Gut Microbiota Dysbiosis Accelerates Prostate Cancer Progression Through Increased LPCAT1 Expression and Enhanced DNA Repair Pathways

Abstract

Background: Gut microbiota dysbiosis is closely related to cancer development and progression. Our previous study showed that Ruminococcus was more abundant in CRPC relative to HSPC individuals. Here, we sought to determine the potential mechanism of microbiota dysbiosis in prostate cancer (PCa) progression. Methods: Metagenomics was used to determine the gut microbial discrepancies between CRPC and HSPC individuals. Fecal microbiota transplantation (FMT) was performed by transferring the fecal suspension of CRPC or HSPC individuals to TRAMP mice. Afterwards, the mice’s prostate histopathology and gut microbiota composition were determined. Since Ruminococcus was showed to correlate with glycerophospholipid metabolism, we used lipidomics to examine the mice’s fecal lipid profiles. The expression of LPCAT1 the key enzyme for phospholipid remodeling in mice prostate was also examined. Meanwhile, both differentiated microbial functions and LPCAT1 GESA analysis indicated DNA repair pathways, we further determined the expressions of RAD51 and DNA-PKcs in mice prostate. Results: Gut Ruminococcus was significantly more abundant in CRPC individuals. FMT using CRPC feces accelerated mice’s PCa progression and increased their intestinal Ruminococcus level. The majority of fecal lipids including lysophosphatidylcholine and phosphatidylcholine were upregulated in CRPC FMT treated mice, accompanied with enhanced expressions of LPCAT1, RAD51, and DNA-PKcs in mice prostate. Conclusions: We reported an abundant colonization of Ruminococcus in the intestines of CRPC individuals and the mice receiving their fecal suspensions. This study revealed the promotive capability of Ruminococcus in PCa progression via upregulating LPCAT1 and DNA repair protein expressions. The bacterium and its downstream pathways may become the targets of therapies for PCa in the future. Funding Statement: This study was supported by National Natural Science Foundation of China, Grant number: 81872102. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: Both human samples study and animal study were approved by IRB of Fudan University (Grant No. 322 2020-531/Grant No. 2020-JS252).