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

Abstract

Mounting evidence supports an association between the intestinal microbiota and diverse pulmonary pathologies (ie, gut-lung axis). Although 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 multinational 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. Patients with SSc 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 radiologic 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. 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 participants with SSc-ILD (n = 103), specific bacterial species and functional pathways were associated with QILD. This multicenter study demonstrates that distinct intestinal bacterial species are linked to the presence and radiologic extent of ILD in SSc. These species and/or their metabolic products may influence ILD pathogenesis and represent novel treatment targets.