A mediterranean-mimicking diet harnesses gut microbiota–derived 3-IAA to rejuvenate T cell
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eLife Assessment
This fundamental study advances our understanding of how dietary patterns shape cancer immunity by identifying a link between a Mediterranean-mimicking diet, gut bacteria, and a metabolite that enhances anti-tumor immune responses. The evidence supporting the main conclusions is solid, based on carefully controlled diet experiments, measurements of gut-derived molecules, and functional immune analyses across multiple models, together with supportive observations in human data. The work will be of broad interest to biologists working on microbiota and cancer. However, there are several issues that the authors should address to improve the manuscript.
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Abstract
Diet profoundly shapes the tumor microenvironment through metabolite modulation, yet the mechanisms linking diet, gut microbiota, and antitumor immunity remain unclear. Here, we demonstrate that a mediterranean-mimicking diet (MedDiet) suppresses tumor growth by orchestrating a microbiota–metabolite–immune axis. MedDiet selectively enriched Bacteroides thetaiotaomicron ( B. thetaiotaomicron ) in the gut, whose administration recapitulated tumor suppression. Both MedDiet and B. thetaiotaomicron elevated plasma levels of the tryptophan metabolite indole-3-acetic acid (3-IAA). Mechanistically, 3-IAA enhanced CD8 + T cell cytotoxicity and alleviated exhaustion by inhibiting the integrated stress response, sustaining antitumor immunity in vivo . Importantly, 3-IAA synergized with anti–PD-1 therapy to further restrain tumor progression. Finally, we developed a MedDiet Score to predict patient survival and response to immunotherapy. These findings reveal that dietary modulation of gut microbiota can reshape systemic metabolites to potentiate T cell–mediated antitumor responses. Our study identifies 3-IAA as a metabolite-based adjuvant for immune checkpoint therapy and highlights the translational potential of diet-driven immunomodulation in cancer treatment.
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eLife Assessment
This fundamental study advances our understanding of how dietary patterns shape cancer immunity by identifying a link between a Mediterranean-mimicking diet, gut bacteria, and a metabolite that enhances anti-tumor immune responses. The evidence supporting the main conclusions is solid, based on carefully controlled diet experiments, measurements of gut-derived molecules, and functional immune analyses across multiple models, together with supportive observations in human data. The work will be of broad interest to biologists working on microbiota and cancer. However, there are several issues that the authors should address to improve the manuscript.
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Reviewer #1 (Public review):
Summary:
In brief, this manuscript addresses a very interesting topic, namely, the impact of the Mediterranean diet on the development of cancer. Using one mouse model and three tumor cell lines, the data show that a Mediterranean diet is sufficient to promote an anti-tumor response mediated by the microbiota, metabolites, and the immune system. Mechanistically, the Mediterranean diet promotes the expansion of Bacteroides thetaiotaomicron (B. theta for short), which converts tryptophan into 3-IAA. Both B. theta and the metabolite are sufficient to phenocopy the effect of the Mediterranean diet on cancer growth in vivo. The manuscript also shows that this effect is mediated by CD8 T cells and suggests, by way of in vitro assays, that 3-IAA sustains the functionality of CD8 T cells, preserving their exhaustion …
Reviewer #1 (Public review):
Summary:
In brief, this manuscript addresses a very interesting topic, namely, the impact of the Mediterranean diet on the development of cancer. Using one mouse model and three tumor cell lines, the data show that a Mediterranean diet is sufficient to promote an anti-tumor response mediated by the microbiota, metabolites, and the immune system. Mechanistically, the Mediterranean diet promotes the expansion of Bacteroides thetaiotaomicron (B. theta for short), which converts tryptophan into 3-IAA. Both B. theta and the metabolite are sufficient to phenocopy the effect of the Mediterranean diet on cancer growth in vivo. The manuscript also shows that this effect is mediated by CD8 T cells and suggests, by way of in vitro assays, that 3-IAA sustains the functionality of CD8 T cells, preserving their exhaustion and blocking the ISR pathway.
Strengths:
The conclusions of this manuscript are potentially interesting and of potential clinical relevance.
Weaknesses:
For a full technical evaluation of the strength of the data, I am missing important technical and experimental details (e.g., number of independent experiments, statistics), and found some legends with potential labelling inaccuracies.
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Reviewer #2 (Public review):
Summary:
The authors aimed to investigate the mechanistic link between a Mediterranean-mimicking diet (MedDiet)-specifically the synergy between high fiber and fish oil-and its ability to suppress tumor growth. They successfully identify that this dietary combination alters the gut microbiome to favor the expansion of Bacteroides thetaiotaomicron. This bacterium metabolizes dietary tryptophan into indole-3-acetic acid (3-IAA), which then acts systemically to prevent CD8+ T-cell exhaustion.
Strengths:
The study integrates controlled dietary interventions, microbiome perturbation, metabolite profiling, and immune functional analyses into a coherent and well-organized framework, making the overall logic of the work easy to follow. The dietary design is carefully controlled, allowing clear interpretation of …
Reviewer #2 (Public review):
Summary:
The authors aimed to investigate the mechanistic link between a Mediterranean-mimicking diet (MedDiet)-specifically the synergy between high fiber and fish oil-and its ability to suppress tumor growth. They successfully identify that this dietary combination alters the gut microbiome to favor the expansion of Bacteroides thetaiotaomicron. This bacterium metabolizes dietary tryptophan into indole-3-acetic acid (3-IAA), which then acts systemically to prevent CD8+ T-cell exhaustion.
Strengths:
The study integrates controlled dietary interventions, microbiome perturbation, metabolite profiling, and immune functional analyses into a coherent and well-organized framework, making the overall logic of the work easy to follow. The dietary design is carefully controlled, allowing clear interpretation of which broad dietary features are associated with the observed antitumor effects. The immune dependence of the phenotype is addressed using appropriate experimental approaches, and the results broadly support a role for gut microbiota-derived metabolites in shaping immune cell function. In addition, analyses of human datasets provide important context and enhance the potential relevance and usefulness of the findings for a broader research community.
Weaknesses:
While the manuscript provides strong support for a role of the microbial metabolite indole-3-acetic acid and downstream stress signaling in shaping immune cell function, the upstream mechanism by which this metabolite exerts its effects remains unresolved. In particular, the specific molecular sensor or binding target through which the metabolite acts has not been identified, and this uncertainty limits mechanistic precision. Framing this point more explicitly as an open question would help align the interpretation with the current data.
In addition, at several points, the presentation may imply that a single microbial species is uniquely responsible for the observed effects. However, the experimental evidence more directly demonstrates sufficiency under the tested conditions rather than necessity. A clearer distinction between "sufficient" and "necessary" claims would help readers better assess the generality of the findings and their applicability to more complex microbial communities.
The interpretation of the human data also warrants some caution. The diet-associated score applied to human datasets is derived from gene-expression signatures identified in mouse models and therefore represents an indirect proxy rather than a direct measure of dietary intake. Although the score correlates with clinical outcomes, it does not establish that patient survival is driven by consumption of specific dietary components such as fiber and fish oil.
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