{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:09:36Z","timestamp":1790946576807,"version":"4.1.0"},"reference-count":73,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014653","name":"NIHR Manchester Biomedical Research Centre","doi-asserted-by":"crossref","award":["NIHR203308"],"award-info":[{"award-number":["NIHR203308"]}],"id":[{"id":"10.13039\/100014653","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH\/NIAMS","award":["R01 AR081382-01A1"],"award-info":[{"award-number":["R01 AR081382-01A1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Gastrointestinal (GI) involvement is the most frequent visceral complication of systemic sclerosis (SSc), affecting up to 90% of patients, yet it remains poorly understood compared to pulmonary or cutaneous manifestations. The aim of this review is to integrate current knowledge on the cellular mechanisms underlying GI disease in SSc and to identify research priorities. Methods: A narrative literature review was conducted through a systematic PubMed search up to September 2025, complemented by manual reference screening. Results: Histopathological and functional evidence consistently demonstrates that neuromuscular alterations, including degeneration of enteric neurons, loss of interstitial cells of Cajal, and smooth muscle atrophy, can precede fibrosis, challenging the traditional \u201cfibrosis-first\u201d paradigm. Fibroblast and myofibroblast activation are present in gastric and colonic samples, sustained by profibrotic mediators such as TGF-\u03b2, CTGF, and endothelin-1, although the cellular origins of these stromal cells remain uncertain. Additional pathogenic contributions include autonomic dysfunction, barrier dysfunction with dysbiosis, impaired vascular reserve of vessels perfusing the gut, and functional autoantibodies targeting interneural and neuromuscular function and communication. Compared with skin and lung, the GI tract displays less fibrosis and fewer inflammatory infiltrates, but immune-derived mediators and autoantibodies suggest distinct immunopathogenic pathways are activated. Conclusions: Collectively, these findings depict GI involvement in SSc as a multi-compartmental process integrating neural, epithelial, endothelial, stromal, and immune alterations. Addressing the lack of validated biomarkers, mechanistic models, and biomarker-stratified trials will be essential to move beyond symptomatic care and toward precision medicine approaches for SSc-related GI disease.<\/jats:p>","DOI":"10.3390\/cells14231930","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T15:14:06Z","timestamp":1764861246000},"page":"1930","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cellular Players in Gastrointestinal Involvement of Systemic Sclerosis: Insights into Pathogenesis"],"prefix":"10.3390","volume":"14","author":[{"given":"Silvia","family":"Peretti","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University Hospital Careggi, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7744-8549","authenticated-orcid":false,"given":"Francesco","family":"Bonomi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University Hospital Careggi, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2076-7319","authenticated-orcid":false,"given":"Giulia","family":"Bandini","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University Hospital Careggi, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiano","family":"Barbetta","sequence":"additional","affiliation":[{"name":"Scleroderma Unit, Rheumatology Department, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3361-4909","authenticated-orcid":false,"given":"Michael","family":"Hughes","sequence":"additional","affiliation":[{"name":"Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Science, School of Biological Sciences, Faculty of Biological Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK"},{"name":"Department of Rheumatology, Salford Care Organisation, Northern Care Alliance NHS Foundation Trust, Salford M6 8HD, UK"},{"name":"NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester M6 8HD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8528-2283","authenticated-orcid":false,"given":"Francesco","family":"Del Galdo","sequence":"additional","affiliation":[{"name":"Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds LS2 9JT, UK"},{"name":"NIHR Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust (LTHT), Leeds LS7 4SA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Matucci Cerinic","sequence":"additional","affiliation":[{"name":"Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"Vita-Salute San Raffaele University, 20132 Milan, Italy"},{"name":"Inflammation Fibrosis and Ageing Initiative (INFLAGE), Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6461-8940","authenticated-orcid":false,"given":"Zsuzsanna H.","family":"McMahan","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine, UTHealth Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5926-6263","authenticated-orcid":false,"given":"Silvia","family":"Bellando Randone","sequence":"additional","affiliation":[{"name":"Scleroderma Unit, Rheumatology Department, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.rdc.2015.04.007","article-title":"Systemic Sclerosis: Gastrointestinal Disease and Its Management","volume":"41","author":"Gyger","year":"2015","journal-title":"Rheum. 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