Combined intervention of Akkermansia muciniphila and sodium butyrate ameliorates oxaliplatin-induced peripheral neuropathy by suppressing neuroinflammation and reducing serum neurofilament light chain

Abstract

Introduction: Oxaliplatin-induced peripheral neuropathy (OIPN) is a major dose-limiting neurotoxic side effect that severely disrupts quality of life and compromises antitumor efficacy. Despite its clinical prevalence, effective neuroprotective strategies remain elusive, and diagnosis largely relies on subjective symptom reporting rather than objective pathological assessment. Emerging evidence suggests that targeting the gut-peripheral nerve axis offers a novel therapeutic avenue/approach. Therefore, this study primarily aimed to investigate the combined neuroprotective efficacy of Akkermansia muciniphila (A. muciniphila) and sodium butyrate in a rat model of OIPN. Furthermore, we evaluated the potential clinical utility of serum neurofilament light chain (NfL) for the early diagnosis, severity assessment, and therapeutic monitoring of OIPN. Methods: An OIPN rat model was established via tail vein injection of oxaliplatin. Sprague-Dawley rats were randomized by body weight into five groups: control, model, A. muciniphila treatment, sodium butyrate (NaB) treatment, and combined A. muciniphila + NaB treatment. Outcome measures encompassed longitudinal body weight monitoring, behavioral assessments (mechanical allodynia and cold allodynia), histopathological examination of the lumbar dorsal root ganglia (DRG) and intraepidermal nerve fiber density (IENFD) in hind paws, as well as quantification of serum inflammatory cytokines and NfL levels. Results: Oxaliplatin administration induced a progressive neuropathy characterized by significant weight loss, mechanical allodynia, and cold allodynia. Histopathologically, neuronal atrophy, axonal degeneration, demyelination, and inflammatory infiltration were observed in the DRG and peripheral nerves, accompanied by a marked reduction in IENFD. Serological analysis indicated a systemic pro-inflammatory shift alongside a substantial elevation in NfL, a specific biomarker of axonal injury. Notably, combination therapy (A. muciniphila + NaB) exerted the most pronounced neuroprotective effects, particularly regarding late-phase pain control, nerve fiber preservation, and the normalization of NfL levels. Conclusions: Our findings confirm that oxaliplatin triggers complex pathological alterations, including pain hypersensitivity, neuroinflammation, and axonal injury. The combinatorial treatment with A. muciniphila and sodium butyrate exerted potent neuroprotective effects, significantly relieving mechanical and cold allodynia while suppressing systemic inflammation. Collectively, our data not only validate the efficacy of this gut-microbiota-targeted strategy but also establish serum NfL as a sensitive, objective metric for monitoring OIPN severity and therapeutic response.