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Circulating sclerostin levels are reduced in axial spondyloarthritis (axSpA) and correlate with structural damage. LRP5, a receptor inhibited by sclerostin, also controls bone formation by regulating gut-derived serotonin synthesis, indicating a hormonal link between the intestine and bone. We hypothesized that gut dysbiosis-dependent downregulation of sclerostin alters intestinal serotonin production, contributing to disease-specific gut-bone signaling in axSpA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We quantified sclerostin and the serotonin-synthesizing enzyme TPH1 by qRT-PCR, and assessed serotonin protein levels by immunohistochemistry in ileal biopsies from treatment-na\u00efve axSpA patients (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200925) and healthy controls (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200920), alongside measurement of circulating serotonin in peripheral blood platelets. We evaluated TPH1 expression in BON-1 cells following sclerostin and WNT3a treatment. Findings were validated in HLA-B27 transgenic rats, SKG mice, and Sost\u207b\/\u207b mice. Serotonin receptor expression in spinal entheseal cells was analyzed by RT-PCR, and LPS-induced HTR2B modulation was examined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In healthy controls, sclerostin modulated TPH1 expression and serotonin synthesis in enterochromaffin cells. In axSpA patients, intestinal sclerostin downregulation coincided with increased numbers of serotonin-positive enterochromaffin cells and elevated platelet serotonin levels. Broad-spectrum antibiotics restored intestinal sclerostin expression and normalized serotonin production in HLA-B27 transgenic rats. Sost\u207b\/\u207b mice exhibited increased intestinal Tph1 expression, while SKG mice showed reduced sclerostin and elevated Tph1 following curdlan-induced colitis\u2014an effect dependent on the presence of intestinal microbiota. Human spinal entheses expressed HTR1B, HTR2A, and HTR2B, with LPS selectively inducing HTR2B expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We identify a gut microbiota-dependent sclerostin-serotonin axis that regulates serotonin production and may contribute to gut-bone pathology in axSpA. These findings reveal novel mechanisms linking gut dysbiosis to bone disease and suggest potential therapeutic targets within the gut-bone-immune axis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s10753-025-02393-3","type":"journal-article","created":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T12:53:26Z","timestamp":1768049606000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Intestinal Sclerostin Deficiency Links Gut Dysbiosis to Altered Serotonin Homeostasis in Axial Spondyloarthritis"],"prefix":"10.1007","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9022-8863","authenticated-orcid":false,"given":"Daniele","family":"Mauro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Sophie","family":"Bergot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliana","family":"Guggino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Salzillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Forte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Ciancio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aroldo","family":"Rizzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Raimondo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Lentini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saviana","family":"Gandolfo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soohyun P.","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"De Marino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Milling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Alessandro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iacopo","family":"Panarese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan C.","family":"Riddle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario M.","family":"Zaiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"McGonagle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjeny","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Ciccia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,10]]},"reference":[{"key":"2393_CR1","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1038\/nm.3074","volume":"19","author":"Roland Baron","year":"2013","unstructured":"Baron, Roland, and Michaela Kneissel. 2013. 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The Johns Hopkins University Institutional Animal Care and Use Committee approved all procedures involving Sost\u207b\/\u207b mice. The University of Queensland Animal Ethics Committee approved all procedures involving SKG mice. Animal experiments adhered to the ARRIVE guidelines. Clinical Trial number is not applicable for the research involved in this study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human and Animal Rights"}},{"value":"During the preparation of this work, the authors utilized ChatGPT-4 (OpenAI) to enhance readability and language clarity. The authors reviewed and edited all AI-generated content as needed and take full responsibility for the content of the published article.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations of generative AI and AI-assisted technologies in the writing process."}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"38"}}