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

Menée à l'aide de modèles murins ainsi que d'échantillons tissulaires humains (sérum, moelle osseuse, intestin, tumeurs mammaires), cette étude met en évidence un mécanisme par lequel un régime alimentaire riche en graisses favorise la progression tumorale en induisant la production de leucine par le microbiote intestinal et la différenciation des cellules myéloïdes suppressives polymorphonucléaires

Résumé en anglais

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.