Gut bacteria may help creatine reach the brain and support its antidepressant effects. Digest

Depression research often focuses on neurotransmitters, but the brain also depends on a steady supply of energy to function properly. A new study tested whether problems in how creatine moves from the gut to the brain play a role in depression, and whether certain gut bacteria can help restore this process.

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To examine this, researchers combined human data with experiments in mice and cell models. They compared adults with major depressive disorder (MDD) to healthy controls, and mice that developed depression-like behaviors during chronic stress to unstressed control mice, using metabolite profiling (measurement of small molecules involved in metabolism), along with behavioral testing, gut microbiome manipulations, genetic models, and a small, 28-day pilot study in MDD patients taking antidepressants (SSRIs).

• Broad metabolite profiling revealed differences in metabolism between MDD patients and healthy controls, and between mice with depression-like behavior and control mice, with creatine emerging as a key altered molecule.
• People with MDD and mice with depression-like behavior had more creatine in feces but less in blood plasma and in the cerebrospinal fluid (liquid that surrounds the brain and spinal cord). In mice with depression-like behavior, creatine was also lower in the medial prefrontal cortex, a brain region involved in mood and decision-making.
• Creatine improved several depression-like behaviors in mice. It reduced how long the animals remained passive in stress-based tests, improved social interaction, and increased preference for sweet solutions, a common measure of motivation or pleasure-related behavior in animals. These effects were not due to increased overall activity, as creatine did not make the mice more active in general.
• When the gut microbiome was depleted with antibiotics, or replaced with microbes from MDD patients, mice showed a smaller rise in blood creatine after supplementation and lost much of creatine's behavioral benefit.
• The bacterium Bifidobacterium pseudolongum was found at lower levels in MDD patients and in mice that received gut microbes from MDD patients. Mice that had more of this specific gut bacterium also tended to have more creatine in their plasma.
• Bifidobacterium pseudolongum increased levels of the creatine transporter Slc6a8 in intestinal cells, supporting creatine uptake from the gut. This effect was observed in mice and reproduced in human intestinal cells using compounds produced by the bacteria, with acetate identified as a key contributing factor.
• Removing this creatine transporter at the blood–brain barrier and in nerve cells in mice disrupted creatine's effects on behavior, while additional nerve cell experiments showed reduced energy production and impaired neuronal activity when Slc6a8 was absent.
• In the human pilot study, among those MDD patients who completed the experiment, receiving a combination of Bifidobacterium adolescentis (a related strain with established applications in food and medicine) and creatine was associated with greater reductions in depression scores than placebo.

The data point to a disrupted gut–brain energy pathway in depression. Creatine supports cellular energy by helping regenerate ATP, the molecule that powers cellular activity, so reduced availability in the brain could impair normal function. Gut bacteria appear to regulate this pathway: B. pseudolongum and B. adolescentis produce acetate, a short-chain fatty acid that increases levels of the transporter that allows intestinal cells to take up creatine, thereby supporting its absorption into the bloodstream. Creatine must then cross the blood–brain barrier and enter nerve cells to support energy production and signaling. Disrupting this transporter at these steps prevented creatine's behavioral effects, indicating that impaired transport along this pathway may contribute to depression, while restoring it could help improve symptoms.

If this potentially synergistic effect of creatine and specific probiotics is confirmed in larger, well-controlled human trials that compare the effects of creatine and probiotics individually to their combination and placebo, targeting this gut–brain energy pathway could offer a new approach to improving depression treatment. In Aliquot #133, Dr. Candow and I discuss the surprising brain benefits of creatine.