Some diets associated with weight gain appeared to help cancer immunotherapy work better in mice, but researchers say the finding should not be interpreted as evidence that people with cancer should eat more high-fat foods.
Instead, the study points to something more complicated: What we eat may change the gut microbiome in ways that affect how the immune system responds to cancer treatment.
Published in Nature, the research primarily involved mice, with additional analysis of samples from people with non-small cell lung cancer. Researchers found that response to a commonly used form of immunotherapy seemed to depend more on interactions between diet and gut bacteria than on body weight or other measures of metabolic health.
That distinction could help scientists better understand a puzzling pattern that has appeared in cancer research.
Some studies have found that people with a higher body mass index, or BMI, respond better to certain immune checkpoint inhibitors, drugs that help the immune system recognize and attack cancer cells. The observation has sometimes been called the “obesity paradox” because obesity is also associated with a higher risk of many cancers and other health problems.
The new study suggests body weight may not be the whole explanation.
Researchers tested 12 different diets in mice. The diets varied widely in their sources of fat, carbohydrates, protein and fiber and included patterns designed to resemble Mediterranean, Japanese, vegan, ketogenic and American-style diets.
The mice then received anti-PD-1 treatment, a type of immune checkpoint therapy.
Some diets produced much stronger treatment responses than others. Three of the four diets associated with the best responses also caused obesity in the mice. But treatment success was not closely tied to body weight, body fat, blood sugar control or other measures of metabolic health.
Instead, researchers saw stronger connections with the gut microbiome.
Certain bacteria were more common in mice that responded well to treatment, while other bacterial patterns appeared more often in mice whose tumors did not respond.
The picture was not as simple as identifying one “good” bacterium or one “good” diet, however. One diet that did not cause obesity still supported a strong treatment response, while another diet that caused weight gain did not.
Those differences led researchers to look at how diet and gut bacteria might be working together.
They found that the microbiome could change fairly quickly after a change in diet, before major differences in body weight appeared. In one experiment, switching mice from a diet associated with poor treatment response to one associated with better response changed their gut bacteria within days and also improved the effectiveness of immunotherapy.
That finding strengthened the researchers’ suspicion that body weight itself was not driving the effect.
The team also studied Lactobacillus johnsonii, one type of bacteria that appeared more often in some mice that responded well to treatment. The bacterium was most effective when paired with a particular dietary environment, suggesting that what gut microbes produce and how they behave may matter as much as which microbes are present.
Researchers also identified chemical compounds made through interactions between gut bacteria and nutrients that may help influence immune activity. In mice, one of those compounds improved the response to immunotherapy even under dietary conditions that had previously been associated with a poor response.
The study included some human data, but the evidence in people remains preliminary.
Researchers analyzed blood samples from 53 people with non-small cell lung cancer who had received immune checkpoint inhibitors. People who responded to treatment had higher levels of some of the same types of microbial byproducts seen in the mouse experiments.
Scientists also transferred gut microbes from a small number of patients into mice. Microbes from people with higher BMI were associated with a stronger treatment response in the animals.
None of those experiments show that changing a person’s diet will improve cancer treatment.
The researchers did not put people with cancer on high-fat or weight-promoting diets and test whether their treatment outcomes improved. Most of the evidence came from mice, and the tumor models used in the experiments cannot fully reproduce the complexity of cancer in people.
The authors also specifically caution against interpreting the findings as support for long-term high-fat or obesity-promoting diets. Such diets carry established health risks.
The more promising possibility is that researchers may eventually be able to identify specific foods, nutrients, gut bacteria or microbial compounds that create some of the same immune effects without those risks.
The study was supported by the Canadian Institutes of Health Research, Canadian Cancer Society, Terry Fox Research Institute, Canada Foundation for Innovation and several philanthropic organizations and foundations.