The gut may be the ticket to reducing chemo’s side effects
In a new study, scientists observed several simultaneous reactions in mice that received a common chemotherapy drug: their intestinal bacteria and tissues changed, their blood and brain showed signs of inflammation, and their behaviours suggested that they were tired and suffering from cognitive disorders.
Research is the first to show these combined events in the context of chemotherapy and opens the door to the possibility that regulating intestinal bacteria can not only calm chemotherapy side effects such as nausea and diarrhea, but also potentially reduce the memory and concentration problems that many cancer survivors report.
Further research is needed to better understand how chemotherapy-modified bowel influences the brain in a way that can have an impact on behaviour. The same laboratory at Ohio State University is conducting mouse studies to test the relationship and is conducting a parallel clinical trial in breast cancer patients.
"This is the first time anyone has ever tried to link intestinal symptoms to brain symptoms associated with chemotherapy," said Leah Pyter, assistant professor of psychiatry and behavioural health and researcher at the Institute for Behavioral Medicine Research in Ohio State. "There have been studies in humans that indicate that chemo alters microbes in the intestine, and our study in mice gave similar results.
"We have seen that there are brain changes as well as intestinal changes. We've 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 for causality."
The study is published today (November 11) in the journal Scientific Reports.
In this study, female mice received six injections of paclitaxel, a chemotherapy drug, and a control group of mice received placebo injections. Compared to controls, the treated mice lost weight and showed signs of fatigue, and their test performance suggested that they had memory loss.
The intestines, blood and brains of treated animals were also affected in a new way in control mice. The mixture of bacteria in the intestinal microbiome has changed, and the tissue lining the colon has spread abnormally. Specific proteins were present in the circulating blood and brain - as well as activated immune cells in the brain - all indicating that the immune system was busy producing a total inflammatory response from the body.
The sequence of events suggested that all these physiological changes were related: The intestine showed signs of permeability, which means that fragments of bacteria could escape from the narrow junctions of the intestine, an event that triggers an attack on the immune system. When the brain detects through blood and neural signals that the body's immune system is activated, the brain reacts in the same way with its own inflammation. And inflammation of the brain is the culprit behind the symptoms of "mental fog" known as chemo-brain.
The Pyter team tested all the data for the associations and found the strongest correlations between changes in intestinal microbes and colon wall and the activation of immune cells called microglia in the brain.
"Whenever chemotherapy reduced bacteria in the gut, this reduction was correlated with these cells in the brain," said Dr. Pyter, also a member of the Cancer Control Research Program at the Comprehensive Cancer Center in Ohio State.
"This suggests that chemotherapy affects microbes in the intestine and intestinal mucosa, and that both these changes cause inflammation at the periphery, creating signals that promote inflammation in the brain," she says. "That's how you get the brain involved - through the immune system. And inflammation in the brain leads to disease behaviours such as fatigue and weight loss, as well as cognitive disorders."
Confirming these links could lead to interventions for cancer patients - either dietary strategies such as probiotics or prebiotics, or perhaps fecal transplantation - to promote bacteria and conditions in the intestine that protect the brain from inflammation, which should reduce chemo-brain symptoms.
"This is only the first step in trying to address the concept to see if these severe intestinal effects of chemo have anything to do with brain chemo. It looks like it has potential," said Mr. Pyter.
This work has been supported by the Ohio State University Wexner Medical Center and grants from the National Institutes of Health.
Kelley Jordan and Browning Haynes of Ohio State and Brett Loman and Michael Bailey of Nationwide Children's Hospital were co-authors of the study.
