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

Descripción del proyecto

Recuperar la salud intestinal tras el uso de antibióticos

El uso excesivo de antibióticos altera la microbiota intestinal, sobre todo en el filo Bacillota. Ello aumenta la susceptibilidad a microorganismos patógenos y contribuye al desarrollo de obesidad y diabetes, así como de otros trastornos metabólicos. En el proyecto MicroDialogue, financiado con fondos europeos, se evaluará el papel de la detección de cuórum, en concreto del autoinductor-2 (AI-2), en el restablecimiento del equilibrio de la microbiota intestinal tras alteraciones inducidas por antibióticos. La investigación se centrará en un nuevo comensal murino,«Klebsiella» sp. ARO112 no neumónica, que puede conferir resistencia frente a microorganismos patógenos, favorecer las bacterias productoras de butirato y producir AI-2. También se evaluarán tratamientos basados en AI-2/ARO112 en ratones con una microbiota compleja afectada por disbiosis, y se empleará la tecnología CRISPR/Cas9 para analizar la colonización y medir las respuestas inmunitarias y la inflamación.

Objetivo

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.