A new study from the University of Pittsburgh School of Medicine illustrates for the first time how exercise improves cancer outcomes by reshaping the gut microbiome and boosting immunotherapy response through the compound formate, marking a significant step in cancer treatment research.
A new study from the University of Pittsburgh School of Medicine has unveiled how exercise can significantly improve cancer outcomes by reshaping the gut microbiome.
This research, published in the journal Cell, demonstrates that exercise-induced changes in gut bacteria produce a metabolite called formate, which enhances the effectiveness of immunotherapy treatments in mice and correlates with better outcomes for melanoma patients.
“We already knew that exercise increases the effectiveness of cancer immunotherapies, and we separately knew that exercise changes the microbiome in mice and humans,” senior author Marlies Meisel, an assistant professor in the Department of Immunology at Pitt’s School of Medicine who is affiliated with the UPMC Hillman Cancer Center, said in a news release. “This study connects those dots by showing how exercise-induced changes in the gut microbiome boost the immune system and enhance immunotherapy efficiency via formate.”
The research team discovered that exercise led to smaller tumors and better survival rates in mice challenged with aggressive melanoma after just four weeks of regular activity.
However, these benefits disappeared when the gut microbiome was disrupted, either by using germ-free mice or administering antibiotics.
“We were surprised to see such a clear signal that the beneficial effects of exercise were due to the microbiome,” added lead author Catherine Phelps, a doctoral student in microbiology and immunology in Meisel’s lab.
To pinpoint the exact mechanisms, the researchers used a machine learning tool called SLIDE to analyze metabolic pathways and identified formate as a crucial component. Formate, a metabolite produced by gut bacteria, was shown to significantly enhance CD8 T cells, vital players in the immune system’s fight against cancer.
Further experiments revealed that daily oral administration of formate in mice with melanoma, adenocarcinoma and lymphoma led to inhibited tumor growth and improved survival rates.
Additionally, formate boosted the efficacy of immune checkpoint inhibitor therapies in melanoma.
“It’s really exciting to identify a specific bacterial metabolite that mimicked the effects of exercise in mice,” Meisel added. “In the future, formate could potentially be investigated as an adjuvant therapy to improve the efficacy of immune checkpoint inhibitors in non-responders.”
Exploring the implications for human patients, the study examined individuals with advanced melanoma undergoing immune checkpoint inhibitor therapy. Patients with higher formate levels in their blood experienced better progression-free survival.
Moreover, fecal microbial transplants (FMT) from these patients with high formate levels into mice demonstrated enhanced T cell activity and improved tumor control.
Despite the promising results, the mechanisms behind why some fecal transplants perform better are not fully understood.
“We want to describe metabolic biomarkers to identify FMT super donors because that’s really a black box,” added Meisel. “Currently everyone focuses on bacterial species, but our research suggests that it’s not just about which microbes are present, but what they are doing and which metabolites they are producing.”
The study opens new avenues for therapeutic strategies focusing on diet and lifestyle changes to target the gut microbiome. Meisel and her team are now investigating the broader implications of exercise-induced microbiome alterations, including potential benefits for autoimmune disorders and other health conditions.