Obesity causes chronic
inflammation and changes in gut microbiome. However, how this contributes to poor survival and
therapy resistance in patients with
pancreatic cancer remain undetermined. Our current study shows that high fat diet-fed obese pancreatic
tumor bearing mice do not respond to standard of care
therapy with
gemcitabine and
paclitaxel when compared to corresponding control diet-fed mice. C57BL6 mice were put on control and high fat diet for 1 month following with pancreatic
tumors were implanted in both groups. Microbiome of lean (control) and obese (high fat diet fed) mice was analyzed. Fecal matter transplant from control mice to obese mice sensitized
tumors to
chemotherapy and demonstrated extensive cell death. Analysis of gut microbiome showed an enrichment of
queuosine (Q) producing bacteria in obese mice and an enrichment of S-adenosyl
methionine (SAM) producing bacteria in control diet-fed mice. Further, supplementation of obese animals with SAM sensitized pancreatic
tumors to
chemotherapy. Treatment of
pancreatic cancer cells with Q increased PRDX1 involved in oxidative stress protection. In parallel,
tumors in obese mice showed increase in CD133+ treatment refractory
tumor populations compared to control animals. These observations indicated that microbial metabolite Q accumulation 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 SAM and
queuosine in fecal samples of
pancreatic cancer patients can be developed as a potential
biomarker and therapeutic target in
chemotherapy refractory
pancreatic cancer.