Creatine shields the brain from inflammation in a rat model of chronic colitis

A new animal study sheds light on how a common dietary supplement may ease both gut and brain symptoms of inflammatory bowel disease. The research, published in the journal Food & Function, suggests that creatine supplementation can reduce the physical symptoms of ulcerative colitis while also preventing mood and motor disturbances. In rats with colitis, creatine appeared to reduce intestinal inflammation, preserve brain function, and prevent the development of anxiety and depression-like behaviors. The protective effects were observed in both male and female rats, though some benefits were more pronounced in females.

Ulcerative colitis is a chronic inflammatory condition of the colon that often follows a cycle of flares and remission. Along with gastrointestinal symptoms like abdominal pain and diarrhea, many patients experience mental health challenges, including depression and anxiety. Some of these symptoms tend to persist even during periods when intestinal inflammation appears to be under control.

Prior research has suggested that the connection between gut inflammation and mental health may be driven by what scientists call the gut–brain axis. This is a complex communication network that includes neural, hormonal, and immune signals linking the digestive system with the brain. When the colon becomes inflamed, this communication pathway may promote changes in the brain that affect mood and behavior.

Studies in both humans and rodents have shown that gut inflammation is associated with increased levels of pro-inflammatory molecules in the brain, particularly in areas involved in mood and motor control. This neuroinflammatory response is often linked to the activation of microglia, the immune cells of the brain.

Current treatments for ulcerative colitis mainly target gastrointestinal symptoms. While these treatments can help reduce flare-ups, they often do not address the emotional or cognitive effects of the disease. That gap motivated researchers at the University of Seville, led by María José Peral, to investigate whether creatine might offer a broader range of benefits.

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“There’s a well-known saying from Hippocrates, the father of medicine: ‘All disease begins in the gut.’ While not every illness comes from the gut, today’s science shows a strong link between gut health and the brain,” the researchers told PsyPost

“In our earlier work in an animal model, we demonstrated that chronic gut inflammation not only damages the intestine but also leads to problems with mood, memory, and locomotion. This fact should be considered in the therapies of inflammatory bowel diseases and made us wonder: could there be a safe and familiar molecule that helps both the gut and the brain at the same time?”

“Creatine quickly caught our attention. It’s already widely used by athletes to boost performance, and it has a long record of safety, even approved by the FDA. On top of that, creatine has known anti-inflammatory and neuroprotective effects, and some studies had hinted it might ease gut symptoms and even depression.”

“We also wanted to explore differences between males and females,” the researchers continued. “Both gut disorders and mood problems are known to vary by sex, but very few studies look at both systems together—the gut and the brain—in a way that allows us to compare results between males and females.”

The researchers used a rat model that mimics the relapsing–remitting nature of ulcerative colitis. They induced chronic colitis in male and female Wistar rats using dextran sulfate sodium, a chemical that causes inflammation in the colon. This model produces symptoms that resemble human colitis, including diarrhea, rectal bleeding, and weight loss.

Some rats were given creatine supplementation in their drinking water starting 10 days before the colitis-inducing treatment and continuing throughout the experiment. The researchers tracked the severity of colitis symptoms using a disease activity index and also assessed behavioral signs of anxiety, depression, and motor function using an open field test. They collected brain and colon tissue at the end of the study to measure creatine concentrations, inflammation markers, and microglial activation.

The study included both sexes to explore whether creatine’s effects differed in males and females. This attention to sex differences is notable, as both ulcerative colitis and mood disorders are more common in women, but animal research often underrepresents female subjects.

The results indicate that creatine supplementation led to widespread improvements in both intestinal and neurological outcomes.

In rats with colitis, creatine reduced the overall disease activity score during flare-up phases. This included less weight loss, improved stool consistency, and reduced bleeding. The intestinal lining also showed less damage, especially in male rats, where creatine appeared to protect the surface epithelium more effectively. Importantly, these benefits were observed throughout the disease progression and did not seem tied to whether the colitis was in an active or remissive state.

In both sexes, creatine supplementation increased creatine levels in the colon and cerebral cortex. This suggests that the compound was absorbed and distributed effectively, reaching both peripheral and central tissues.

The behavioral results showed that rats with colitis exhibited reduced locomotion, signs of anxiety, and depression-like symptoms such as increased immobility and decreased grooming. Creatine prevented these changes, keeping behavior in treated rats comparable to healthy controls.

Females tended to benefit more strongly in certain areas. For example, the improvement in traveled distance, a measure of motor activity, was greater in females than males. Similarly, reductions in immobility time and increases in center exploration—measures associated with lower anxiety and depression—were more pronounced in females.

“Interestingly, creatine worked in both sexes, though in some cases females benefited more,” the researchers told PsyPost. “This highlights how important it is to study treatments in both males and females rather than assuming the results are the same.”

The biological mechanisms behind these behavioral improvements appeared to involve reductions in neuroinflammation. In rats with colitis, the researchers observed elevated levels of pro-inflammatory cytokines, including interleukin-1 beta, interleukin-6, and tumor necrosis factor, in both the prefrontal and motor cortices. These increases were prevented by creatine. The pattern of change varied slightly by sex, with creatine appearing to reduce interleukin-6 more strongly in males and interleukin-1 beta more strongly in females.

Microscopic analysis of the brain showed that colitis activated microglia in both sexes, a sign of inflammation in the central nervous system. Creatine supplementation prevented these changes, and again, some effects were stronger in females, particularly in the prefrontal cortex.

“The key message is that creatine could be a promising nutritional strategy to help with both gut inflammation and emotional issues that sometimes come with it,” the researchers said. “In our study with rats, creatine reduced the severity of colitis symptoms like diarrhea and weight loss, protected the gut barrier, and prevented anxiety- and depression-like behaviors. It even helped avoid brain inflammation that is linked to these problems.”

The findings offer preliminary support for the idea that creatine might be a useful supplement for managing both the intestinal and neurological symptoms of inflammatory bowel diseases such as ulcerative colitis. The supplement not only improved physical symptoms of colitis but also protected brain function and behavior, possibly by reducing inflammation and preserving tissue function in the brain.

“The important point is this: creatine is not just a sports supplement,” the researchers said. “It may also be a safe, affordable tool to protect both gut health and mental health at the same time.”

While these findings are promising, they come from a rat model and cannot be directly applied to human treatment without further research. Human trials would be needed to confirm whether creatine supplementation has similar benefits in people with ulcerative colitis, especially in terms of mood and cognition.

It is also important to note that creatine is not a replacement for standard medical treatment. Instead, it may offer a complementary approach, possibly helping to improve quality of life and reduce psychiatric symptoms that are not always addressed by conventional therapies. Although creatine is widely considered safe and is already used as a dietary supplement, especially by athletes, its use in clinical populations still requires careful testing..

The study, “Creatine differently prevents chronic colitis-induced motor deficits, anxiety and depressive behaviors, neuroinflammation, and microglial activation in male and female rats,” was authored by Gema Sotelo-Parrilla, Alejandro Ruiz-Calero, Pablo García-Miranda, María Luisa Calonge, María Dolores Vázquez-Carretero, and María José Peral.