Diet and the gut microbiome play an important role in the immune response to cancer. A study led by researchers at Université de Montréal's affiliated hospital research centre (the CRCHUM) and McGill University, published in Nature, shows that interactions between the two may help explain why some people respond better than others to immunotherapy.

Led in part by Dr. Bertrand Routy, a researcher in the CRCHUM’s Cancer Research Theme and Co-Director of the CHUM Microbiome Centre, in collaboration with Dr. Arielle Elkrief, a researcher and Co-Director of the CHUM Microbiome Centre, the study shows that the effectiveness of certain immunotherapies may depend less on body weight than on the complex interplay between diet, the gut microbiome, and the immune system.

Understanding the obesity paradox

For several years, scientists have been trying to understand an intriguing phenomenon. Although obesity is generally associated with an increased risk of developing several types of cancer, some studies have shown that people with a high body mass index sometimes respond better to immune checkpoint inhibitors, a class of immunotherapies used to treat various cancers. This phenomenon is often referred to as the “obesity paradox.”

However, the mechanisms underlying this observation have remained poorly understood. Does obesity itself improve treatment response? Or do other related factors, such as diet or the gut microbiome, play a more important role?

To answer these questions, the researchers analyzed the effects of 12 different diets in preclinical models representing various forms of obesity. They also studied the contribution of the gut microbiome to the response to immunotherapy. 

More than a matter of weight

The findings show that favourable responses to immunotherapy were more closely associated with certain characteristics of the gut microbiome and with diet than with body weight itself. The researchers found that some obesity-promoting diets were also associated with a microbiome capable of enhancing the immune response against tumours.

The study also shows that certain gut bacteria, when combined with specific dietary conditions, promote the production of metabolites that can enhance immune activity against cancer. Conversely, less favourable microbiomes limited the effectiveness of treatment.

The researchers also showed that certain gut microbiomes could restore sensitivity to immunotherapy. In different experimental models, this effect was observed following dietary changes as well as microbiota transplantation. These findings suggest that modifying the intestinal environment may improve the response to treatment. Results obtained using human microbiota also support this finding.

In mice, microbiota transplants from people with a high body mass index improved the response to immunotherapy compared with transplants from people with a normal body mass index.

The analyses indicate that the “obesity paradox” may be explained, at least in part, by a synergy between diet and the gut microbiome rather than by obesity itself.

Toward more personalized approaches

For Dr. Arielle Elkrief, Dr. Bertrand Routy, and their collaborators, these findings contribute to a better understanding of the factors that influence the response to immunotherapy. They also open the door to new approaches for optimizing treatment by taking patients’ gut microbiome and nutritional environment into account.

The findings do not suggest that patients should change their diet to gain weight or adopt diets associated with obesity. Rather, they indicate that certain biological interactions between the foods we eat, gut bacteria, and the immune system could potentially be harnessed to improve the effectiveness of cancer treatment.

The researchers are now working to identify more precisely the gut bacteria and molecules responsible for these effects and determine how they could be used therapeutically.

Ultimately, this knowledge could contribute to the development of more personalized strategies, ranging from dietary adjustments to targeted modulation of the gut microbiome, with the goal of increasing the likelihood of a response to immunotherapy in people with cancer.