Abstract

Cancer cachexia (CC) is a complex pathological condition associated with cancer progression and poor prognosis, particularly in gastrointestinal cancers, and is closely linked to the gut microbiota. Lipolysis in CC may play a key role in driving cachexia progression. However, the role of the gut microbiota in CC-induced lipolysis and the underlying mechanisms remains unclear. In this study, we found that significant gut microbiota dysbiosis in pancreatic cancer cachexia, characterized by diminished abundance of Eubacterium rectale ( E.rectale ), was negatively associated with lipolysis severity. Furthermore, we demonstrated for the first time that E. rectale derived extracellular vesicles (EVs) can ameliorate lipolysis across multiple CC models. Mechanistically, these effects are mediated by modulating pro-inflammatory macrophages through inhibition of NF-kB signalling, reducing macrophage polarization and inflammatory cytokine secretion. Our findings indicated E. rectale EVs could offer potential therapeutic benefits for CC and emphasize the importance of host-microbiota interactions. Trial Registration : This study was registered at ClinicalTrials.gov (NCT06378853).