Scientists at Ohio State University have uncovered a correlation between treatment using the chemotherapy agent paclitaxel, and changes to the gut microbiome, inflammation, and symptoms of fatigue and cognitive impairment. The research, in mice, is the first to demonstrate these combined events in the context of chemotherapy, and suggests that regulating gut bacteria may represent a new approach to diminishing some of the side effects of chemotherapy such as nausea and diarrhea, and also potentially reducing some of the memory and concentration problems reported by patients receiving treatment.

“This is the first time anyone has even looked to see if there’s a link between the gut symptoms and the brain symptoms associated with chemotherapy,” said Leah Pyter, PhD, assistant professor of psychiatry and behavioral health, and an investigator in the Institute for Behavioral Medicine Research at Ohio State. “There have been studies in humans indicating that chemo alters microbes in the gut, and our study in mice had similar results. We were able to see that there are brain changes at the same time as the gut changes. We also looked at inflammation, and yes, there are all these changes happening at the same time. So there are correlations, and now we’re looking into causality.” Pyter is senior author of the team’s published paper in Scientific Reports, which is titled, “Chemotherapy-induced neuroinflammation is associated with disrupted colonic and bacterial homeostasis in female mice.”

Chemotherapy agents that block cell proliferation are still the mainstay of treatment for many types of cancer, but can affect the nervous and immune systems and alter gastrointestinal function and microbial composition, the authors explained. “… the combination of systemic administration of chemotherapy and its lack of cellular specificity results in numerous deleterious side effects, both behavioral (e.g., “chemobrain” cognitive impairment, fatigue) and gastrointestinal (e.g., diarrhea, nausea, vomiting). These side effects can be debilitating, costly, and occasionally life-threatening, in part because they reduce adherence to cancer treatments.

It has been reasoned that chemotherapy may directly affect brain tissue, through mechanisms that may cause toxicity to brain cells, results in oxidative stress, inflammation, or damage to the neurovascular elements. However, many chemotherapy agents, such as paclitaxel, don’t easily penetrate into the brain. This suggests that indirect—so far undiscovered—mechanisms may contribute to chemotherapy-induced behavioral problems.

One possibility is a role for the gut microbiome in mediating such mechanisms, the authors suggested. “Specifically, the intestinal bacteriome sends biological signals (either directly or indirectly) to the brain, thereby influencing CNS homeostasis, behavior, and mood. While changes in mood or cognitive function have not been linked to the intestinal microbiome in chemotherapy-treated cancer patients or animal models, existing studies support its plausibility.”

Leah Pyter, PhD [Ohio State University]

Another contributor to chemotherapy-induced behavioral side effects is the bidirectional communication between the gut and its resident microbiota, and the host immune system, the researchers noted. Changes in intestinal microbial composition has been linked with systemic inflammation and neuroimmune function. “Relevant to this study, elevated circulating cytokines and neuroinflammation are associated with cognitive impairment, fatigue, and mood disorders in cancer patients and are causal in rodent cancer models. Thus, here we hypothesized that the gut microbiota contributes to chemotherapy-induced neuroinflammation and behavioral changes.”

For their reported study, the investigators gave one cohort of female mice a course of six injections of the chemotherapy drug paclitaxel, and another, control group of mice placebo injections. Compared to the controls, the treated mice lost weight and showed signs of fatigue, and their performance on tests suggested that they experienced memory loss. The chemotherapy-treated animals’ guts, blood, and brains were also affected in ways that were not seen in the control mice. The mix of bacteria in their gut microbiome changed, and the tissue lining the colon became abnormally extended. More specifically, paclitaxel therapy decreased the relative abundance of multiple types of bacteria that are important to colon health, including Lachnospiraceae bacteria, and butyrate-producing species.

The combined presence of specific proteins in the treated animals’ blood and brain, along with activated immune cells in the brain, indicated that the immune system was mounting a total-body inflammatory response. “Taken together, chemotherapy-induced moderate sickness behaviors (anorexia, fatigue, retarded growth), impaired cognitive performance, acutely increased central and peripheral inflammation, induced evidence of endotoxin release into the circulation, altered colonic membrane morphology, as well as, reduced colonic and fecal bacterial community diversity,” the investigators reported.

The sequence of treatment-related effects suggested that the different physiological changes were related. The gut demonstrated markers of permeability that could trigger an immune response. When the brain detects through the blood and neural signals that the body’s immune system is activated, it responds in kind with its own inflammation. Brain inflammation is the culprit behind the “mental fog” symptoms known as chemo brain.

Pyter’s team tested all the data for associations and found the strongest correlations between changes in the gut microbes and in the colon lining and the activation of microglia immune cells in the brain. “Every time chemo reduced bacteria in the gut, that reduction was correlated with these cells in the brain,” said Pyter, also a member of the Cancer Control Research Program at Ohio State’s Comprehensive Cancer Center. “This suggests chemotherapy is affecting the microbes in the gut and affecting the lining of the gut, and both of those changes cause inflammation in the periphery, which creates signals that promote inflammation in the brain,” she added. “That’s how we get the brain involvement— through the immune system. And inflammation in the brain leads to sickness behaviors like fatigue and weight loss, as well as cognitive impairment.”

If scientists can confirm all of the connections identified, the new insights could help direct the development of new treatments cancer patients—perhaps dietary strategies such as probiotics or prebiotics, or possibly fecal transplantation—to promote gut bacterial populations and conditions that protect the brain from inflammation. This should then reduce chemo brain symptoms. “These findings suggest that therapeutic strategies that target the gut microbiota, (e.g., dietary interventions, prebiotics, and/or probiotics) that can attenuate the deleterious effects of chemotherapy on gut integrity, may also be helpful for alleviating the behavioral side effects of chemotherapy,” the authors concluded.

“This is just the first step of trying to broach the concept to see if these harsh gut effects of chemo have anything to do with chemo brain. It looks like it has potential,” Pyter noted. More research is needed to further understand how the chemo-modified gut influences the brain in a way that can have an impact on behavior. The Ohio State University lab is now continuing mouse studies to test the relationship, and is running a parallel clinical trial in breast cancer patients.

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