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

Paclitaxel leads to peripheral neuropathy (paclitaxel-induced 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 microbiome and metabolome analysis of feces and serum from breast cancer patients with different PIPN grades due to paclitaxel treatment. Our analysis re-veals that levels of deoxycholic acid (DCA) are highly increased because of ingrowth of Clostridium species, which is associated with severe neuropathy. DCA, in turn, elevates serum level of C-C motif ligand 5 (CCL5) and induces CCL5 receptor 5 (CCR5) overexpression in dorsal root ganglion (DRG) through the bile acid re-ceptor Takeda G-protein-coupled receptor 5 (TGR5), contributing to neuronal hyperexcitability. Consistent with this, administration of CCR5 antagonist maraviroc suppresses the development of neuropathic nocicep-tion. These results implicate gut microbiota/bile acids/CCR5 signaling in the induction of PIPN, thus suggest-ing a target for PIPN treatment.

Automated summary

This study analyzed the microbiome and metabolome of feces and serum from breast cancer patients receiving paclitaxel treatment. The results showed that increased levels of deoxycholic acid (DCA) due to the growth of Clostridium species were associated with severe neuropathy. DCA further induced overexpression of CCR5 in dorsal root ganglion (DRG) through the TGR5 receptor, leading to neuronal hyperexcitability. Inhibition of CCR5 suppressed the development of neuropathic nociception.