Informed ecological rewiring of gut microbiome for dysbiosis-associated disorders

Descripción del proyecto

Tratamiento del microbioma de precisión para trastornos asociados a la disbiosis

Los trastornos asociados a la disbiosis se deben a la alteración del microbioma intestinal. Sin embargo, los tratamientos existentes no están dirigidos y son ineficaces. El equipo del proyecto MicroRestore, financiado por el CEI, pretende demostrar que el recableado ecológico del microbioma intestinal basado en el metagenoma es prometedor como tratamiento de los trastornos asociados a la disbiosis, demostrando su eficacia en el síndrome del colon irritable posinfeccioso (SCI-PI). En el proyecto se incluirán estudios observacionales, «in silico», «in vitro» e «in vivo». Se establecerán poblaciones de microbios diana en pacientes, se simularán estrategias de recuperación y se evaluarán tratamientos microbianos utilizando simuladores intestinales o ratones. Si tiene éxito, el tratamiento se validará mediante un estudio aleatorizado en pacientes con SCI-PI. El objetivo es llevar la medicina del microbioma del laboratorio a la cabecera del paciente.

Objetivo

Gut microbiome disruption contributes to the so-called “dysbiosis-associated disorders”. Although the interindividual variability and plasticity of microbiome support its precise modulation, to date only untargeted treatments are available, mostly with inconsistent results. My preliminary data hint that tailored microbial therapy, guided by microbiome profiling, may improve post-infectious irritable bowel syndrome (PI-IBS), a common but understudied dysbiosis-associated disease.
MicroRestore aims to prove that metagenome-informed ecological rewiring of gut microbiome can improve dysbiosis-associated disorders, using PI-IBS as disease model. I will apply a comprehensive multimodal approach, moving from observational/in-silico data to experimental in-vitro and in-vivo outputs to clinical validation. In Aim1 I will assess the microbiome of PI-IBS patients, identify target taxa by machine learning, build ecological models to predict recovery strategies (e.g. competition, pathobiont suppression, antagonism, mutualism, symbiont growth, full rewiring). Based on such strategies, in Aim2 I will use a gut simulator to test the effect of microbial therapeutics (antibiotics, prebiotics, microbial consortia, targeted fecal transplant) on patient microbiota, narrowing them down to build an ecological framework for microbial restoration. In parallel I will rig up known PI-IBS mouse models by colonizing germ-free and C. rodentium-infected mice with patient microbiota or target taxa. Then I will test down-selected interventions in such mice. In Aim3 I will validate this metagenome-informed, targeted framework for microbiome rewiring in a randomized trial of PI-IBS patients. My strategy may offer a notable clinical benefit to PI-IBS and other dysbiosis-associated diseases. By developing an innovative ecological approach for microbial therapy, MicroRestore will promote a microbiome-based precision medicine, filling the knowledge gap between science and clinical practice in this field