Quorum quenching enzymes disrupt bacterial communication in a sex- and dose-dependent manner

Background: Over the past 50 years, the incidence of obesity has gradually increased, necessitating investigation into the multifactorial contributors to this disease, including the gut microbiota. Bacteria within the human gut microbiome communicate using a density-dependent process known as quorum sensing (QS), in which autoinducer (AI) molecules (e.g., N-acyl-homoserine lactones [AHLs]) are produced to enable bacterial interactions and regulate gene expression. Methods: We aimed to disrupt QS using quorum quenching (QQ) lactonases GcL and SsoPox, which cleave AHL signaling molecules in a taxa-specific manner based on differing enzyme affinities for different substrates. We hypothesized that QQ hinders signals from obesity-associated pathobionts, thereby slowing or preventing obesity. Results: In a murine model of diet-induced obesity, we observed GcL and SsoPox treatments have separate sex-dependent and dose-dependent effects on intestinal community composition and diversity. Notably, male mice given 2 mg/mL SsoPox exhibited significant changes in the relative abundances of gram-negative taxa, including Porphyromonadaceae, Akkermansiaceae, Muribaculaceae, and Bacteroidales (Kruskal–Wallis p < 0.001). Additionally, we used covariance matrix network analysis to model bacterial taxa co-occurrence due to QQ enzyme administration. There were more associations among taxa in control mice, particularly among gram-negative bacteria, whereas mice receiving SsoPox had the fewest associations. Conclusions: Overall, our study establishes proof of concept that QQ is a targetable strategy for microbial control in vivo. Further characterization and dosage optimization of QQ enzymes are necessary to harness their therapeutic capability for the treatment of chronic microbial-associated diseases.