Cushing's Syndrome is associated with Gut Microbial Dysbiosis and Cortisol-Degrading Bacteria

Abstract Context Cushing's Syndrome (CS) is a severe endocrine disease characterized by excessive secretion of cortisol with multiple metabolic disorders. While gut dysbiosis plays a vital role in metabolic disorders, the role of gut microbiota in CS remains unclear. Objective The objective of this work is to examine the alteration of gut microbiota in patients with CS. Methods We performed shotgun metagenomic sequencing of fecal samples from 78 patients with CS and 78 healthy controls matched for age and body mass index. Furthermore, we verify the cortisol-degradation capacity of Ruminococcus gnavus in vitro and identify the potential metabolite by LC-MC/MS. Results We observed significant differences in microbial composition between CS and controls in both sexes, with CS showing reduced Bacteroidetes (Bacteroides vulgatus) and elevated Firmicutes (Erysipelotrichaceae_bacterium_6_1_45) and Proteobacteria (Enterobacter cloacae). Despite distinct causes of hypercortisolism in ACTH-dependent and ACTH-independent CS, we found no significant differences in metabolic profiles or gut microbiota between the two subgroups. Furthermore, we identified a group of gut species, including R. gnavus, were positively correlated with cortisol levels in CS. These bacteria were found to harbor cortisol-degrading desAB genes and were consistently enriched in CS. Moreover, we demonstrated the efficient capacity of R. gnavus to degrade cortisol to 11-oxygenated androgens in vitro. Conclusions This study provides evidence of gut microbial dysbiosis in patients with CS and identifies a group of CS-enriched bacteria capable of degrading cortisol. These findings highlight the potential role of gut microbiota in regulating host steroid hormone levels, and consequently host health.