Abstract
Emerging evidence reveals a strong connection between the gut microbiota and cancer. However, the exact role of gut microbiota dysbiosis in multiple myeloma (MM) is poorly understood, and the therapeutic potential of microbiota-targeted interventions represents a promising strategy that demands urgent mechanistic and translational investigation. First, we conducted a comprehensive microbiome-metabolite analysis between MM patients and healthy individuals. The result revealed a marked compositional difference characterized by reduced abundances of butyrate-producing bacteria and diminished butyrate levels in the MM cohort. Subsequent fecal microbiota transplantation demonstrated that the gut microbiota critically modulates MM progression, with healthy donor-derived microbiota reducing the tumor burden and concomitantly elevating serum butyrate. Furthermore, through function-based culturomics screening, Clostridium butyricum (C. butyricum) was identified as a key butyrate-producing specialist. C. butyricum or its metabolite butyrate significantly reduced the systemic tumor burden in 5TGM1 mice. Notably, C. butyricum and butyrate alleviated bone marrow inflammation and osteolytic lesions by suppressing Th17 cells and IL-17 levels in the bone marrow. Moreover, cellular assays and transcriptome sequencing further revealed that butyrate could induce MM cells' apoptosis via HDAC inhibition-mediated upregulation of PPARγ, leading to sequential suppression of the PI3K/AKT pathway and antiapoptotic BCL-2 expression. This apoptotic signaling cascade was reversed by PPARγ antagonism. The direct antitumor effect was further confirmed in M-NSG mice. Our research systematically verifies the specific role of the gut microbiota in MM and provides the first evidence of the immune and molecular mechanisms by which C. butyricum alleviates MM progression, offering preclinical support for probiotic-based therapies against MM.