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Hepatobiliary and pancreatic cancers have been associated with poor prognosis owing to their high level of tumor invasiveness, distant metastasis, and resistance to conventional treatment options, such as chemotherapy. Accumulating evidence from animal models suggests that specific microbes and microbial dysbiosis can potentiate hepatobiliary-pancreatic tumor development by damaging DNA, activating oncogenic signaling pathways, and producing tumor-promoting metabolites. Emerging evidence suggests that the gut microbiota may influence not only the efficacy of cancer chemotherapies and novel targeted immunotherapies such as anti-CTLA4 and anti-CD274 therapies but also the occurrence of postoperative complications after hepatobiliary and pancreatic surgery, which have been associated with tumor recurrence and worse patient survival in hepatobiliary-pancreatic cancers. 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