A popular workout supplement might protect the brain from gut inflammation

Creatine, a popular dietary supplement, prevented brain inflammation, nerve cell damage, and disrupted electrical activity in the hippocampus of rats with chronic colitis, according to new research published in Brain, Behavior, and Immunity. The colitis-related damage was far more pronounced in male rats than in females. The findings add to evidence linking gut inflammation to changes in the brain, though they have not been tested in people.

The gut-brain axis is the complex, two-way communication network connecting the digestive tract and the central nervous system. Inflammatory bowel disease is a group of chronic conditions marked by persistent inflammation of the digestive tract, including Crohn’s disease and ulcerative colitis, which causes sores and swelling in the lining of the colon and rectum. In these conditions, inflammatory signals from the gut can travel to the brain and trigger secondary inflammation there, which is thought to contribute to the mood and cognitive problems frequently experienced by people with intestinal diseases.

Prior research has mapped how this process unfolds. A 2018 study found that a short bout of gut inflammation made both male and female mice more prone to seizures and increased anxiety-like behavior. In a 2022 study, members of the current team found that acute gut inflammation in rats was accompanied by brain inflammation and made neurons in the motor cortex more excitable.

The same group later reported in a 2024 study that chronic colitis produced memory problems, motor deficits, and anxiety- and depression-like behaviors in rats, with females showing more anxiety-like behavior and males showing stronger inflammation in the brain.

Building on this progression, a research group at the Universidad de Sevilla studying gut-brain pathophysiology led by María José Peral, Pablo García-Miranda, and Livia Carrascal set out to examine exactly what happens to the cells in the hippocampus during chronic colitis. The hippocampus is a seahorse-shaped structure deep in the brain that manages learning and memory.

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“Inflammatory bowel disease primarily affects the intestine, but people with IBD also have a high prevalence of mood disorders and cognitive difficulties, particularly involving memory,” study co-author María D. Vázquez-Carretero, a researcher in the Department of Physiology at the university’s Faculty of Pharmacy, told PsyPost. “Our previous studies showed that chronic colitis can be associated with alterations in the hippocampus, a brain region that is important not only in memory but also in emotional processes. This led us to investigate how it affects hippocampal neurons and whether males and females respond differently.”

The researchers also wanted to test the potential protective effects of creatine, teaming up with a group focused on neurogenesis and neuroregeneration. While widely known as a sports supplement used to build muscle, creatine is a natural compound that helps supply energy to cells throughout the body, including brain cells, acting as a reserve that quickly replenishes cellular fuel during times of high demand or stress.

“Because managing the effects of IBD beyond the intestine remains challenging, we investigated whether creatine, a naturally occurring compound, could protect the hippocampus from the effects of intestinal inflammation,” Vázquez-Carretero explained.

To explore these questions, the researchers used young male and female rats, with 15 to 21 animals of each sex in each of four groups: healthy rats given plain water, healthy rats given creatine, rats with colitis, and rats with colitis given creatine. Colitis was induced with dextran sulfate sodium in the drinking water over three one-week cycles separated by weeks of plain water, mimicking the flare-ups and remissions of human ulcerative colitis. Creatine was added to the drinking water at a daily dose of 1 gram per kilogram of body weight, starting 10 days before colitis was induced and continuing throughout. Each type of measurement used five to seven animals per group.

After a period of over a month, the researchers examined the rats’ hippocampi. They measured the levels of inflammatory molecules, assessed the physical health of the neurons, and tested the cells’ electrical properties. For the electrical tests, they used a technique called patch-clamp recording. This involves placing a microscopic glass tube against a single cell to monitor the tiny electrical currents flowing across its membrane.

The results indicated that chronic colitis reduced creatine levels in the hippocampus of both male and female rats. The gut inflammation also spurred a strong immune response in the brain. Microglia, which act as the brain’s first line of immune defense, became activated in both sexes, accompanied by elevated levels of inflammatory molecules.

The consequences of this brain inflammation differed sharply by sex. Male rats developed physical damage to their hippocampal neurons, showing a loss of structural proteins and fewer neurons in the CA1 region, a specific area of the hippocampus. In contrast, female rats maintained their neuronal structure despite the presence of inflammation.

The electrical tests revealed a similar divide. In male rats with colitis, the neurons became leakier: their membranes lost electrical resistance, and the minimum current needed to make a neuron fire an electrical signal, known as the rheobase, rose by roughly 60 percent. This suggests the neurons became less excitable, the opposite of the hyperexcitability reported in studies of short-term colitis.

The males also had higher levels of a potassium channel called Kv2.1, which helps neurons reset after firing, along with larger electrical currents flowing into and out of the cells. Female neurons showed no significant electrical changes, although colitis did raise levels of a calcium channel called Cav1.2 in their hippocampus.

“The changes were not limited to a single marker,” Vázquez-Carretero noted. “We found converging evidence of neuroinflammation, neuronal damage, and altered electrical properties of hippocampal neurons, particularly in males. Together, these findings suggest that chronic colitis can produce biologically meaningful alterations in hippocampal function.”

“The sex differences were particularly striking,” she added. “Male rats showed greater hippocampal neuroinflammation, neuronal damage, and alterations in neuronal electrical properties, whereas females were less affected at the functional level.”

Creatine supplementation largely prevented these changes. In rats with colitis that consumed creatine, hippocampal creatine levels were about 20 to 30 percent higher than in unsupplemented rats with colitis, matching those of healthy animals. The supplement prevented the activation of microglia and stopped the rise of inflammatory molecules in both sexes. In females, creatine had an especially strong effect in suppressing a specific inflammatory molecule called tumor necrosis factor.

Because the female rats did not experience the physical and electrical cell damage caused by colitis, creatine’s protective effects in these areas were mostly visible in the males. For the male rats, creatine protected the structural health of the neurons and maintained their normal electrical resistance and firing thresholds. The authors noted that creatine acts selectively on the parameters altered by disease, rather than artificially boosting the performance of healthy cells.

“Creatine also appeared to have a greater effect in males, but this seems to reflect their greater initial pathological burden rather than a sex-specific response to creatine,” Vázquez-Carretero observed.

The findings are in line with earlier work by the same research group, covered by PsyPost in 2025. That earlier study, which examined neuroinflammation in the cortex and behavioral deficits rather than cellular and electrical changes in the hippocampus, similarly found that creatine prevents colitis-induced brain inflammation across both sexes.

As with all research, there are a few things to keep in mind, including that the exact sequence of events might differ in human patients. “It is important not to interpret our results as showing that creatine is a treatment for inflammatory bowel disease or that people with colitis should take creatine to protect their brains,” Vázquez-Carretero cautioned. “Our study was conducted in rats under controlled experimental conditions. The results suggest that creatine may protect the brain from some consequences of chronic intestinal inflammation, but further research is needed to determine whether these effects also occur in humans.”

“Although these findings cannot be directly extrapolated to humans, growing evidence in people with IBD also suggests alterations in brain function and structure,” she noted.

The study used relatively small numbers of animals for the specific electrical and molecular tests, with five to seven rats per group. This reduced statistical power might have masked some subtle changes in the female rats, making them appear completely unaffected when they might have experienced minor alterations.

Additionally, the electrical recordings measured the overall flow of ions across the cell membrane rather than isolating individual channels with specialized drugs. Future research will need to pinpoint the exact molecular pathways responsible for the electrical changes.

It is also important to note that creatine was given before colitis began, so the study tested prevention rather than the treatment of existing damage. The study measured cells and electrical activity rather than memory or behavior, and it could not determine whether creatine protects the brain mainly by reducing inflammation in the gut or by acting directly on brain cells, though the authors suspect both play a role.

“We think this study highlights how closely connected the gut and the brain are,” Vázquez-Carretero told PsyPost. “It also reinforces the importance of studying both sexes when investigating how chronic inflammation affects the brain.”

“We want to better understand how chronic intestinal inflammation affects the brain and why these effects differ between males and females,” she said. “We are also interested in determining how creatine protects hippocampal neurons and whether this protection is related to its role in cellular energy metabolism. Ultimately, our goal is to determine whether these mechanisms are also relevant in humans and whether creatine could eventually be explored as a complementary strategy in people with chronic intestinal inflammation.”

The study, “Modulating effects of creatine prevent sex-dependent hippocampal neuroinflammation, neuronal damage, and electrophysiological dysfunction induced by chronic colitis,” was authored by Alejandro Ruiz-Calero, María Ortego-Domínguez, María D. Vázquez-Carretero, Gema Sotelo-Parrilla, Nora Martínez-Gómez, María L. Calonge, Ricardo Pardillo-Díaz, Carmen Castro, Pedro Nunez-Abades, María J. Peral, Livia Carrascal, and Pablo García-Miranda.