{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T15:00:04Z","timestamp":1783090804971,"version":"3.54.6"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>Akkermansia muciniphila<\/jats:italic>\n                      (\n                      <jats:italic>A. muciniphila<\/jats:italic>\n                      ) 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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,\n                      <jats:italic>A. muciniphila<\/jats:italic>\n                      treatment, sodium butyrate (NaB) treatment, and combined\n                      <jats:italic>A. muciniphila<\/jats:italic>\n                      + 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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 (elevated IL-6, IL-1\u03b2, and TNF-\u03b1; decreased IL-10) alongside a substantial elevation in NfL, a specific biomarker of axonal injury. All therapeutic interventions attenuated neuropathic pain, ameliorated structural nerve damage, modulated inflammatory cytokine profiles, and reduced serum NfL levels. Notably, combination therapy (\n                      <jats:italic>A. muciniphila<\/jats:italic>\n                      + NaB) exerted the most pronounced neuroprotective effects, particularly regarding late-phase pain control, nerve fiber preservation, and the normalization of NfL levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our findings confirm that oxaliplatin triggers complex pathological alterations, including pain hypersensitivity, neuroinflammation, and axonal injury. The combinatorial treatment with\n                      <jats:italic>A. muciniphila<\/jats:italic>\n                      and sodium butyrate exerted potent neuroprotective effects, significantly relieving mechanical and cold allodynia while suppressing systemic inflammation. Intriguingly, these therapeutic benefits were closely mirrored by a marked reduction in serum NfL levels. 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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1787012","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T05:42:38Z","timestamp":1772602958000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Combined intervention of Akkermansia muciniphila and sodium butyrate ameliorates oxaliplatin-induced peripheral neuropathy by suppressing neuroinflammation and reducing serum neurofilament light chain"],"prefix":"10.3389","volume":"17","author":[{"given":"Dan","family":"Xu","sequence":"first","affiliation":[{"name":"The Integrated Traditional Chinese and Western Medicine School of Clinical Medicine, Zhejiang Chinese Medical University","place":["Hangzhou, China"]},{"name":"Department of Gastrointestinal Surgery, Tongde Hospital of Zhejiang Province Affiliated to Zhejiang Chinese Medical University","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danting","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Experimental Animals, Zhejiang Academy of Traditional Chinese Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, Tongde Hospital of Zhejiang Province Affiliated to Zhejiang Chinese Medical University","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, Tongde Hospital of Zhejiang Province Affiliated to Zhejiang Chinese Medical University","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanning","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, Tongde Hospital of Zhejiang Province Affiliated to Zhejiang Chinese Medical University","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfeng","family":"Wu","sequence":"additional","affiliation":[{"name":"The Integrated Traditional Chinese and Western Medicine School of Clinical Medicine, Zhejiang Chinese Medical University","place":["Hangzhou, China"]},{"name":"Department of Gastrointestinal Surgery, Tongde Hospital of Zhejiang Province Affiliated to Zhejiang Chinese Medical University","place":["Hangzhou, China"]},{"name":"Department of Experimental Animals, Zhejiang Academy of Traditional Chinese Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-025-01037-7","article-title":"Novel colorectal cancer screening methods - opportunities and challenges","volume":"22","author":"McCabe","year":"2025","journal-title":"Nat Rev Clin Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2024.116492","article-title":"LC-MS-based serum metabolomics analysis and potential biomarkers for oxaliplatin induced neurotoxicity in colorectal cancer","volume":"252","author":"Hua","year":"2024","journal-title":"J Pharm BioMed Anal"},{"key":"B4","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1186\/s12885-024-11856-z","article-title":"Study protocol: fish oil supplement in prevention of oxaliplatin-induced peripheral neuropathy in adjuvant colorectal cancer patients - a randomized controlled trial","volume":"24","author":"Gehr","year":"2024","journal-title":"(OxaNeuro) BMC Cancer"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2023.102063","article-title":"The association of clinical and patient factors with chemotherapy-induced peripheral neuropathy (CIPN) in colorectal cancer: secondary analysis of the SCOT trial","volume":"8","author":"Lemanska","year":"2024","journal-title":"ESMO Open"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.01399","article-title":"Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: ASCO guideline update","volume":"38","author":"Loprinzi","year":"2020","journal-title":"J Clin Oncol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/s00280-025-04773-w","article-title":"Neurofilament light chain as a marker for neuronal damage: integrating in vitro studies and clinical findings in patients with oxaliplatin-induced neuropathy","volume":"95","author":"Gehr","year":"2025","journal-title":"Cancer Chemother Pharmacol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1186\/s12974-025-03431-5","article-title":"Fucoidan reduces NET accumulation and alleviates chemotherapy-induced peripheral neuropathy via the gut-blood-DRG axis","volume":"22","author":"Jia","year":"2025","journal-title":"J Neuroinflam"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.112671","article-title":"Treatment and diagnosis of chemotherapy-induced peripheral neuropathy: An update","volume":"147","author":"Desforges","year":"2022","journal-title":"BioMed Pharmacother"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-025-04216-6","article-title":"Analgesic and neuroprotective effect of a lipid transfer protein isolated from Morinda citrifolia L. (noni) seeds on oxaliplatin-induced peripheral sensory neuropathy in mice","volume":"398","author":"Ces\u00e1rio","year":"2025","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1186\/s13046-021-02141-z","article-title":"Targeting strategies for oxaliplatin-induced peripheral neuropathy: clinical syndrome, molecular basis, and drug development","volume":"40","author":"Yang","year":"2021","journal-title":"J Exp Clin Cancer Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1080\/14656566.2025.2499665","article-title":"A subgroup analysis of the MiroCIP study to evaluate chemotherapy-induced peripheral neuropathy: symptom profile, severity, and analgesia efficacy depending on type of chemotherapy","volume":"26","author":"Misawa","year":"2025","journal-title":"Expert Opin Pharmacother"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2024.08.001","article-title":"Neurofilament light chain as a biomarker of chemotherapy-induced peripheral neuropathy","volume":"45","author":"Andersen","year":"2024","journal-title":"Trends Pharmacol Sci"},{"key":"B14","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1186\/s12974-020-01966-3","article-title":"Evaluation of neurofilament light chain in the cerebrospinal fluid and blood as a biomarker for neuronal damage in experimental pneumococcal meningitis","volume":"17","author":"Le","year":"2020","journal-title":"J Neuroinflam"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-024-00955-x","article-title":"Neurofilaments as biomarkers in neurological disorders - towards clinical application","volume":"20","author":"Khalil","year":"2024","journal-title":"Nat Rev Neurol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2024.102566","article-title":"Molecular mechanisms of neurofilament alterations and its application in assessing neurodegenerative disorders","volume":"102","author":"Devarakonda","year":"2024","journal-title":"Ageing Res Rev"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.912005","article-title":"Multidimensional overview of neurofilament light chain contribution to comprehensively understanding multiple sclerosis","volume":"13","author":"K\u00f6lliker Frers","year":"2022","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.2337\/dc23-2208","article-title":"Longitudinal change in serum neurofilament light chain in type 2 diabetes and early diabetic polyneuropathy: ADDITION-Denmark","volume":"47","author":"M\u00e4\u00e4tt\u00e4","year":"2024","journal-title":"Diabetes Care"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.852563","article-title":"Prognostic value of serum neurofilament light chain for disease activity and worsening in patients with relapsing multiple sclerosis: results from the phase 3 ASCLEPIOS I and II trials","volume":"13","author":"Ziemssen","year":"2022","journal-title":"Front Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2024.176516","article-title":"Paeoniflorin ameliorates oxaliplatin-induced peripheral neuropathy via inhibiting neuroinflammation through influence on gut microbiota","volume":"971","author":"Xu","year":"2024","journal-title":"Eur J Pharmacol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2024.1345811","article-title":"Current understanding of the molecular mechanisms of chemotherapy-induced peripheral neuropathy","volume":"17","author":"Chen","year":"2024","journal-title":"Front Mol Neurosci"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-022-00631-9","article-title":"Akkermansia muciniphila: paradigm for next-generation beneficial microorganisms","volume":"19","author":"Cani","year":"2022","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-024-01106-1","article-title":"Akkermansia muciniphila: biology, microbial ecology, host interactions and therapeutic potential","volume":"23","author":"Ioannou","year":"2024","journal-title":"Nat Rev Microbiol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci14030238","article-title":"Akkermansia muciniphila Is Beneficial to a Mouse Model of Parkinson\u2019s Disease, via Alleviated Neuroinflammation and Promoted Neurogenesis, with Involvement of SCFAs","volume":"14","author":"Qiao","year":"2024","journal-title":"Brain Sci"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2025.114374","article-title":"Akkermansia muciniphila protects against dopamine neurotoxicity by modulating butyrate to inhibit microglia-mediated neuroinflammation","volume":"152","author":"Xu","year":"2025","journal-title":"Int Immunopharmacol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-025-01179-w","article-title":"Sodium butyrate attenuates microglia-mediated neuroinflammation by modulating the TLR4\/MyD88\/NF-\u03baB pathway and microbiome-gut-brain axis in cardiac arrest mice","volume":"18","author":"Sun","year":"2025","journal-title":"Mol Brain"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3390\/nu15040930","article-title":"Neuroprotective effects of sodium butyrate by restoring gut microbiota and inhibiting TLR4 signaling in mice with MPTP-induced parkinson\u2019s disease","volume":"15","author":"Guo","year":"2023","journal-title":"Nutrients"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurot.2024.e00481","article-title":"Sodium butyrate restored TRESK current controlling neuronal hyperexcitability in a mouse model of oxaliplatin-induced peripheral neuropathic pain","volume":"22","author":"Ho","year":"2025","journal-title":"Neurotherapeutics"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2025.117903","article-title":"Sodium Butyrate ameliorates pain and mood disorders in a mouse model of Parkinson disease","volume":"184","author":"Avagliano","year":"2025","journal-title":"BioMed Pharmacother"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/ilar\/ilt053","article-title":"Rodent models of chemotherapy-induced peripheral neuropathy","volume":"54","author":"H\u00f6ke","year":"2014","journal-title":"ILAR J"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-1331.2010.03023.x","article-title":"European Federation of Neurological Societies\/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society","volume":"17","author":"Lauria","year":"2010","journal-title":"Eur J Neurol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"7995","DOI":"10.1038\/s41598-020-64511-5","article-title":"Serum neurofilament light chain levels as a biomarker of neuroaxonal injury and severity of oxaliplatin-induced peripheral neuropathy","volume":"10","author":"Kim","year":"2020","journal-title":"Sci Rep"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22031393","article-title":"Therapeutic agents for oxaliplatin-induced peripheral neuropathy; experimental and clinical evidence","volume":"22","author":"Kawashiri","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B34","doi-asserted-by":"publisher","first-page":"104470","DOI":"10.1016\/j.jpain.2024.01.335","article-title":"Discovery and preclinical evaluation of a novel inhibitor of FABP5, ART26.12, effective in oxaliplatin-induced peripheral neuropathy","volume":"25","author":"Warren","year":"2024","journal-title":"J Pain"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1443-5","article-title":"Potential roles of gut microbiome and metabolites in modulating ALS in mice","volume":"572","author":"Blacher","year":"2019","journal-title":"Nature"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2025.117651","article-title":"The potential amelioration of oxaliplatin-induced peripheral neuropathy in Sprague Dawley rats by sodium butyrate via targeting neuro-immuno-inflammatory axis","volume":"506","author":"AlKady","year":"2025","journal-title":"Toxicol Appl Pharmacol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1186\/s13020-023-00826-5","article-title":"Huangqi Guizhi Wuwu decoction alleviates oxaliplatin-induced peripheral neuropathy via the gut-peripheral nerve axis","volume":"18","author":"Zhang","year":"2023","journal-title":"Chin Med"},{"key":"B38","doi-asserted-by":"publisher","first-page":"20324","DOI":"10.1038\/s41598-019-56832-x","article-title":"Dominant role of the gut microbiota in chemotherapy induced neuropathic pain","volume":"9","author":"Ramakrishna","year":"2019","journal-title":"Sci Rep"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-025-01183-w","article-title":"Gut microbiota-derived short-chain fatty acids and their role in human health and disease","volume":"23","author":"Mukhopadhya","year":"2025","journal-title":"Nat Rev Microbiol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1007\/s12640-025-00775-x","article-title":"Neuroinflammatory mechanisms and therapeutic targets in oxaliplatin-induced peripheral neuropathy: a comprehensive review","volume":"43","author":"Dehghani","year":"2025","journal-title":"Neurotox Res"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.114308","article-title":"Butyrate ameliorates chronic alcoholic central nervous damage by suppressing microglia-mediated neuroinflammation and modulating the microbiome-gut-brain axis","volume":"160","author":"Wei","year":"2023","journal-title":"BioMed Pharmacother"},{"key":"B42","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/s13020-024-00929-7","article-title":"Danggui Sini decoction alleviates oxaliplatin-induced peripheral neuropathy by regulating gut microbiota and potentially relieving neuroinflammation related metabolic disorder","volume":"19","author":"Chen","year":"2024","journal-title":"Chin Med"},{"key":"B43","doi-asserted-by":"publisher","first-page":"e20230675","DOI":"10.1084\/jem.20230675","article-title":"CD163+ macrophages monitor enhanced permeability at the blood-dorsal root ganglion barrier","volume":"221","author":"Lund","year":"2024","journal-title":"J Exp Med"},{"key":"B44","doi-asserted-by":"publisher","first-page":"eadj1277","DOI":"10.1126\/scitranslmed.adj1277","article-title":"B cells drive neuropathic pain-related behaviors in mice through IgG-Fc gamma receptor signaling","volume":"16","author":"Lacagnina","year":"2024","journal-title":"Sci Transl Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01455","article-title":"Toll-like receptor 4 (TLR4)\/opioid receptor pathway crosstalk and impact on opioid analgesia, immune function, and gastrointestinal motility","volume":"11","author":"Zhang","year":"2020","journal-title":"Front Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2025.578521","article-title":"Cerebrospinal fluid biomarkers associated with neurofilament light levels: A study in HIV disease","volume":"400","author":"Ripamonti","year":"2025","journal-title":"J Neuroimmunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2025.19400","article-title":"Peripheral neuropathy: A review","volume":"335","author":"Mauermann","year":"2026","journal-title":"JAMA"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1787012\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T05:42:40Z","timestamp":1772602960000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1787012\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,4]]},"references-count":47,"alternative-id":["10.3389\/fimmu.2026.1787012"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1787012","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,4]]},"article-number":"1787012"}}