Blockade of CCR5 suppresses paclitaxel-induced peripheral neuropathic pain caused by increased deoxycholic acid

Paclitaxel leads to peripheral neuropathy (PIPN) in approximately 50% of cancer patients. At present, there are no effective treatment strategies for PIPN, the mechanisms of which also remain unclear. In this study, we performed microbiomic and metabolomic analysis of feces and serum from breast cancer patients with different PIPN grades due to paclitaxel treatment. Our analysis reveals that levels of deoxycholic acid (DCA) are highly increased due to ingrowth of Clostridium species, which is associated with severe neuropathy. DCA, in turn, elevates serum level of C-C motif ligand 5 (CCL5) and induced its receptor 5 (CCR5) overexpression in dorsal root ganglia (DRG) through the bile acid receptor Takeda G protein-coupled receptor 5 (TGR5), contributing to neuronal hyperexcitability. Consistent with this, administration of CCR5 antagonist maraviroc suppresses the development of neuropathic nociception. These results implicate gut microbiota/bile acids/CCR5 signaling in the induction of PIPN thus suggesting a target for PIPN treatment.