Abstract

Background Oxaliplatin-induced peripheral neuropathy (OIPN) is a common dose-limiting toxicity that significantly affects patients’ quality of life. Although neuroinflammation has been implicated, the precise contribution of the gut–nerve axis remains incompletely understood. This study aimed to investigate the role of gut microbiota and associated inflammatory signaling in OIPN. Methods An OIPN model was established in Sprague Dawley rats. Gut microbiota depletion was achieved via antibiotic (ABX) treatment, and fecal microbiota transplantation (FMT) from healthy donors was performed to restore microbial communities. Mechanical allodynia and cold hypersensitivity were assessed using the von Frey filament test and the acetone test, respectively. Systemic inflammation was evaluated by measuring serum cytokine levels via enzyme-linked immunosorbent assay (ELISA). The composition of the gut microbiota was analyzed by 16S rRNA gene sequencing. Intestinal barrier integrity and local inflammation were assessed through histopathology, immunofluorescence, and quantification of tight junction proteins (ZO-1, occludin) and inflammatory markers (NF-κB, TNF-α) via quantitative polymerase chain reaction (qPCR) and Western blotting. Network pharmacology was employed to screen for potential common targets of oxaliplatin and neurotoxicity. Molecular alterations in the dorsal root ganglia (DRG) were examined using histology, qPCR, Western blotting, and immunofluorescence, with a focus on the TLR4/MyD88/NF-κB signaling pathway and pro-inflammatory cytokines. Results Antibiotic-mediated depletion of gut microbiota significantly attenuated OXA-induced neuropathic pain and systemic inflammation, as evidenced by reduced levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1beta (IL-1β), whereas FMT reversed these protective effects. Analysis of 16S rRNA gene sequencing revealed that OXA altered gut microbiota composition, including reduced alpha diversity