Blockade of CCR5 suppresses paclitaxel-induced peripheral neuropathic pain caused by increased deoxycholic acid
Shanshan Zhong,
Fangxi Liu,
Rashid Giniatullin,
Jukka Jolkkonen,
Yong Li,
Zhike Zhou,
Xinyu Lin,
Chang Liu,
Xiuchun Zhang,
Zhouyang Liu,
Cheng Lv,
Qianqian Guo,
Chuansheng Zhao
Affiliations
Shanshan Zhong
Department of Neurology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China; Liaoning Provincial Key Laboratory of Big Data for Neurological Diseases, Shenyang, Liaoning 110001, China
Fangxi Liu
Department of Neurology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
Rashid Giniatullin
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland
Jukka Jolkkonen
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland
Yong Li
Department of Biochemistry and Molecular Cell Biology, Institution of Medicine Science, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Zhike Zhou
Department of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
Xinyu Lin
Department of Neurology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
Chang Liu
Department of Neurology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China; Liaoning Provincial Key Laboratory of Big Data for Neurological Diseases, Shenyang, Liaoning 110001, China
Xiuchun Zhang
Department of Neurology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China; Liaoning Provincial Key Laboratory of Big Data for Neurological Diseases, Shenyang, Liaoning 110001, China
Zhouyang Liu
Department of Neurology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
Cheng Lv
Department of Neurology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
Qianqian Guo
Department of Neurology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
Chuansheng Zhao
Department of Neurology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China; Liaoning Provincial Key Laboratory of Big Data for Neurological Diseases, Shenyang, Liaoning 110001, China; Corresponding author
Summary: 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 reveals 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 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.
