Cellular Players in Gastrointestinal Involvement of Systemic Sclerosis: Insights into Pathogenesis

Area of Science:

• Gastroenterology
• Rheumatology
• Immunology
• Cellular Biology

Background:

• Gastrointestinal (GI) involvement is the most common visceral complication of systemic sclerosis (SSc), affecting up to 90% of patients.
• GI manifestations in SSc are less understood than pulmonary or cutaneous complications.
• Current understanding often follows a 'fibrosis-first' paradigm, which may be incomplete.

Purpose of the Study:

• To review and integrate current knowledge on the cellular mechanisms of GI disease in SSc.
• To identify research priorities for SSc-related GI complications.

Main Methods:

• A narrative literature review was performed.
• Systematic PubMed search up to September 2025, supplemented by manual reference screening.

Main Results:

• Evidence suggests neuromuscular alterations (enteric neuron degeneration, loss of interstitial cells of Cajal, smooth muscle atrophy) can precede fibrosis.
• Fibroblast and myofibroblast activation occur, sustained by profibrotic mediators like TGF-β.
• Other factors include autonomic dysfunction, barrier dysfunction with dysbiosis, impaired gut vascular reserve, and autoantibodies.
• The GI tract shows less fibrosis and inflammation than skin/lung, indicating distinct immunopathogenic pathways.

Conclusions:

• GI involvement in SSc is a multi-compartmental process involving neural, epithelial, endothelial, stromal, and immune alterations.
• Lack of validated biomarkers, mechanistic models, and biomarker-stratified trials hinders progress.
• Future research should focus on precision medicine approaches for SSc-related GI disease.