Compositional and Functional Profiling of the Gut Microbiome in Sarcoidosis

Background: Sarcoidosis is a chronic inflammatory disease characterized by systematic granuloma formation, predominantly in the lungs. While its etiology remains under investigation, one leading hypothesis posits that prolonged exposure to microbial antigens may trigger chronic and dysregulated inflammation. Prior studies have examined the lung microbiota of sarcoidosis patients, but the role of the gut microbiota along the gut-immune axis remains largely unexplored. We elucidate the community composition and function of the gut microbiome in sarcoidosis. Methods: Subjects diagnosed with sarcoidosis (n=37) were recruited and matched with healthy control subjects (n=37). Stool samples were collected from sarcoidosis patients for metagenomic sequencing, followed by taxonomic classification and functional annotation as KEGG Orthology (KO) pathways. Control gut microbiome data from a previously published study was processed using the same bioinformatics pipeline as the sarcoidosis cohort. Differential analysis between sarcoidosis and control cohorts was performed using both standard and compositional approaches. Results: Overall, sarcoidosis microbiomes exhibited similar alpha diversity but significantly different beta diversity from control microbiomes (p<0.05). At the phylum level, the proportion of Actinobacteria and Firmicutes expanded whereas Bacteroides and Verrucomicrobia proportionally shrunk in sarcoidosis gut microbiomes compared to healthy control ones. At the species level, 1,495 species were significantly more abundant and 279 less abundant in sarcoidosis compared to controls (FDR<0.05). Of these, 13 species demonstrated greater intergroup than intragroup variation (effect size>1), including microbes previously detected in the lungs and granulomas of sarcoidosis. Functional profiling revealed 409 KO pathways that were significantly underrepresented in sarcoidosis compared to control (FDR<0.05), of which 79 met an effect size > 1. These include pathways in amino acid and energy metabolism as well as HIF-1 signaling. Conclusions: Our findings highlight the potential role of gut microbiome composition and function in inflammatory processes that are associated with granuloma formation in sarcoidosis.