{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T15:00:26Z","timestamp":1783090826079,"version":"3.54.6"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T00:00:00Z","timestamp":1686700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017610","name":"Shenzhen Science and Technology Innovation Program","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100017610","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Chronic cancer pain is one of the most unbearable symptoms for the patients with advanced cancer. The treatment of cancer pain continues to possess a major challenge. Here, we report that adjusting gut microbiota via probiotics can reduce bone cancer pain (BCP) in rats.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The model of BCP was produced by tumor cell implantation (TCI) to the tibia in rats. Continuous feeding of Lactobacillus rhamnosus GG (LGG) was used to modulate the gut microbiota. Mechanical allodynia, bone destruction, fecal microbiota, and neurochemical changes in the primary dorsal root ganglion (DRG) and the spinal dorsal horn (DH) were assessed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>LGG supplementation (10<jats:sup>9<\/jats:sup> CFU\/rat\/day) delayed the production of BCP for 3\u20134 days and significantly alleviated mechanical allodynia within the first 2 weeks after TCI. TCI-induced proinflammatory cytokines TNF-\u03b1 and IL-\u03b2 in the DH, and TCI-induced bone destruction in the tibia were both significantly reduced following LGG supplementation examined on day 8 after TCI. Meanwhile, we found that LGG supplementation, in addition to inhibiting TCI-induced pain, resulted in a significantly increased expression of the \u03bc-opioid receptor (MOR) in the DH, but not in the DRG. LGG supplementation significantly potentiated the analgesic effect of morphine. Furthermore, LGG supplementation led to an increase in butyrate levels in the feces and serum and a decrease in histone deacetylase 2 (HDAC2) expression in the DH. Feeding TCI-rats with sodium butyrate solution alone, at a dose of 100 mg\/kg, resulted in decreased pain, as well as decreased HDAC2 expression and increased MOR expression in the DH. The increased expression of MOR and decreased HDAC2 were also observed in neuro-2a cells when we treated the cells with serum from TCI rats with supplementation of LGG or sodium butyrate.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>This study provides evidence that reshaping the gut microbiota with probiotics LGG can delay the onset of cancer pain. The butyrate-HDAC2-MOR pathway may be the underlying mechanism for the analgesic effect of LGG. These findings shed light on an effective, safe, and non-invasive approach for cancer pain control and support the clinical implication of probiotics supplementation for patients with BCP.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnmol.2023.1207911","type":"journal-article","created":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T04:33:07Z","timestamp":1686717187000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Lactobacillus rhamnosus GG and butyrate supplementation in rats with bone cancer reduces mechanical allodynia and increases expression of \u03bc-opioid receptor in the spinal cord"],"prefix":"10.3389","volume":"16","author":[{"given":"Wenxi","family":"Yuan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huabao","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiran","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keying","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Jun","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2193","DOI":"10.1073\/pnas.0711891105","article-title":"Commensal microbiota is fundamental for the development of inflammatory pain.","volume":"105","author":"Amaral","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B2","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1038\/nature12726","article-title":"Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation.","volume":"504","author":"Arpaia","year":"2013","journal-title":"Nature"},{"key":"B3","author":"Balows","year":"1992","journal-title":"The Prokaryotes: A handbook on the biology of bacteria: Ecophysiology, isolation, identification, applications."},{"key":"B4","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/0092-8674(78)90305-7","article-title":"Sodium butyrate inhibits histone deacetylation in cultured cells.","volume":"14","author":"Candido","year":"1978","journal-title":"Cell"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2247","DOI":"10.1073\/pnas.1322269111","article-title":"The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition.","volume":"111","author":"Chang","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B6","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/0165-0270(94)90144-9","article-title":"Quantitative assessment of tactile allodynia in the rat paw.","volume":"53","author":"Chaplan","year":"1994","journal-title":"J. Neurosci. Methods"},{"key":"B7","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1146\/annurev-neuro-080317-061522","article-title":"Endogenous and exogenous opioids in pain.","volume":"41","author":"Corder","year":"2018","journal-title":"Annu. Rev. Neurosci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1038\/s41575-019-0157-3","article-title":"The role of short-chain fatty acids in microbiota\u2013gut\u2013brain communication.","volume":"16","author":"Dalile","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1007\/3-540-29623-9_6913","article-title":"Enterobacteriaceae","author":"Ganten","year":"2006","journal-title":"Encyclopedic reference of genomics and proteomics in molecular medicine"},{"key":"B10","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1016\/j.bja.2019.07.026","article-title":"Pain regulation by gut microbiota: Molecular mechanisms and therapeutic potential.","volume":"123","author":"Guo","year":"2019","journal-title":"Br. J. Anaesth."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-020-01740-5","article-title":"Suppression of histone deacetylases by SAHA relieves bone cancer pain in rats via inhibiting activation of glial cells in spinal dorsal horn and dorsal root ganglia.","volume":"17","author":"He","year":"2020","journal-title":"J. Neuroinflammation"},{"key":"B12","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1111\/j.1574-6968.2010.02197.x","article-title":"Quantification of butyryl CoA: Acetate CoA-transferase genes reveals different butyrate production capacity in individuals according to diet and age.","volume":"316","author":"Hippe","year":"2011","journal-title":"FEMS Microbiol. Lett."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3390\/nu14030649","article-title":"Lactulose modulates the structure of gut microbiota and alleviates colitis-associated tumorigenesis.","volume":"14","author":"Hiraishi","year":"2022","journal-title":"Nutrients"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1302","DOI":"10.1111\/j.1365-2036.2011.04665.x","article-title":"Meta-analysis: Lactobacillus rhamnosus GG for abdominal pain-related functional gastrointestinal disorders in childhood.","volume":"33","author":"Horvath","year":"2011","journal-title":"Aliment Pharmacol. Ther."},{"key":"B15","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.brainres.2017.05.014","article-title":"HDAC inhibitor TSA ameliorates mechanical hypersensitivity and potentiates analgesic effect of morphine in a rat model of bone cancer pain by restoring \u03bc-opioid receptor in spinal cord.","volume":"1669","author":"Hou","year":"2017","journal-title":"Brain Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.neuroscience.2018.02.026","article-title":"Suppression of HDAC2 in spinal cord alleviates mechanical hyperalgesia and restores KCC2 expression in a rat model of bone cancer pain.","volume":"377","author":"Hou","year":"2018","journal-title":"Neuroscience"},{"key":"B17","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1124\/mol.110.064311","article-title":"Up-regulation of the mu-opioid receptor gene is mediated through chromatin remodeling and transcriptional factors in differentiated neuronal cells.","volume":"78","author":"Hwang","year":"2010","journal-title":"Mol. Pharmacol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"4720","DOI":"10.1128\/MCB.00073-07","article-title":"Evidence of endogenous mu opioid receptor regulation by epigenetic control of the promoters.","volume":"27","author":"Hwang","year":"2007","journal-title":"Mol. Cell Biol."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2019.106004","article-title":"Butyrate alleviates inflammatory response and NF-\u03baB activation in human degenerated intervertebral disc tissues.","volume":"78","author":"Jia","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"46464","DOI":"10.1074\/jbc.M403633200","article-title":"Neuron-restrictive silencer factor (NRSF) functions as a repressor in neuronal cells to regulate the mu opioid receptor gene.","volume":"279","author":"Kim","year":"2004","journal-title":"J. Biol. Chem."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0090702","article-title":"Gut microbiota signatures predict host and microbiota responses to dietary interventions in obese individuals.","volume":"9","author":"Korpela","year":"2014","journal-title":"PLoS One"},{"key":"B22","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1016\/j.jfma.2013.05.013","article-title":"Attenuation of neuropathic pain by sodium butyrate in an experimental model of chronic constriction injury in rats.","volume":"113","author":"Kukkar","year":"2014","journal-title":"J. Formos. Med. Assoc."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1186\/s40168-019-0637-2","article-title":"Sequence and cultivation study of Muribaculaceae reveals novel species, host preference, and functional potential of this yet undescribed family.","volume":"7","author":"Lagkouvardos","year":"2019","journal-title":"Microbiome"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2823","DOI":"10.1016\/j.pain.2013.08.017","article-title":"EphrinB-EphB receptor signaling contributes to bone cancer pain via Toll-like receptor and proinflammatory cytokines in rat spinal cord.","volume":"154","author":"Liu","year":"2013","journal-title":"Pain"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-022-02523-w","article-title":"Gut microbiota depletion by antibiotics ameliorates somatic neuropathic pain induced by nerve injury, chemotherapy, and diabetes in mice.","volume":"19","author":"Ma","year":"2022","journal-title":"J. Neuroinflammation"},{"key":"B26","doi-asserted-by":"publisher","first-page":"S54","DOI":"10.1016\/j.pain.2013.07.044","article-title":"Bone cancer pain: Causes, consequences, and therapeutic opportunities.","volume":"154","author":"Mantyh","year":"2013","journal-title":"Pain"},{"key":"B27","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1093\/ibd\/izy318","article-title":"An increased abundance of clostridiaceae characterizes arthritis in inflammatory bowel disease and rheumatoid arthritis: A cross-sectional study.","volume":"25","author":"Mu\u00f1iz Pedrogo","year":"2019","journal-title":"Inflamm. Bowel Dis."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.1016\/j.jcmgh.2021.06.001","article-title":"Lactobacillus rhamnosus GG orchestrates an antitumor immune response.","volume":"12","author":"Owens","year":"2021","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1038\/nm1521","article-title":"Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors.","volume":"13","author":"Rousseaux","year":"2007","journal-title":"Nat. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"3930","DOI":"10.2174\/0929867324666170216113756","article-title":"Gut-brain axis: Role of lipids in the regulation of inflammation, pain and CNS diseases.","volume":"25","author":"Russo","year":"2018","journal-title":"Curr. Med. Chem."},{"key":"B31","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/j.phrs.2015.11.026","article-title":"Sodium butyrate and its synthetic amide derivative modulate nociceptive behaviors in mice.","volume":"103","author":"Russo","year":"2016","journal-title":"Pharmacol. Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1038\/nn.4606","article-title":"Gut microbiota is critical for the induction of chemotherapy-induced pain.","volume":"20","author":"Shen","year":"2017","journal-title":"Nat. Neurosci."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1186\/s12877-020-01644-2","article-title":"Dysbiosis, gut barrier dysfunction and inflammation in dementia: A pilot study.","volume":"20","author":"Stadlbauer","year":"2020","journal-title":"BMC Geriatr."},{"key":"B34","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1007\/s00431-020-03809-y","article-title":"Use of probiotics in the treatment of functional abdominal pain in children-systematic review and meta-analysis.","volume":"180","author":"Trivi\u0107","year":"2021","journal-title":"Eur. J. Pediatr."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1116.e7","DOI":"10.1016\/j.immuni.2018.10.013","article-title":"The microbial metabolite butyrate stimulates bone formation via T regulatory cell-mediated regulation of WNT10B expression.","volume":"49","author":"Tyagi","year":"2018","journal-title":"Immunity"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms8040573","article-title":"The controversial role of human gut Lachnospiraceae.","volume":"8","author":"Vacca","year":"2020","journal-title":"Microorganisms"},{"key":"B37","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1016\/j.jnutbio.2010.07.009","article-title":"Suppressive effect of short-chain fatty acids on production of proinflammatory mediators by neutrophils.","volume":"22","author":"Vinolo","year":"2011","journal-title":"J. Nutr. Biochem."},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11010038","article-title":"Gut microbiota and cancer: From pathogenesis to therapy.","volume":"11","author":"Vivarelli","year":"2019","journal-title":"Cancers"},{"key":"B39","doi-asserted-by":"publisher","first-page":"3603","DOI":"10.1172\/JCI133334","article-title":"PD-1 blockade inhibits osteoclast formation and murine bone cancer pain.","volume":"130","author":"Wang","year":"2020","journal-title":"J. Clin. Invest."},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.131692","article-title":"Focal adhesion proteins Pinch1 and Pinch2 regulate bone homeostasis in mice.","volume":"4","author":"Wang","year":"2019","journal-title":"JCI Insight"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2021.658292","article-title":"Cross-talk between butyric acid and gut microbiota in ulcerative colitis following fecal microbiota transplantation.","volume":"12","author":"Xu","year":"2021","journal-title":"Front. Microbiol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1016\/j.neuroscience.2007.11.025","article-title":"Down-regulation of mu opioid receptor expression within distinct subpopulations of dorsal root ganglion neurons in a murine model of bone cancer pain.","volume":"151","author":"Yamamoto","year":"2008","journal-title":"Neuroscience"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20236047","article-title":"Bone pain in cancer patients: Mechanisms and current treatment.","volume":"20","author":"Zaj\u0105czkowska","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2021.665085","article-title":"Distinct gene expression patterns of ion channels and cytokines in rat primary sensory neurons during development of bone cancer and cancer pain.","volume":"14","author":"Zhai","year":"2021","journal-title":"Front. Mol. Neurosci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1368","DOI":"10.1111\/jgh.14536","article-title":"Beneficial effect of butyrate-producing Lachnospiraceae on stress-induced visceral hypersensitivity in rats.","volume":"34","author":"Zhang","year":"2019","journal-title":"J. Gastroenterol. Hepatol."},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/5188202","article-title":"Changes of intestinal flora and its relationship with nutritional status for patients with cancer pain.","volume":"2022","author":"Zhang","year":"2022","journal-title":"Comput. Math. Methods Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/j.talanta.2018.12.049","article-title":"A sensitive GC\/MS detection method for analyzing microbial metabolites short chain fatty acids in fecal and serum samples.","volume":"196","author":"Zhang","year":"2019","journal-title":"Talanta"},{"key":"B48","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1097\/j.pain.0000000000000848","article-title":"Neuron-restrictive silencer factor-mediated downregulation of \u03bc-opioid receptor contributes to the reduced morphine analgesia in bone cancer pain.","volume":"158","author":"Zhu","year":"2017","journal-title":"Pain"}],"container-title":["Frontiers in Molecular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2023.1207911\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T04:33:12Z","timestamp":1686717192000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2023.1207911\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,14]]},"references-count":48,"alternative-id":["10.3389\/fnmol.2023.1207911"],"URL":"https:\/\/doi.org\/10.3389\/fnmol.2023.1207911","relation":{},"ISSN":["1662-5099"],"issn-type":[{"value":"1662-5099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,14]]},"article-number":"1207911"}}