Depression is common but hard to treat. Now, researchers have found that gut bacteria, especially Bifidobacterium, can boost the absorption and delivery to the brain of a molecule that helps cells produce energy, revealing a microbiota-gut-brain pathway that can be targeted to improve depression.

The findings, published in Cell Metabolism, suggest that supplementing creatine alongside specific gut bacteria such as Bifidobacterium could offer a treatment for depression by restoring brain energy metabolism. 

Previous research suggested that depression is linked to problems in how the brain uses energy, which may also explain symptoms such as fatigue and appetite changes. The gut may play a role through the gut-brain connection, but treatments targeting this system are still limited.

To address this question, researchers led by Cheng-Lin Lu at Southern Medical University in Guangzhou, China, analyzed blood, cerebrospinal fluid, and feces from people with major depressive disorder and healthy individuals.

Brain energy 

The team found differences in key molecules such as amino acids and vitamins, with a particular disruption in pathways involving creatine—a natural substance that supports brain energy. Creatine levels were low in the blood and brain but high in feces of people with depression. Mice with depressive symptoms showed similar patterns, with decreased creatine in the brain—especially in a brain region important for mood.

Giving creatine to these mice reduced depression-like behaviors and prevented stress-induced social withdrawal. These benefits depended on the gut microbiota: mice whose gut bacteria were eliminated with antibiotics did not respond to creatine, and transferring gut microbes from people with depression to mice blocked creatine’s effects. 

Certain gut bacteria, especially Bifidobacterium pseudolongum and B. adolescentis, were reduced in people with depression, the researchers also found. In mice, adding these bacteria increased blood creatine levels and improved depressive behaviors, especially when combined with creatine. 

Antidepressant strategy 

Further experiments in mice showed that acetate produced by Bifidobacterium boosted the intestinal creatine transporter Slc6a8, improving creatine absorption and reducing depressive behaviors. Deleting Slc6a8 in gut or brain cells blocked these effects. 

In a small human trial, combining B. adolescentis with creatine raised blood creatine more than creatine alone and improved depression scores compared with placebo. 

“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 authors say.