Intestinal Sclerostin Deficiency Links Gut Dysbiosis to Altered Serotonin Homeostasis in Axial Spondyloarthritis

Mauro D, Bergot AS, Guggino G, Salzillo A, Forte G, Ciancio A, Rizzo A, Raimondo S, Lentini L, Gandolfo S, Kim SP, Wong C, De Marino B, Milling S, Alessandro R, Panarese I, Riddle RC, Zaiss M, McGonagle D, Thomas R, Ciccia F (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Inflammation Springer Verlag (Germany)

Book Volume: 49

Article Number: 38

Journal Issue: 1

DOI: 10.1007/s10753-025-02393-3

Abstract

Background: Sclerostin regulates bone formation via Wnt/β-catenin signaling inhibition and contributes to intestinal epithelial homeostasis. 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. Methods: We quantified sclerostin and the serotonin-synthesizing enzyme TPH1 by qRT-PCR, and assessed serotonin protein levels by immunohistochemistry in ileal biopsies from treatment-naïve axSpA patients (n = 25) and healthy controls (n = 20), 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⁻/⁻ mice. Serotonin receptor expression in spinal entheseal cells was analyzed by RT-PCR, and LPS-induced HTR2B modulation was examined. Results: 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⁻/⁻ mice exhibited increased intestinal Tph1 expression, while SKG mice showed reduced sclerostin and elevated Tph1 following curdlan-induced colitis—an effect dependent on the presence of intestinal microbiota. Human spinal entheses expressed HTR1B, HTR2A, and HTR2B, with LPS selectively inducing HTR2B expression. Conclusions: 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.

Authors with CRIS profile

Mario Zaiss Department of Medicine 3 – Rheumatology and Immunology

Involved external institutions

Università degli studi della Campania Luigi Vanvitelli IT Italy (IT) University of Queensland AU Australia (AU) Università degli Studi di Palermo IT Italy (IT) Ospedali Riuniti Villa Sofia-Cervello IT Italy (IT) Ospedale del Mare IT Italy (IT) University of Maryland School of Pharmacy US United States (USA) (US) University of Leeds GB United Kingdom (GB) University of Glasgow GB United Kingdom (GB)

How to cite

APA:

Mauro, D., Bergot, A.S., Guggino, G., Salzillo, A., Forte, G., Ciancio, A.,... Ciccia, F. (2026). Intestinal Sclerostin Deficiency Links Gut Dysbiosis to Altered Serotonin Homeostasis in Axial Spondyloarthritis. Inflammation, 49(1). https://doi.org/10.1007/s10753-025-02393-3

MLA:

Mauro, Daniele, et al. "Intestinal Sclerostin Deficiency Links Gut Dysbiosis to Altered Serotonin Homeostasis in Axial Spondyloarthritis." Inflammation 49.1 (2026).

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