The gut bacterium Bifidobacterium pseudolongum promotes intestinal creatine absorption via acetate-mediated histone acetylation of the creatine transporter Slc6a8, and combined Bifidobacterium and creatine supplementation increased plasma creatine levels and reduced depression scores in patients taking antidepressants.
Key Findings
Results
Patients with depression and mouse depression models showed elevated fecal creatine alongside reduced plasma and cerebrospinal fluid creatine.
Metabolic profiling was used to identify creatine dysregulation across multiple biological compartments simultaneously.
The pattern was consistent across both human patients with depression and mouse depression models.
Elevated fecal creatine suggests impaired intestinal absorption rather than reduced systemic synthesis.
Reduced cerebrospinal fluid creatine indicates that central nervous system creatine availability is compromised in depression.
Results
Exogenous creatine supplementation produced antidepressant-like effects that were mediated by the gut microbiota.
Antidepressant-like effects of creatine were demonstrated in mouse depression models.
The mediation by gut microbiota suggests creatine's antidepressant action depends on intestinal microbial activity.
This finding implies that gut microbiota composition may determine individual responsiveness to creatine supplementation.
The mechanism connects peripheral creatine availability to central antidepressant effects via the gut-brain axis.
Results
Bifidobacterium pseudolongum was identified as a significantly reduced gut bacterial species in depression and correlated with impaired creatine absorption.
B. pseudolongum abundance was reduced in both patients with depression and mouse depression models.
Reduced B. pseudolongum levels correlated with the observed impairment in intestinal creatine absorption.
This species was identified through comparative microbiota analysis between depressed and non-depressed subjects.
The correlation between this specific species and creatine absorption links microbiome composition to peripheral-brain energy metabolism.
Results
B. pseudolongum-derived acetate promoted expression of the creatine transporter Slc6a8 in intestinal epithelial cells via histone acetylation.
The short-chain fatty acid acetate was identified as the key metabolite produced by B. pseudolongum responsible for this effect.
Acetate acted epigenetically by promoting histone acetylation at the Slc6a8 gene locus in intestinal epithelial cells.
This represents a mechanistic link from gut bacterial metabolism to intestinal transporter expression to systemic creatine availability.
Results
Slc6a8 mediated the antidepressant-like effects of creatine in mouse models.
Experiments manipulating Slc6a8 expression in intestinal epithelial cells were used to confirm its mediating role.
This positions intestinal Slc6a8 as a critical bottleneck between dietary creatine intake and antidepressant efficacy.
The finding mechanistically links the gut transporter to behavioral outcomes in depression models.
Neuronal creatine deficiency resulting from impaired Slc6a8-mediated absorption influenced energetic metabolism and neurophysiological function.
Results
Neuronal creatine deficiency in depression influenced energetic metabolism and neurophysiological function.
Reduced creatine delivery to the brain led to measurable changes in neuronal energy metabolism.
Neurophysiological function was also altered as a consequence of creatine deficiency in neurons.
This finding connects peripheral creatine absorption deficits to central nervous system functional impairment.
The results support the hypothesis that depression involves disrupted brain energy homeostasis downstream of gut-brain axis dysfunction.
Results
Supplementation with Bifidobacterium enhanced the antidepressant effects of creatine in mouse models.
Bifidobacterium supplementation alone had effects on creatine metabolism, and combined treatment showed enhanced antidepressant outcomes.
The combination likely works by increasing Slc6a8 expression (via acetate) while simultaneously providing substrate (creatine) for absorption.
This synergistic relationship identifies the combination as a promising therapeutic strategy.
Results in mouse models preceded the clinical investigation in human patients.
Results
In patients with depression taking antidepressants, co-administration of creatine and Bifidobacterium increased plasma creatine levels and reduced depression scores.
The clinical study enrolled patients with depression who were already on antidepressant medications.
Co-administration of both creatine and Bifidobacterium together was tested as an add-on to existing antidepressant treatment.
Outcomes included both a biomarker measure (plasma creatine levels) and a clinical measure (depression scores).
The reduction in depression scores alongside increased plasma creatine supports the mechanistic model linking peripheral creatine to antidepressant outcomes.
What This Means
This research suggests that depression is associated with a problem in how the body absorbs creatine — an energy molecule — from the gut into the bloodstream and brain. People with depression and depressed mice were found to have unusually high creatine in their stool but unusually low creatine in their blood and brain fluid, suggesting the creatine is not being properly absorbed from the intestines. The study found that a specific gut bacterium called Bifidobacterium pseudolongum, which is reduced in people with depression, normally helps the intestine absorb creatine by producing a substance called acetate that switches on a creatine-absorbing protein (called Slc6a8) in the gut lining.
When researchers gave depressed mice both creatine supplements and Bifidobacterium bacteria together, the antidepressant effects were stronger than either treatment alone. The mechanism appears to work as follows: Bifidobacterium produces acetate, which causes the gut to make more creatine transporter protein, which then allows more dietary creatine to enter the bloodstream and eventually reach the brain — where creatine helps neurons maintain their energy supply and function normally. Without sufficient creatine in the brain, neuronal energy metabolism and brain activity are disrupted in ways associated with depressive symptoms.
In a clinical component of the study, patients with depression who were already taking antidepressant medications were given supplemental creatine and Bifidobacterium together. This combination raised their blood creatine levels and reduced their depression scores, supporting the relevance of this gut-brain energy pathway in human depression. This research suggests that the combination of Bifidobacterium probiotic and creatine supplementation could be a promising add-on strategy to existing antidepressant treatments, and highlights gut-brain energy metabolism as an important but previously underappreciated factor in depression.
Lu C, Ren J, Lei Y, Lian X, Jiang H, Guo F, et al.. (2026). The gut microbiota alleviates depression by remodeling gut-brain energy metabolism.. Cell metabolism. https://doi.org/10.1016/j.cmet.2026.03.002