Obesity – an established, modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC) – has increased in prevalence worldwide yet the precise mechanisms underlying its propensity to promote cancer have remained an enigma. Alterations to the gut microbiota, the microorganisms that colonize the intestinal tract of humans and mice, may provide a link between obesity and PDAC, offering a previously untapped target to develop novel anti-cancer strategies in this highly lethal disease. To ascertain the importance of the obesity-associated microbiome in PDAC progression, we leveraged our previously established autochthonous model of obesity-associated PDAC (Pdx1-Cre; KrasLSL-G12D/+; LepOb/Ob) (KCO) which allows for rapid and reversible weight gain in a Kras-driven mouse tumor model that closely mimics the genetic and histologic features of human PDAC progression. Ablation of the gut microbiome via broad-spectrum antibiotics intercepted tumor development in KCO mice highlighting the importance of the gut microbiome in obesity-driven PDAC. By correlating microbial composition to tumor burden in antibiotic-treated and control mice via 16S rRNA sequencing, we are identifying microbial communities that may be causal for tumor development. In parallel studies, we performed 16S rRNA sequencing on feces serially collected from wild-type, LepOb/Ob ad libitum-fed mice (AL), and LepOb/Ob mice on calorie restriction (CR), which induces rapid weight loss. We found that obesity causes reversible changes to gut microbial composition including an increase in Proteobacteria, a phylum that holds the most known species to secrete histamine, a bioamine implicated in pancreatitis, a PDAC risk factor, and PDAC development itself. Concordant with these findings, Parallel Receptorome Expression and Screening via Transcriptional Output-SALSA (PRESTO-SALSA), a novel high-throughput system that allows for sensitive detection of microbial metabolites that exhibit mammalian GPCR agonism, feces from LepOb/Ob AL mice showed robust activation of histamine receptors (HRHs), while feces from obese mice subject to CR exhibited reduced Proteobacteria species and decreased capacity to activate mammalian HRHs, suggesting weight loss by CR mitigates microbe-derived histamine. Ongoing studies are testing whether microbe-derived histamine is necessary and sufficient for the tumor-promoting effects of obesity. Collectively, our results establish a dependency for the gut microbiome in obesity-driven PDAC, identify reversible obesity-induced microbial communities in the gut, and nominate microbial metabolites capable of activating pro-tumorigenic GPCR pathways as potential causative mechanisms.

Citation Format: Christian F. Ruiz, Rylee McDonnell, Lauren Lawres, Yiyun Cao, Deguange Song, Nicole Sonnert, Noah Palm, Mandar D. Muzumdar. Obesity transforms the gut microbiome to invoke a cancer permissive state [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C048.