According to a new study published in Brain, behavior and immunity. Colitis-related damage was much more pronounced in male rats than in females. The findings add to evidence linking gut inflammation to changes in the brain, although they have not been tested in humans.
The gut-brain axis is the complex, bidirectional 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 cause sores and swelling of the lining of the colon and rectum. Under these conditions, inflammatory signals from the gut can travel to the brain and trigger secondary inflammation there, which may contribute to the mood and cognitive problems commonly experienced by people with gut diseases.
Previous research has mapped how this process unfolds. A 2018 study found that brief intestinal inflammation made male and female mice more prone to seizures and increased anxiety-like behaviors. In a 2022 study, members of the current team found that acute intestinal 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 behaviors and males showing stronger brain inflammation.
Building on this progression, a University of Seville research group studying gut-brain pathophysiology led by María José Peral, Pablo García-Miranda, and Livia Carrascal set out to examine exactly what happens to cells in the hippocampus during chronic colitis. The hippocampus is a seahorse-shaped structure located deep in the brain that manages learning and memory.
“Inflammatory bowel disease primarily affects the gut, but people with IBD also have a high prevalence of mood disorders and cognitive difficulties, particularly involving memory,” María D. Vázquez-Carretero, study co-author and researcher in the department of physiology at the university’s School of Pharmacy, told PsyPost. “Our previous studies have shown that chronic colitis may be associated with alterations in the hippocampus, a brain region important not only in memory but also in emotional processes. This led us to study how it affects hippocampal neurons and whether men and women respond differently.”
The researchers also wanted to test the potential protective effects of creatine, partnering with a group focused on neurogenesis and neuroregeneration. Although widely known as a sports supplement used to build muscle, creatine is a natural compound that helps provide energy to cells throughout the body, including brain cells, acting as a reserve that quickly replenishes cellular fuel in times of high demand or stress.
“As managing the effects of IBD beyond the gut remains a challenge, we investigated whether creatine, a natural 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 drinking water over three 1-week cycles separated by weeks of plain water, mimicking the flares and remissions of human ulcerative colitis. Creatine was added to drinking water at a daily dose of 1 gram per kilogram of body weight, beginning 10 days before induction of colitis and continuing throughout. Each type of measurement used five to seven animals per group.
After more than a month, the researchers examined the rats’ hippocampi. They measured levels of inflammatory molecules, assessed the physical health of neurons, and tested the cells’ electrical properties. For electrical testing, 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 through its membrane.
The results indicated that chronic colitis reduced creatine levels in the hippocampus of both male and female rats. The intestinal inflammation also triggered a strong immune response in the brain. Microglia, which constitute the brain’s first line of immune defense, were activated in both sexes, accompanied by high levels of inflammatory molecules.
The consequences of this brain inflammation differed greatly depending on 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 retained their neuronal structure despite the presence of inflammation.
Electrical testing revealed a similar fracture. In male rats with colitis, neurons became less tight: Their membranes lost electrical resistance and the minimum current needed for a neuron to fire an electrical signal, known as rheobase, increased by about 60%. This suggests that the neurons became less excitable, in contrast to the hyperexcitability reported in short-term colitis studies.
Males also had higher levels of a potassium channel called Kv2.1, which helps neurons reset after firing, as well as greater electrical currents flowing in and out of cells. The female neurons showed no significant electrical changes, although colitis increased the levels of a calcium channel called Cav1.2 in their hippocampus.
“The changes were not limited to a single scorer,” Vázquez-Carretero emphasized. “We found converging evidence of neuroinflammation, neuronal damage, and altered electrical properties of hippocampal neurons, particularly in men. Together, these results suggest that chronic colitis may produce biologically significant alterations in hippocampal function.”
“The gender differences were particularly striking,” she added. “Male rats exhibited greater hippocampal neuroinflammation, neuronal damage, and alterations in neuronal electrical properties, while females were less functionally affected.”
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 rats with colitis without the supplement, matching those in healthy animals. The supplement prevented the activation of microglia and stopped the rise of inflammatory molecules in both sexes. In women, creatine had a particularly powerful effect by suppressing a specific inflammatory molecule called tumor necrosis factor.
Because female rats did not experience the physical and electrical damage caused to cells by colitis, the protective effects of creatine in these areas were mainly seen in males. For male rats, creatine protected the structural health of neurons and maintained their normal electrical resistance and firing thresholds. The authors noted that creatine acts selectively on parameters altered by disease, rather than artificially stimulating the performance of healthy cells.
“Creatine also appears to have a greater effect in men, but this appears to reflect their greater initial disease burden rather than a sex-specific response to creatine,” Vázquez-Carretero observed.
The findings are consistent with previous work from 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, also found that creatine prevents colitis-induced brain inflammation in both sexes.
As with any research, there are a few things to keep in mind, including that the exact sequence of events may 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 brain,” 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 a relatively small number of animals for the specific electrical and molecular tests, with five to seven rats per group. This reduced statistical power could have masked some subtle changes in the female rats, making them appear completely unresponsive when they could have undergone minor changes.
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 identify the exact molecular pathways responsible for the electrical changes.
It’s also important to note that creatine was administered before the onset of colitis, so the study tested prevention rather than treatment of existing damage. The study measured cells and electrical activity rather than memory or behavior, and could not determine whether creatine protects the brain primarily by reducing inflammation in the gut or by acting directly on brain cells, although the authors suspect both play a role.
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