• Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
• Department of Statistics, University of California, Berkeley, Berkeley, CA, USA.
• Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
• Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
• Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
• Dana-Farber Brigham and Women's Cancer Center, Division of Gastrointestinal Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
• Division of Digestive and Liver Diseases, Columbia University Irving Medical Cancer and the Vagelos College of Physicians and Surgeons, New York, NY, USA.
• Division of Digestive and Liver Diseases, Columbia University Irving Medical Cancer and the Vagelos College of Physicians and Surgeons, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
• Dana-Farber Brigham and Women's Cancer Center, Division of Surgical Oncology, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA USA.
• Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Emerging evidence implicates microbiome involvement in the development of pancreatic cancer (PaCa). Here, we investigate whether increases in circulating microbial-related metabolites associate with PaCa risk by applying metabolomics profiling to 172 sera collected within 5 years prior to PaCa diagnosis and 863 matched non-subject sera from participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cohort. We develop a three-marker microbial-related metabolite panel to assess 5-year risk of PaCa. The addition of five non-microbial metabolites further improves 5-year risk prediction of PaCa. The combined metabolite panel complements CA19-9, and individuals with a combined metabolite panel + CA19-9 score in the top 2.5th percentile have absolute 5-year risk estimates of >13%. The risk prediction model based on circulating microbial and non-microbial metabolites provides a potential tool to identify individuals at high risk of PaCa that would benefit from surveillance and/or from potential cancer interception strategies.