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 huma...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 dietinduced 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.展开更多
基金Biotechnology Institute and the MnDrive initiative(to MHE)。
文摘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 dietinduced 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.
