1. Academic Validation
  2. Clostridium butyricum and its metabolite butyrate promote ferroptosis susceptibility in pancreatic ductal adenocarcinoma

Clostridium butyricum and its metabolite butyrate promote ferroptosis susceptibility in pancreatic ductal adenocarcinoma

  • Cell Oncol (Dordr). 2023 Jun 1. doi: 10.1007/s13402-023-00831-8.
Xiaotong Yang # 1 Zhengyan Zhang # 1 Xuqing Shen 1 Junyi Xu 1 Yawen Weng 1 Wei Wang 2 Jing Xue 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Systems Medicine for Cancer , Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai, 200127, China.
  • 2 Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No 100, Haining Road, Shanghai, 200080, China. wangwei_0306@163.com.
  • 3 State Key Laboratory of Systems Medicine for Cancer , Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai, 200127, China. jingxue@sjtu.edu.cn.
  • # Contributed equally.
Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited therapeutic options. The diversity and composition of the intratumoral microbiota are associated with PDAC outcomes, and modulating the tumor microbiota has the potential to influence tumor growth and the host immune response. Here, we explore whether intervention with butyrate-producing probiotics can limit PDAC progression.

Methods: Based on the TCGA (PAAD) database, we analyzed the differential communities of intratumoral microbiota in PDAC patients with long survival and short survival and explored the relevant mechanisms of Clostridium butyricum and its metabolite butyrate in the treatment of PDAC. Treatment with Clostridium butyricum or butyrate in combination with the Ferroptosis inducer RSL3 in a PDAC mouse model has an inhibitory effect on PDAC progression. The potential molecular mechanisms were verified by flow cytometry, RNA-seq, Western blotting, qRT‒PCR and immunofluorescence.

Results: We found that the tumoral butyrate-producing microbiota was linked to a better prognosis and less aggressive features of PDAC. Intervention with Clostridium butyricum or its metabolite butyrate triggered superoxidative stress and intracellular lipid accumulation, which enhanced Ferroptosis susceptibility in PDAC.

Conclusion: Our study reveals a novel antitumor mechanism of butyrate and suggests the therapeutic potential of butyrate-producing probiotics in PDAC.

Keywords

Butyrate; Clostridium butyricum; Ferroptosis; Intratumoral microbiota; PDAC.

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