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Creatine and Microbiomes
A new 2026 Cell Metabolism study explores a compelling and increasingly central idea in modern biology: the gut/brain/immune/metabolism axis is not just associative, it is mechanistic. Specifically, Dr. Lu and colleagues investigate how the gut microbiota can directly influence depressive behavior by reshaping systemic and neural metabolism. This is another in a long running list of papers describing the amazing work that bacterial commensal microbes do for us. In this case, our minds and moods.
“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.” “The brain, as an energy-intensive organ, relies on precise metabolic regulation to maintain synaptic plasticity, neurotransmitter synthesis, and stress response systems. Accumulating evidence implicates energy metabolism dysregulation as a hallmark of depression. Neuroimaging studies using positron emission tomography (PET) have identified marked glucose hypometabolism in the medial prefrontal cortex (mPFC) of patients with depression. Cerebral mitochondrial dysfunction and ATP imbalance have been mechanistically linked to depression progression. Notably, emerging studies emphasize the bidirectional interplay between peripheral metabolic signals and central energy regulation, which is fundamental to neural metabolism. Clinical observations such as fatigue, appetite dysregulation, and unexplained weight fluctuations in patients with depression further suggest systemic metabolic disturbances spanning peripheral organs and the CNS..” (Lu et. al. 2026)
This is next-level medicine. Mental health can no longer be framed as a disorder of genetics, experience, or circumstance alone. This work opens a clearer window, showing how the microbiome participates as an active partner, shaping brain function through the metabolites it helps produce and deliver. Compounds like creatine are no longer just peripheral players. They become signals, fuel, structure, and information, bridging gut and brain, metabolism and behavior…. and more
Enjoy,
Dr. M
