1263 High-fiber diet induces favorable gut microbiota, reduces immunosuppression and inhibits lung cancer development

<h3>Background</h3> Emerging evidence suggests that resident microbial communities act as a central regulator of host homeostasis. The dynamic structure, composition, and function of gut microbiota can be influenced by numerous factors, among which nutritional profile as it as most crucial determinant. Microbial consortia inhabiting the gut have been implicated in the etiology and pathogenesis of various cancers and are known to influence cancer immunosurveillance and response to immunotherapy. Despite these known associations, the underlying mechanisms by which dietary interventions such as those rich in fiber regulate gut-immune axis in prevention of lung cancer are poorly defined. <h3>Methods</h3> We employed a human-relevant mouse model in which knockout of G-protein coupled receptor 5A (<i>Gprc5a^-/-</i>) and exposure to tobacco lead to development of preneoplasia and lung adenocarcinoma (LUAD). We investigated the effects of no fiber and pectin-inulin diets on LUAD pathogenesis in both syngeneic (early life or later dietary intervention) and tobacco carcinogenesis models. We conducted16S rRNA-Seq of fecal samples collected prior to switching diets and at several timepoints during LUAD development. The levels of gut-derived metabolites were assessed with mass spectrometry. We investigated changes in the tumor immune microenvironment using flow cytometry analysis. <h3>Results</h3> Tumor volumes were most significantly reduced in mice fed pectin-inulin diet, following tobacco carcinogen exposure as well as during early life and later dietary intervention. These effects were recapitulated in an independent syngeneic model (344SQ cells in WT mice). 16S rRNA-Seq analysis revealed significant differences in beta diversity evident from clear separation of community structure between fiber-deprived versus high-fiber diet groups. Evidently, gut microbiota of pectin-inulin fed mice displayed significantly elevated relative abundance of <i>Akkermansia muciniphila</i> and<i> Bifidobacterium pseudolongum,</i> taxa that have been reported to be strongly associated with favorable responses to immunotherapy. These changes were accompanied by notable upregulation of gut metabolites, particularly butyrate and TCA-cycle intermediates (malate and oxoglutarate). Pectin-inulin fed mice displayed enhanced antitumor immune responses evident by remarkably increased fractions of B lineage cells, cDC1s and M1-likemacrophages and, conversely, reduced levels of activated cDC2s, M2 macrophages and polymorphonuclear myeloid-derived suppressor cells. Mice that received fecal microbiota transplant (FMT) from syngeneic pectin-inulin-fed donors had decreased tumor development compared to littermates receiving FMT from no-fiber-fed donors. <h3>Conclusions</h3> Our findings inform on novel mechanisms by which dietary fiber robustly impacts gut consortia and immune milieu in inhibition of LUAD. Our findings also suggest that incorporation of dietary fiber in cancer treatment (e.g., immunotherapy) could improve outcomes of patients with LUAD. <h3>Ethics Approval</h3> All animal experiments were conducted in accordance with Institutional Animal Care and Use Committee-approved protocols.