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

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.

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.

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.

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.