The gut microbiota alleviates depression by remodeling gut-brain energy metabolism.

Although peripheral-brain crosstalk regulates energy metabolism, its role in depression remains unclear. Here, we used metabolic profiling to reveal elevated fecal creatine alongside reduced plasma and cerebrospinal fluid creatine in both patients with depression and mouse depression models. Exogenous creatine produced antidepressant-like effects mediated by gut microbiota. Bifidobacterium pseudolongum was identified as a significantly reduced gut bacterial species in depression, correlating with impaired creatine absorption. Subsequent supplementation with Bifidobacterium enhanced the antidepressant effects of creatine. Mechanistically, B. pseudolongum-derived acetate promoted the creatine transporter (Slc6a8) expression in intestinal epithelial cells via histone acetylation. The Slc6a8 mediated the antidepressant-like effects of creatine. Neuronal creatine deficiency influenced energetic metabolism and neurophysiological function. In patients with depression taking antidepressants, co-administration of creatine and Bifidobacterium increased plasma creatine levels and reduced depression scores. These findings identify the Bifidobacterium-creatine combination as a promising antidepressant strategy and highlight the critical role of gut-brain energy metabolism in depression.