Exercise-Fueled Microbiome Shift Boosts Cancer Immunotherapy, Study Finds
A groundbreaking new study reveals how exercise enhances cancer treatment outcomes by reshaping the gut microbiome and boosting the production of a key compound, formate. The research, published in the journal Cell, offers a potential pathway for improving immunotherapy effectiveness and identifying “super donors” for fecal microbiota transplantation.
A team at the University of Pittsburgh has, for the first time, demonstrated a direct link between exercise, changes in the intestinal microbiome, and improved response to immunotherapy in mice. The findings suggest that harnessing the power of the gut could be a game-changer in the fight against cancer.
The Gut-Exercise-Immunotherapy Connection
Researchers have long known that exercise improves the efficacy of cancer immunotherapy and alters the gut microbiome in both mice and humans. This new study bridges those observations, pinpointing how exercise-induced changes in the gut microbiome stimulate the immune system and amplify the effects of immunotherapy. The key, according to the research, lies in formate, a compound produced by intestinal bacteria.
“We already knew that exercise increases the effectiveness of immunotherapy against cancer, and we knew separately that exercise changes the microbiome in mice and humans,” explained a senior researcher involved in the study. “This research connects these points by showing how the changes induced by exercise in the intestinal microbiome stimulate the immune system and improve the effectiveness of immunotherapy via formate.”
Mouse Models Reveal the Power of the Microbiome
The research team began by comparing mice subjected to four weeks of regular exercise with a sedentary control group. Mice that exercised exhibited smaller tumors and improved survival rates when challenged with an aggressive form of melanoma. However, these benefits vanished when the researchers used germ-free mice – those lacking any gut bacteria – or treated mice with antibiotics to eliminate their microbiome.
“When we removed the microbes from the equation, the exercise no longer had an effect on cancer results in mice,” said Catherine Phelps, a student researcher and lead author of the study. “We were surprised to see such a clear signal that the beneficial effects of the exercise were due to the microbiome.”
Further investigation revealed that it wasn’t the bacteria themselves, but rather the metabolites they produce, driving the observed effects. Using an artificial intelligence tool called Slide to analyze metabolic pathways, the team identified formate as the critical player.
Formate Fuels Immune Response
Subsequent experiments demonstrated that formate enhances the potency of CD8 T cells, the primary immune cells responsible for killing cancer cells. In mouse models of melanoma, adenocarcinoma, and lymphoma, daily oral formate significantly inhibited tumor growth and improved survival rates. Formate also boosted the effectiveness of immune checkpoint inhibitor immunotherapy in mice with melanoma.
“It is really exciting to identify a specific bacterial metabolite which imitated the effects of the exercise in mice,” stated Marlies Meisel, Ph.D., principal author and assistant professor in the Immunology Department of Pitt School of Medicine. “In the future, formate could potentially be studied as adjuvant therapy to improve the efficiency of immune checkpoint inhibitors in non-responders.”
Human Studies Show Promise
To assess the relevance of formate in humans, the researchers analyzed data from patients with advanced melanoma undergoing immune checkpoint inhibitor treatment. Patients with higher levels of formate in their blood demonstrated improved progression-free survival compared to those with lower levels.
Further bolstering the findings, fecal microbial transplants (FMT) from individuals with high or low formate levels were administered to mice with aggressive melanoma. Strikingly, animals receiving transplants from “high-formate” donors exhibited enhanced T cell activity and better tumor control.
FMT is already being explored as a therapy to improve immunotherapy outcomes, but the reasons why some donor stools are more effective than others remain unclear. “We want to describe metabolic biomarkers to identify FMT super donors because it’s really a black box,” Meisel explained. “Currently, everyone focuses on bacterial species, but our research suggests that it is not only the microbes present, but what they do and the metabolites they produce.”
Beyond Cancer: Exploring Autoimmune Disorders
The research team is now investigating whether exercise-induced changes in the gut microbiome could play a role in other diseases, such as autoimmune disorders. They are also working to understand the underlying mechanisms by which exercise influences the microbiome in the first place. This research opens up exciting new avenues for therapeutic intervention, potentially leveraging the power of the gut to improve health outcomes across a range of conditions.
