. By contrast, in mice exposed to CRS plus Gln, gene expression of multiple tight junction–related elements (including Tjp2, Tjp3, Cldn12, Cgn, F11r and Marveld2) and innate immune signaling markers (Tlr2, Myd88, Irf3) was increased. These divergent transcriptional responses indicate that glutamine interacts with stress to modify intestinal barrier and immune gene programs in a context-dependent manner.
In unstressed obese mice, Gln supplementation altered the composition of the gut microbiota; the report highlights changes in specific bacterial taxa, notably members of Thermodesulfobacteriota and Clostridiaceae. These compositional shifts were associated with altered cecal metabolite profiles: levels of short-chain fatty acids (SCFAs) were decreased while branched-chain fatty acids (BCFAs) were increased in the cecal content of Gln-treated unstressed mice. The manuscript links these microbiota and metabolite changes to the observed intestinal and metabolic effects, and notes that under stress the pattern of microbiota/metabolite changes and their relation to intestinal inflammation differ from the unstressed condition.
The authors conclude that oral glutamine supplementation can improve body weight trajectory, body composition and visceral adipose inflammatory markers in genetically obese male mice when animals are not exposed to acute chronic restraint stress. However, these benefits are not observed when mice are subjected to CRS: stress abolishes Gln-associated metabolic and anti-inflammatory improvements and is accompanied by increased fasting glycaemia and markers consistent with colonic inflammation. Gln’s effects on intestinal tight junction genes and immune signaling were opposite depending on stress status, and Gln altered the gut microbiota and cecal metabolite profile in unstressed mice. Taken together, the data indicate that the effects of Gln in obesity are context-dependent and can be limited or reversed by stress exposure.
The study received funding from the French National Agency for Research (ANR-20-CE17-0012) and the Nutricia Research Foundation (grant indicated). Two authors declared collaborations with an external laboratory (DIELEN Laboratory). The report is presented as a preprint and has not been certified by peer review.