Abstract 2225: Diet with high soluble fiber induces favorable gut microbiota and metabolomic profiles, increases anti-tumor immunity, and suppresses lung cancer progression

Accumulating evidence suggests that taxonomic composition and phenotypic traits of the gut microbiome, which acts as a central regulator of cancer progression and response to immunotherapy, are influenced by diet. Prior studies have demonstrated that dietary constituents, notably soluble fibers, stimulate probiotic proliferation in the gut, maintain integrity of the intestinal barrier, and modulate immune responses. Yet, mechanisms by which a high soluble fiber diet (HSFD) impacts the gut-immune axis and pathogenesis of cancers external to the gut are poorly defined. Here, we employed a human-relevant mouse model in which knockout of G-protein coupled receptor 5A (Gprc5a-/-) and exposure to tobacco lead to development of preneoplasia and lung adenocarcinoma. Mice were randomized in dietary treatments: no fiber, high insoluble fiber, or HSFD, administered either post-weaning (early life) or after transplant of lung cancer cells (prophylactic intervention). Tumor growth was most significantly reduced in HSFD-fed mice, with notable anti-tumor effects observed in both early life and prophylactic intervention settings. These effects were recapitulated in an independent syngeneic model and tobacco carcinogen-exposed Gprc5a-/- mice. 16S rRNA-Seq analysis revealed HSFD-induced enrichment of beneficial taxa including Bacteroides, Faecalibaculum, Akkermansia, and Bifidobacterium, alongside evident decrease in tumor-promoting genera such as Odoribacter and Alistipes, with some of these microbial changes correlated with dietary fiber intake in cancer-free individuals. These microbial shifts corresponded with elevated levels of key gut metabolites, notably butyrate. Flow cytometry of colonic lamina propria revealed changes in immune profiles, characterized by reduced pro-IL-1β+ macrophages and dendritic cells, with parallel systemic effects evidenced by decreased inflammatory cytokines in sera. HSFD also skewed the tumor microenvironment toward an antitumorigenic milieu, marked by expanded B lineage cells, cDC1s and M1-like macrophages and, conversely, decreased levels of activated cDC2s and M2 macrophages. Fecal microbiota transplant models showed that effects of HSFD were largely mediated by the gut microbiome as mice that received fecal microbiota from syngeneic HSFD-fed donors showed significant tumor inhibition compared to littermates receiving microbiota from no-fiber-fed donors. Moreover, butyrate supplementation in a fiber-free diet mimicked the anti-tumor effects of HSFD, as reflected in gut immune populations, tumor metabolomics and systemic cytokines. Our findings inform on novel mechanisms by which HSFD robustly impacts gut consortia and immune milieu in the inhibition of lung cancer, suggesting that incorporation of HSFD in cancer treatments could improve outcomes for patients with lung cancer. Citation Format: Manvi Sharma, Yuejiang Liu, Altai Enkhbayar, Sujuan Yang, Inti C. Reischle, Mohamed A. Jamal, Tieling Zhou, Zahraa Rahal, Lorena I. B., Hannah Moreno, Matthew C. Ross, Lin Tan, Chidera O. Chukwuocha, Eleeka Nia, Anusha S. Thomas, Jennifer A. Wargo, Nadim J. Ajami, Philip L. Lorenzi, Robert R. Jenq, Seyed Javad Moghaddam, Kristi L. Hoffman, Humam Kadara. Diet with high soluble fiber induces favorable gut microbiota and metabolomic profiles, increases anti-tumor immunity, and suppresses lung cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2225.