Scientists looking for evidence of bowel involvement in cognitive and mood problems related to chemotherapy treatment are testing their theories with the help of an unpleasant rodent habit: eating feces.
Because chemotherapy is so difficult for the digestive system to cause diarrhea, nausea and anorexia, researchers at Ohio State University are exploring the potential role of the gut in the "mental fog" phenomenon known as chemotherapy brain.
"This may be part of the reason cancer patients undergo chemotherapy is because the gut has changed and is talking to the brain differently," said Leah Pyter, assistant professor of psychiatry and behavioral health and researcher at the Institute for Behavioral Medicine Research from Ohio State.
To test the possible relationship, Pyter's lab is examining the effects of chemotherapy on mice whose intestines were manipulated prior to treatment. One experiment involves feeding the mice with antibiotics. The other is based on coprophagy – the universal practice among rats of eating their own poop and that of their roommates. In fact, mice go through something like faecal microbial transplants.
In a new study, Pyter found that mice receiving chemotherapy with untreated mice showed clear signs of changes in the intestinal bacteria of all animals. Mice receiving chemotherapy lost less weight if they had been housed with untreated mice – meaning that eating feces from non-chemotherapy mice changed their intestinal bacteria and partially reversed at least one side effect of chemotherapy.
While any solution is likely to be years away, the goal of the research is to identify possible ways to help combat cognitive problems and post-chemotherapy anxiety.
"If we find relationships between the gut microbiome and the brain of chemotherapy, clinicians can manipulate the gut of patients with probiotics or prebiotics or alter the diet in a way that promotes bacteria that appear to be beneficial to brain symptoms of chemotherapy," he said. Pyter
Pyter presented the paper on Wednesday (October 23, 2019) at the Society for Neuroscience meeting in Chicago.
The mice in these studies never have cancer. Half receive six chemotherapy injections over 11 days, and the control mice receive six injections from a placebo.
In the first experiment, all rats were fed regular food with or without mixed antibiotics before undergoing chemotherapy or placebo treatment. Researchers continued testing the animals for behaviors and signs of inflammation known to accompany chemotherapy.
Mice receiving antibiotics and chemotherapy had higher levels than untreated protein mice in their brains, which signaled inflammation in areas linked to cognition and mood. In a motion test, mice on chemotherapy moved less than placebo mice – an expected sign of fatigue. In mice treated with antibiotics and chemotherapy, fatigue was more pronounced.
"This suggests that if you break the gut and then get chemotherapy, fatigue is even worse," said Pyter, also a member of the Cancer Control Research Program at the Comprehensive Cancer Center in Ohio.
In the next experiment, Pyter took advantage of an observation made by scientists who are part of the growing body of research on the gut-brain connection: caged rodents tend to have similar intestinal and brain characteristics because they consume each other's feces.
The model was simple. Four rats were housed in each cage. One cage contained mice on chemotherapy, another contained mice given placebo, and the third contained two of each type of mouse.
"Because poop is only 10% of the intake, we did not expect drastic changes, but we expected subtle changes based on housing conditions," said Pyter. "Our hypothesis was that the vehicle mice (placebo) would be fine, the chemo rats would get sick, the chemo rats in mixed dwellings would be better off eating healthy poop and the guys in the car would get worse off eating chemo poop."
Body mass measurements told most of the story. Placebo mice living together were the largest and healthiest, and mice receiving chemotherapy living together lost more weight, suggesting disease. The average weight of the placebo and chemotherapy mice living together was right in the middle.
Pyter is following studies in which the ratio of treated and untreated rats, or vice versa, is 3 to 1. She is also conducting a parallel clinical study in breast cancer patients, collecting faecal samples, measuring immune response and assessing cognition with questionnaires before, during and after chemotherapy treatment.
"In my dreams, I took people's microbes before chemotherapy and returned their profile during chemotherapy," she said. "Even if it didn't alleviate the brain symptoms of chemotherapy, if I reduced nausea and anorexia – any of those gastrointestinal symptoms – I'd be happy to help."
This research is supported by a grant from the National Institutes of Health.