The relationship between diet, the gut microbiome, and cancer immunotherapy has been an active area of research for years, but a new Nature study from McGill University and the University of Montreal provides the most detailed causal picture yet, and delivers a surprising finding: what you eat can completely override the microbiome of a donor fecal transplant.
The study, led by Lysanne Desharnais, Daniela F. Quail, Logan A. Walsh, and Bertrand Routy, tested 12 different mouse diet models, ranging from low-fat and Mediterranean to high-fat, Western, American, ketogenic, vegan, and fiber-modified diets, and assessed how each affected responses to immune checkpoint inhibitors (ICIs) targeting PD-1.
Diet, not obesity
The first key finding is that it is diet composition, not obesity, that drives ICI efficacy. Four of six obesogenic diets (high-fat, American, American plus aspartame, and inulin) were ICI-responsive. But there was no correlation between ICI response and body weight, fat mass, glucose tolerance, or metabolic score. Mice on a psyllium fiber diet remained ICI-resistant even when obese.
The microbe and the metabolite
Across the responsive diets, one bacterial species consistently distinguished responders from non-responders: Lactobacillus johnsonii. The bacterium produces a tyrosine-derived phenylpropionate metabolite called desaminotyrosine (DAT).
In germ-free mice colonized only with L. johnsonii and fed a high-fat diet, anti-PD-1 therapy produced complete tumor regression. L. johnsonii plus a psyllium (non-responder) diet produced only partial responses. A control bacterium plus high-fat diet also produced only partial responses. The synergy requires both the specific organism and the obesogenic diet.
DAT supplementation alone, added to drinking water, was sufficient to sensitize mice on a non-responder diet to anti-PD-1. The metabolite enhances CD8-positive T cell function via type I interferon signaling, expanding functional, cytokine-producing T cells in the tumor microenvironment.
Diet overrides FMT
The most striking finding involves fecal microbiome transplants (FMT). When mice on a psyllium (non-responder) diet received FMT from a high-fat-fed donor mouse, the diet overrode the donor microbiome: the recipients remained ICI-sensitive, and their gut microbiome converged toward the high-fat-fed pattern, not the donor pattern.
Even more dramatic: FMT from a human patient who was ICI-refractory, whose microbiome would normally confer resistance, was rescued by feeding the recipient mice a high-fat diet. The L. johnsonii population expanded, and ICI sensitivity was restored.
The study also analyzed plasma metabolomics from non-small cell lung cancer patients and found that aromatic amino acid metabolites, indolelactic acid and 3-HPP sulfate, were elevated in ICI responders, consistent with the diet-microbiome axis operating in humans.
Implications
The results suggest that dietary interventions could be used to optimize ICI responses in patients without the need for FMT, or to override a non-responder microbiome. The finding that microbial shifts occur within 48 hours of a diet change means that short-term dietary modifications around the time of treatment could be clinically practical.
The authors note that the mechanism, L. johnsonii producing DAT, which activates CD8-positive T cells via type I interferon, provides a defined molecular target that could eventually be developed as a therapeutic adjunct rather than requiring live bacterial therapy.
Sources
[1] Desharnais, L., Swaby, A., Messaoudene, M., et al. “Diet–microbiome synergy underlies obesity-associated immunotherapy efficacy.” Nature (2026). DOI: 10.1038/s41586-026-10750-x