Mechanisms and Clinical Translational Prospects of the Microbiota–Gut–Lung Axis in Connective Tissue Disease-Associated Interstitial Lung Disease

Abstract

Connective tissue disease-associated interstitial lung disease (CTD-ILD) is one of the most severe pulmonary complications of connective tissue diseases, featuring rapid progression and heterogeneous prognosis. Early recognition and prognostic prediction remain substantial clinical challenges. Accumulating evidence indicates that the microbiota–gut–lung axis participates in key pathological cascades, including autoimmune dysregulation, chronic inflammatory activation, and tissue fibrotic remodeling, which provides new insights into the pathogenesis of autoimmune-mediated lung diseases. This review systematically summarizes regulatory mechanisms of CTD-ILD involving gut dysbiosis, intestinal mucosal barrier impairment, disturbed metabolism of short-chain fatty acids, bile acids, and tryptophan, and systemic immune imbalance. We further compare evidence and pathological discrepancies of gut–lung–axis disturbance across CTD subtypes: systemic sclerosis-associated interstitial lung disease (SSc-ILD), rheumatoid arthritis-associated interstitial lung disease (RA-ILD), systemic lupus erythematosus-associated interstitial lung disease (SLE-ILD), idiopathic inflammatory myopathy interstitial lung disease (IIM-ILD), and primary Sjögren’s syndrome-associated interstitial lung disease (pSS-ILD). We also highlight the translational potential of gut–lung axis-related biomarkers for screening and assessment, summarize targeted interventions and integrated Chinese–Western therapeutic regimens, and pinpoint major evidence gaps and methodological limitations. This review refines the inter-organ regulatory framework of CTD-ILD and offers scientific references for mechanistic investigation, precise clinical evaluation, and novel therapeutic development.