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Introduction and Objective: Recently, gut microbiota emerged as an important factor for success of immunity-based cancer treatments. However, its steady-state interaction and contribution to developing tumors is largely unexplored in non-intestinal cancers. Our objective was to investigate the connection between prostate tumor and the gut microbiota independently of cancer therapies. Methods: Human fecal samples were obtained from men participating into a phase IIb double-blind randomized controlled trial testing 3g/day of monoglyceride-eicosapentaenoic acid (MAG-EPA) versus placebo for a 4-10 week period before their radical prostatectomy (NCT02333435). A second set of samples were from men taking the same intervention of MAG-EPA or placebo after a PSA increase following their radical prostatectomy (NCT03753334). Short chain fatty acids (SCFA) analysis of patient stool samples between baseline and surgery was performed by gas chromatography coupled with flame ionization detection. 16srRNA libraries were amplified by targeting a fragment of the V3-V4 hypervariable region of the bacterial 16S rRNA gene. High-throughput sequencing of the bar-coded amplicons was performed on a MiSeq apparatus and the bioinformatics analysis was conducted using Mothur pipeline. In addition to human fecal samples, fully immunocompetent C57BL/6 mice were injected subcutaneously with TRAMP-C2 or PTEN−/− or PTEN−/− RB1−/− mouse prostate cancer cells to measure changes in the gut microbiota during tumor growth. We also recapitulated the MAG-EPA intervention in our TRAMP-C2 mice model and fed by gavage four different fatty acids (omega-9 (high oleic sunflower oil), omega-6 (MAG-arachidonic acid) and two omega-3 (MAG-docosahexaenoic and MAG-EPA). Results: In human fecal samples from prostate cancer patients, we observed a reduced gut microbiota diversity correlating with tumor stage. We also found that tumor growth was sufficient to modulate the microbiota in three independent prostate cancer syngeneic mouse models. We showed that transplanted human gut flora was sufficient to modulate ectopic prostate tumor growth, supporting the causal impact of gut microbiota for prostate cancer. The analysis of SCFA in patient stool samples between baseline and surgery showed that MAG-EPA prebiotic intervention was associated with a decrease of fecal butyric acid levels in prostate cancer patients with downgrade at surgery. We finally investigated this gut-tumor connection using purified polyunsaturated fatty acids prebiotics in patients and mice. We observed a reduction in the levels of Ruminococcaceae following dietary omega-3 supplementation that correlated with prostate cancer downgrade in patients and reduced tumor growth in mice. Conclusion: Overall our findings suggest that diet-actionable components of the gut microbiome can regulate prostate cancer growth. Citation Format: Jalal Laaraj, Gabriel Lachance, Nikunj Gevariya, Thibaut Varin, Andrei Feldiorean, Fanny Gaignier, Isabelle Boudreau Julien, Hui Wen Xu, Tarek Hallal, Jean-François Pelletier, Sidki Bouslama, Nadia Boufaied, Nicolas Derome, Yves Fradet, Leigh Ellis, Ciriaco A. Piccirillo, Frédéric Raymond, David P. Labbé, Alain Bergeron, André Marette, Karine Robitaille, Vincent Fradet. The gut microbiome-prostate tumor crosstalk is modulated by dietary polyunsaturated fatty acids [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P001.