Summary: Altering gut bacteria in mice before chemotherapy reduces the cognitive fog commonly known as “chemo brain.”
Source: Ohio State University
Researchers investigating the gut’s role in cognitive and mood changes after chemotherapy are using an unexpected rodent behavior—coprophagia—to study how gut microbes influence chemo-related brain effects.
Chemotherapy frequently damages the digestive system, producing symptoms such as diarrhea, nausea and loss of appetite. Because of these strong gastrointestinal effects, a team at Ohio State University is examining whether changes in the gut microbiome contribute to the cognitive impairment and mood disturbances often described as chemo brain.
“Part of why patients experience chemo brain may be that chemotherapy alters the gut and that altered gut signals affect the brain,” said Leah Pyter, assistant professor of psychiatry and behavioral health and an investigator at Ohio State’s Institute for Behavioral Medicine Research.
To explore this gut–brain link, Pyter’s lab is studying mice whose gut bacteria have been altered before chemotherapy treatment. One approach uses antibiotics to disrupt the microbiome. The other exploits mice’s natural tendency to eat feces, which effectively transfers microbes between cage-mates in a way similar to fecal microbial transplantation.
In a recent study, Pyter and colleagues found that when mice treated with chemo were housed with untreated mice, the gut bacterial communities of all animals shifted. Notably, chemo-treated mice that lived with untreated mice lost less weight than chemo-treated mice housed only with other treated animals. That result suggests that consuming feces from healthy, untreated mice partially restored gut populations and reduced at least one chemotherapy side effect.
Although practical human treatments are likely years away, the broader aim is to identify strategies that might prevent or lessen post-chemotherapy cognitive problems and anxiety by targeting the gut microbiome. “If we uncover links between the gut microbiome and chemo brain, clinicians could consider probiotics, prebiotics or dietary changes to promote bacteria that appear to protect against chemo brain symptoms,” Pyter said.
Pyter presented these findings on Wednesday, Oct. 23, 2019, at the Society for Neuroscience meeting in Chicago.
Importantly, the mice used in these experiments never had cancer. Half of the animals received six injections of a chemotherapy regimen over 11 days; control animals received six placebo injections. The researchers then measured behavior, body weight and markers of inflammation in the brain and body—measures commonly associated with chemo-related cognitive and mood changes.
In one experiment, groups of mice were fed regular chow either with or without antibiotics before undergoing chemo or placebo treatment. The results showed that mice given both antibiotics and chemotherapy had higher levels of inflammatory proteins in brain regions tied to cognition and mood, compared with untreated controls. In movement tests designed to detect fatigue, mice receiving chemo were less active than placebo animals, and the addition of antibiotics made that fatigue worse.
“This suggests that disrupting the gut microbiome before chemotherapy can worsen fatigue associated with treatment,” said Pyter, who is also a member of the Cancer Control Research Program at Ohio State’s Comprehensive Cancer Center.
In a follow-up experiment, the team used the natural microbial transfer that occurs when rodents share a cage. Because mice routinely consume one another’s feces, animals housed together tend to develop similar gut microbial profiles and related physiological characteristics.
The housing design was straightforward: four mice per cage, with one cage containing only chemo-treated mice, another containing only placebo mice, and a third containing a mix of two chemo-treated and two placebo animals.
“Since feces only represent a portion of their intake, we didn’t expect dramatic shifts, but we did anticipate subtle changes driven by housing conditions,” Pyter explained. The research team hypothesized that placebo mice housed together would remain healthy, chemo-only groups would show the strongest signs of illness, mixed cages would produce intermediate outcomes, and that placebo mice living with chemo-treated mice might acquire some negative effects through microbial transfer.
Body weight tracked these patterns clearly. Placebo-only cages produced the heaviest, healthiest animals. Chemo-only cages yielded the greatest weight loss, indicating sickness. Mixed cages produced intermediate average weights, suggesting that exchange of gut microbes through coprophagia moderated some negative effects in chemo-treated animals while possibly introducing mild adverse shifts in the placebo animals.
Pyter is extending this work by testing different ratios of treated to untreated mice (for example, 3-to-1) to better understand how microbial dose and exposure influence outcomes. Parallel clinical work is underway with breast cancer patients: researchers are collecting fecal samples, measuring immune responses and assessing cognition with standardized questionnaires before, during and after chemotherapy.
“An ideal future strategy would be to preserve or restore a patient’s own microbial profile during chemotherapy,” Pyter said. “Even if that approach only reduces gastrointestinal symptoms like nausea and loss of appetite, it would represent a meaningful improvement for people undergoing treatment.”
Funding: This research is supported by a grant from the National Institutes of Health.
Current and former students Ashley Lahoud, Kelley Jordan, Browning Haynes, Selina Vickery, Jasskiran Kaur and Kyle Sullivan contributed to the study.
Source:
Ohio State University
Media Contacts:
Leah Pyter – Ohio State University
Image Source:
The image is credited to Ohio State University.
Original Research: The study was presented at Neuroscience 2019.