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. 2024 May 14;121(20):e2306776121.
doi: 10.1073/pnas.2306776121. Epub 2024 May 6.

A high-fat diet promotes cancer progression by inducing gut microbiota-mediated leucine production and PMN-MDSC differentiation

Jiewen Chen #  1   2   3 , Xiyuan Liu #  4 , Yi Zou  4 , Junli Gong  4 , Zhenhuang Ge  4 , Xiaorong Lin  5 , Wei Zhang  6 , Hongyan Huang  7 , Jianli Zhao  1 , Phei Er Saw  1 , Yongjun Lu  4 , Hai Hu  1   6 , Erwei Song  1   2
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A high-fat diet promotes cancer progression by inducing gut microbiota-mediated leucine production and PMN-MDSC differentiation

Jiewen Chen et al. Proc Natl Acad Sci U S A. .

Abstract

A high-fat diet (HFD) is a high-risk factor for the malignant progression of cancers through the disruption of the intestinal microbiota. However, the role of the HFD-related gut microbiota in cancer development remains unclear. This study found that obesity and obesity-related gut microbiota were associated with poor prognosis and advanced clinicopathological status in female patients with breast cancer. To investigate the impact of HFD-associated gut microbiota on cancer progression, we established various models, including HFD feeding, fecal microbiota transplantation, antibiotic feeding, and bacterial gavage, in tumor-bearing mice. HFD-related microbiota promotes cancer progression by generating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, the HFD microbiota released abundant leucine, which activated the mTORC1 signaling pathway in myeloid progenitors for PMN-MDSC differentiation. Clinically, the elevated leucine level in the peripheral blood induced by the HFD microbiota was correlated with abundant tumoral PMN-MDSC infiltration and poor clinical outcomes in female patients with breast cancer. These findings revealed that the "gut-bone marrow-tumor" axis is involved in HFD-mediated cancer progression and opens a broad avenue for anticancer therapeutic strategies by targeting the aberrant metabolism of the gut microbiota.

Keywords: breast cancer; gut microbiota; high-fat diet; myeloid-derived suppressor cells.

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Conflict of interest statement

Competing interests statement:The authors declare no competing interest.

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