Fecal Microbiota Transplantation Alleviated Paclitaxel-Induced Peripheral Neuropathy by Interfering with Astrocytes and TLR4/p38MAPK Pathway in Rats

Abstract

Purpose

Paclitaxel-induced peripheral neuropathy (PIPN) constitutes a refractory and progressive adverse consequence of paclitaxel treatment, causing pain and sensory anomalies in cancer survivors. Although the gut-brain axis is involved in multiple disorders including cancer, its impact on peripheral pain conditions remains elusive. Thus, we assessed the importance of gut microbiota and related mechanisms in PIPN.

Methods

By implementing fecal microbiota transplantation (FMT) in a rat PIPN model (ie, rats treated with paclitaxel; hereafter as PIPN rats), we explored the effect of gut microbiota on PIPN rats using multiple methods, including different behavioral tests, 16S ribosomal DNA (rDNA) sequencing, and biochemical techniques.

Results

Sequencing of 16S rDNA revealed that the abundance of genera Bacteroides and UCG-005 increased, while that of genera Turicibacter, Clostridium sensu stricto 1 and Corynebacterium decreased in the PIPN rats. However, when treated with FMT using fecal from normal rats, the mechanical allodynia and thermal hyperalgesia in PIPN rats were significantly alleviated. In addition, FMT treatment reduced the expression of toll-like receptor 4 (TLR4), phospho-p38 mitogen-activated protein kinase (p-p38MAPK), and the astrocytic marker glial fibrillary acidic protein in the colon and spinal dorsal horn. TAK242 (a TLR4 inhibitor) significantly alleviated the behavioral hypersensitivity of PIPN rats and inhibited the TLR4/p38MAPK pathway in astrocytes in these rats.

Conclusion

The gut microbiota played a critical role in PIPN. Future therapies treating PIPN should consider microbe-based treatment as an option.

Keywords:

• astrocyte
• gut microbiota
• paclitaxel
• p38
• peripheral neuropathy
• TLR4

Acknowledgments

This study is funded by the Zhejiang Provincial Medical and Health Science and Technology Project of China (Grant Numbers 2020KY231 and 2022KY943). The authors acknowledge TopEdit LLC for the linguistic editing and proofreading during the preparation of this manuscript.

Disclosure

All authors declare that they have no conflicts of interest in this work.