International Investigation of the Gut-Lung Axis in Systemic Sclerosis-Interstitial Lung Disease.

Objectives: Mounting evidence supports an association between the intestinal microbiota and diverse pulmonary pathologies (i.e., gut-lung axis). While intestinal dysbiosis is a feature of systemic sclerosis (SSc), no prior studies have investigated the relationship between intestinal microbiota and SSc-associated interstitial lung disease (ILD) in a multi-national cohort. This study aimed to characterize the intestinal microbiota of SSc-ILD and determine whether specific bacterial species and functional pathways are associated with ILD severity.

Methods: SSc patients with and without ILD from seven SSc Centers across five continents provided a stool sample. Shotgun metagenomic sequencing was performed using the Illumina NovaSeq 6000 to characterize microbial composition at the species level. Quantitative image analysis of high-resolution computed tomography scans of the chest was used to measure radiological extent of ILD (QILD). Multivariate sparse partial least squares analyses were employed to identify a species signature of ILD and to determine whether specific species and functional pathways are associated with QILD.

Results: Among 285 participants (mean disease duration of 9.8 years), 62.5% had ILD. In a multivariate analysis of all participants, patients with ILD had a unique microbial signature compared to those without ILD characterized by increased abundance of candidate pathobiont species. In a subgroup of SSc-ILD participants (N=103), specific bacterial species and functional pathways were associated with QILD.

Conclusion: This multicenter study demonstrates that distinct intestinal bacterial species are linked to the presence and radiological extent of ILD in SSc. These species and/or their metabolic products may influence ILD pathogenesis and represent novel treatment targets.