How exercise transforms your microbiome to fight cancer more effectively

A study from the University of Pittsburgh (USA) has discovered a surprising mechanism behind the benefits of physical exercise in fighting cancer. According to the researchers, exercise not only reduces tumor size in mice, but also improves the response to immunotherapy by modifying the gut microbiome.

The research, published in the journal Cell , identified the compound formate, produced by gut bacteria in exercising animals, as responsible for these beneficial effects. This same compound has also been associated with improved outcomes in human patients with melanoma.

“We already knew that exercise improves the effectiveness of cancer immunotherapies and also modifies the microbiome. What we didn't know was how these two factors were connected,” explains Marlies Meisel, senior author of the study and a professor in the Department of Immunology at Pitt School of Medicine. “Our work shows that exercise-induced changes in the gut microbiome strengthen the immune system and enhance immunotherapy thanks to the format.”

The team, led by Catherine Phelps, compared mice that exercised for four weeks with sedentary mice. The active mice developed smaller tumors and lived longer when faced with an aggressive form of melanoma. However, these benefits disappeared when the animals were treated with antibiotics or raised without a microbiome, confirming that gut bacteria were key.

"When we eliminated the bacteria, exercise no longer had any effect on cancer. It was surprising to see that it all depended on the microbiome ," Phelps notes.

Using artificial intelligence tools, the researchers identified formate as the metabolite produced by the bacteria that generated these positive effects. In models of melanoma, adenocarcinoma, and lymphoma, oral administration of formate significantly reduced tumor growth and enhanced the efficacy of immunotherapy based on immune checkpoint inhibitors.

To test whether these findings were relevant to humans, the team analyzed blood samples from patients with advanced melanoma treated with immunotherapy. Those with higher levels of formate in their blood had better progression-free survival.

They also performed fecal transplants in mice using samples from human patients with high or low levels of formate. The mice that received microbiota from patients with high formate levels showed increased T cell activity and improved tumor control.

Fecal transplantation is already being explored as a therapy to improve immunotherapy outcomes in patients who do not respond . However, it is not entirely clear why some "super donor" stools produce better results.

"We want to describe metabolic biomarkers to identify FMT super donors, as this is truly a black box," Meisel notes. "Currently, everyone focuses on bacterial species, but our research suggests it's not just about which microbes are present, but what they're doing and what metabolites they're producing."