Gut microbiome may contribute to cognitive problems after chemotherapy
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Chemotherapy-induced changes to the gut microbiome may explain why some patients with cancer experience post-chemotherapy cognitive decline.
This association appeared independent of chemotherapy-induced inflammation, according to investigators.
The longitudinal, observational Intelligut study included 77 women with breast cancer. Researchers collected fecal samples, obtained blood samples and performed cognitive assessments prior to, during and after chemotherapy.
“It’s been known that chemotherapy can have a disruptive effect on the gut. In this study, we wanted to see whether these changes are related to some of the behavioral side effects of chemotherapy,” Leah Pyter, PhD, associate professor of psychiatry at the Institute for Behavioral Medicine at The Ohio State University Wexner Medical Center and College of Medicine, told Healio. “We’re trying to determine whether the gut-brain axis plays a role in the context of chemotherapy.”
Pyter and colleagues determined chemotherapy changed the community structure of the gut microbiome and increased levels of circulating tumor necrosis factor-alpha.
Study participants reported subjective cognitive decline during chemotherapy, but investigators determined this was not due to changes in the gut microbiome or inflammatory markers.
However, researchers determined decreases in overall objective cognition were related to a decrease in microbial diversity, independent of circulating inflammatory cytokines.
A microbial abundance analysis revealed unique taxonomic shifts among patients with cognitive decline compared with those who did not have cognitive decline.
Healio spoke with Pyter about the implications of the findings and next steps in research.
Healio: Why did you conduct this study?
Pyter: Many of the behavioral and cognitive side effects of chemotherapy are poorly understood and not well treated. Oncologists are understandably focused on treating the cancer, so side effects are less understood and less treated.
If the gut is contributing to cognitive side effects, this may represent a new way to treat the behavioral side effects. Manipulating the gut would be less invasive, potentially cheap and doesn’t require adding another drug. These patients are getting all kinds of drugs, and they have interactions. This has the potential to address the issue in a more natural way.
Healio: How did you conduct the study?
Pyter: We visited patients with breast cancer at three time points during their treatment. Before they received chemotherapy, we got baseline microbiome measurements through a fecal sample and blood to evaluate inflammatory immune markers. We also did a battery of cognitive tests. We took the same measurements at the time of their last chemotherapy infusion, and we took samples approximately 3 months after they completed chemotherapy.
Healio: What did you find?
Pyter: Some patients did display cognitive decline after undergoing chemotherapy, and these cognitive side effects were associated with changes to their gut microbiome. We also saw inflammation related to gut changes, but this inflammation did not relate to their cognitive decline. This suggests the gut-brain axis may not involve the immune system in the context of chemobrain. This is one of the communication pathways that has been considered — the idea is that the disruption in the gut microbiome could activate the immune system, and the immune system signals could then cause cognition problems.
However, other gut-brain mechanisms might play a role. Specifically, the gut might talk to the brain in this context through the metabolites they produce. These can get into the bloodstream and affect the brain. Some of these metabolites are active in the brain, like short-chain fatty acids and even bile acids. When you disrupt your gut microbiome, you disrupt the quantity of these metabolites.
That’s something we’re pursuing right now. We’re evaluating whether some of these other gut-to-brain pathways might be related to cognitive decline after chemotherapy.
Healio: What are the potential implications of the findings?
Pyter: We might be able to use patients’ microbiome samples before they undergo chemotherapy to predict who might be vulnerable to behavioral side effects. Not everyone experiences these side effects, so a way to predict this would be very helpful. If a patient has a microbiome profile that suggests he or she would be vulnerable to fatigue, neuropathy or cognitive decline, there is potential to preventively change the microbiome to be more robust and resistant to effects of chemotherapy. This could be through a dietary interventions, some sort of probiotic or even a fecal microbial transplant. The long-term goals are predicting who would be vulnerable and then using the microbiome to treat behavioral side effects and quality-of-life issues.
Healio: What are the next steps in research?
Pyter: We are probing the non-immune gut-to-brain communication pathways. We’re doing metabolomics in leftover samples we have. We will be able to assess from these same women, through fecal samples, what metabolites the microbes are producing. Through their blood, we can determine which of those metabolites got into the bloodstream to potentially impact the brain. We then can relate those changes in the metabolites with their microbiome and with their cognitive function.
We’re also starting to work on using a fecal microbial transplant as an intervention. Most of this work will start in mice. However, we have funding to start a pilot feasibility study of women with breast cancer.
Healio: Is there anything else you’d like to mention?
Pyter: The microbiome is still a brand-new area in cancer, so a lot of research needs to be done. We’re so grateful to our funding sources and to these women who were willing to participate in this. We’re really hoping to make an impact.
Reference:
For more information:
Leah Pyter, PhD, can be reached at leah.pyter@osumc.edu.
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