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

Abstract

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.

Gut Microbiota Modulation and Its Implications on Neuropathic Pain: A Comprehensive Literature Review

“…FMT also alleviated Paclitaxel-Induced Peripheral neuropathy in rats by interfering with the TLR4 pathway [80].…”

The Potential Antinociceptive Effect and Mechanism of Cannabis sativa L. Extract on Paclitaxel-Induced Neuropathic Pain in Rats Uncovered by Multi-Omics Analysis

“…Gut microbiota serves as the intersection of immune, neural, endocrine, and metabolic signaling pathways and has become an intense focus of research [37]. Several studies have demonstrated that gut microbiota can modulate chemotherapy-induced neuropathic pain [38,39], even that the gut bacteria, rather than host genetics or physiology, are the primary determinants of PTX-induced pain based on a comparative study of paclitaxel responses in B6 and 129 germ-free reciprocally transplanted mice [40]. The study by Loman et al revealed the relationship among behavior, central and peripheral immune activation, and microbiota in PTX-treated mice [41].…”