MicroDialogue · Unraveling the potential of Quorum Sensing inter-species dialogue to restore microbiota’s community dynamics.

The overuse of antibiotics has led to a disruption in gut microbiota, particularly in the Bacillota phylum, increasing susceptibility to pathogens, obesity, diabetes, and other metabolic disorders. MicroDialogue aims to evaluate the capacity of Quorum Sensing (QS) interspecies communication, a bacterial communication mechanism mediated by Autoinducer-2 (AI-2), to restore gut microbiota balance after antibiotic-induced perturbations and improve health outcomes. MicroDialogue will focus on the novel murine commensal non-pneumoniae Klebsiella sp. ARO112, which can provide colonization resistance against pathobionts, promote butyrate-producing bacteria, and produce AI-2, making it a promising candidate for promoting microbiota recovery. We hypothesize that manipulating AI-2 signaling with ARO112 can facilitate the recovery of the microbiota from antibiotic-induced dysbiosis.MicroDialuge’s main goal is to capitalize on the ability of ARO112, isolated by the host’s lab, to favor re-establishment of the Bacillota phylum while improving host immunity, via QS manipulation. To achieve this, we will manipulate the levels of AI-2 directly in the mouse gut using ARO112 WT and mutants already validated to assess the mechanistic effect of AI-2/ARO112 on axenic mice colonized with a defined microbiota. We will use metabolomics, and transcriptomics as part of a secondment at Jena University to reveal the molecular mechanisms involved in microbiota recovery. Additionally, we will test AI-2/ARO112-based therapies in mice colonized with a complex microbiota under antibiotic-induced dysbiosis. We will use CRISPR/Cas9 to modify ARO112 to track its colonization and flow cytometry to measure recovery of immune responses and inflammation. This research will expand our understanding of microbial QS and its potential to combat microbiota imbalances, with significant social and economic potential for human health by offering new strategies to mitigate the adverse effects of antibiotic use.