Obesity causes a number of systemic alterations including chronic inflammation and changes in gut microbiome. However, whether these actively contribute to poor survival and therapy resistance in patients with pancreatic cancer remain undetermined. Our current study shows that high fat diet fed pancreatic tumor bearing mice do not respond to standard of care therapy with gemcitabine and paclitaxel when compared to corresponding control diet fed mice. Upon fecal matter transplant from control mice to high fat diet fed mice, the tumors became sensitive to standard of care therapy and showed extensive cell death. Analysis of gut microbiome showed an enrichment of queuosine (Q) producing bacteria in high fat diet fed mice and an enrichment of S-adenosyl methionine (SAM) producing bacteria in control diet fed mice. Further, treatment of high fat diet fed animals with SAM recapitulated the observation with lean to obese fecal matter transplant. Additionally, treatment of pancreatic and colon cancer cell lines in vitro with Q promoted resistance to the paclitaxel and oxaliplatin respectively, while treatment with SAM promoted sensitivity to these drugs. Treatment of pancreatic cancer cells with Q showed upregulation PRDX1, that is involved in oxidative stress protection. Analysis of tumor tissues in high fat diet fed mice showed high PRDX1, low apoptosis and increased proliferation, which were reversed upon treatment with SAM as well as by lean to obese fecal matter transplant. In parallel, high fat diet fed mice showed increase in CD133+ treatment refractory population compared to the control animals. Interestingly, treatment with Q in vitro did not enrich for CD133+ population, indicating that Q mediated protection from cell death was independent of enrichment of treatment refractory cells. These observations indicated that microbial metabolite Q accumulated in high fat diet fed mice protected tumors from chemotherapy induced oxidative stress by upregulating PRDX1. This protection could be reversed by treatment with SAM. We conclude that relative concentration of S-adenosyl methionine and queuosine in fecal samples of pancreatic cancer patients can be indicative of therapy response in this disease.

中文翻译：

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饮食诱导的高脂血症通过选择“肿瘤保护性”微生物代谢产物和治疗难治性细胞，赋予了胰腺癌对标准疗法的抵抗力。

肥胖会引起许多系统性改变，包括慢性炎症和肠道微生物组的改变。但是，这些因素是否能积极促成胰腺癌患者的不良生存和治疗抗性尚不确定。我们当前的研究表明，与相应的对照饮食喂养小鼠相比，高脂饮食喂养的胰腺肿瘤小鼠对吉西他滨和紫杉醇的护理治疗标准无反应。在将粪便从对照小鼠移植到高脂饮食喂养的小鼠中后，肿瘤对护理标准疗法变得敏感，并显示出广泛的细胞死亡。肠道微生物组的分析显示，高脂饮食喂养的小鼠中富含产生奎因（Q）的细菌，而对照饮食喂养的小鼠中富含S-腺苷甲硫氨酸（SAM）的细菌。进一步，用SAM处理高脂饮食喂养的动物，可以将瘦肉到肥胖的粪便移植到实验中。此外，在体外用Q处理胰腺和结肠癌细胞系分别增强了对紫杉醇和奥沙利铂的耐药性，而用SAM处理则增强了对这些药物的敏感性。Q对胰腺癌细胞的治疗显示PRDX1上调，这参与了氧化应激的保护。高脂饮食喂养小鼠的肿瘤组织分析显示PRDX1高，细胞凋亡低，增殖增加，在用SAM以及瘦到肥胖的粪便移植后，这些现象被逆转。同时，与对照动物相比，高脂饮食喂养的小鼠显示出CD133 +治疗难治性人群的增加。有趣的是 体外Q处理不能丰富CD133 +群体，表明Q介导的细胞死亡保护与治疗难治性细胞的富集无关。这些观察结果表明，高脂饮食喂养的小鼠中积累的微生物代谢产物Q通过上调PRDX1来保护肿瘤免受化疗诱导的氧化应激。通过使用SAM处理可以逆转这种保护。我们得出结论，胰腺癌患者粪便样本中S-腺苷甲硫氨酸和奎松碱的相对浓度可以指示该疾病的治疗反应。这些观察结果表明，高脂饮食喂养的小鼠中积累的微生物代谢产物Q通过上调PRDX1来保护肿瘤免受化疗诱导的氧化应激。通过使用SAM处理可以逆转这种保护。我们得出结论，胰腺癌患者粪便样品中S-腺苷甲硫氨酸和奎宁的相对浓度可以指示该疾病的治疗反应。这些观察结果表明，高脂饮食喂养的小鼠中积累的微生物代谢产物Q通过上调PRDX1来保护肿瘤免受化疗诱导的氧化应激。通过使用SAM处理可以逆转这种保护。我们得出结论，胰腺癌患者粪便样品中S-腺苷甲硫氨酸和奎宁的相对浓度可以指示该疾病的治疗反应。