Function-Based Selection of Synthetic Communities Enables Mechanistic Microbiome Studies

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Summary Understanding the complex interactions between microbes and their environment requires robust model systems such as synthetic communities (SynComs). We developed a functionally directed approach to generate SynComs by selecting strains that encode key functions identified in metagenomes. This approach enables the rapid construction of SynComs tailored to any ecosystem. To optimize community design, we implemented genome-scale metabolic models, providing in silico evidence for cooperative strain coexistence prior to experimental validation. Using this strategy, we designed multiple host-specific SynComs, including those for the rumen, mouse, and human microbiomes. By weighting functions differentially enriched in diseased versus healthy individuals, we constructed SynComs that capture complex host-microbe interactions. Notably, we designed an inflammatory bowel disease SynCom of 10 members that successfully induced colitis in gnotobiotic IL10 -/- mice, demonstrating the potential of this method to model disease-associated microbiomes. Our study establishes a targeted framework for designing SynComs to advance mechanistic insights into host-microbe interactions. Highlights Automated functional selection of SynComs based on metagenomic data Ecosystem-specific SynComs capture the functional landscape of microbiota Colitis-inducing SynCom developed as a model for inflammatory bowel diseases

Authors 9

1. Thomas C. A. Hitch corresponding Aachen Functional Microbiome Research Group Institute of Medical Microbiology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH Aachen, Aachen, Germany

2. Silvia Bolsega

   Medizinische Hochschule Hannover

   Affiliation as printed

   Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany

   MHH - Medizinische Hochschule Hannover = Hannover Medical School (Carl-Neuberg-Straße 1, 30625 Hannover, - Germany)

3. Charlotte Deschamps

   Université Clermont Auvergne · Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement · Microbiologie Environnement Digestif Santé

   Affiliation as printed

   UMR 454 MEDIS, Microbiologie Environnement Digestif et Santé, Université Clermont Auvergne – INRAE, Clermont-Ferrand, France

   MEDIS - Microbiologie Environnement Digestif Santé (Site INRAE Theix : 63122 Saint-Gènes-Champanelle // Site Clermont : CBRV, TSA 50400, 28 Place Henri Dunant 63001 Clermont-Ferrand - France)

4. Lucie Etienne‐Mesmin

   Université Clermont Auvergne · Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement · Microbiologie Environnement Digestif Santé

   Affiliation as printed

   UMR 454 MEDIS, Microbiologie Environnement Digestif et Santé, Université Clermont Auvergne – INRAE, Clermont-Ferrand, France

   MEDIS - Microbiologie Environnement Digestif Santé (Site INRAE Theix : 63122 Saint-Gènes-Champanelle // Site Clermont : CBRV, TSA 50400, 28 Place Henri Dunant 63001 Clermont-Ferrand - France)

5. Nicole Simone Treichel Aachen Functional Microbiome Research Group Institute of Medical Microbiology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH Aachen, Aachen, Germany

   RWTH Aachen - RWTH Aachen University = Rheinisch-Westfälische Technische Hochschule Aachen (RWTH Aachen – Templergraben 55 – 52062 Aachen (Hausanschrift) – 52056 Aachen (Postanschrift) – Deutschland - Germany)

6. Stéphanie Blanquet‐Diot

   Université Clermont Auvergne · Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement · Microbiologie Environnement Digestif Santé

   Affiliation as printed

   UMR 454 MEDIS, Microbiologie Environnement Digestif et Santé, Université Clermont Auvergne – INRAE, Clermont-Ferrand, France

   MEDIS - Microbiologie Environnement Digestif Santé (Site INRAE Theix : 63122 Saint-Gènes-Champanelle // Site Clermont : CBRV, TSA 50400, 28 Place Henri Dunant 63001 Clermont-Ferrand - France)

7. Soeren Ocvirk

   German Institute of Human Nutrition · Technical University of Munich

   Affiliation as printed

   Intestinal Microbiology Research Group, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany

   ZIEL – Institute for Food and Health, Technical University of Munich, Freising, Germany

8. Marijana Basic

   Medizinische Hochschule Hannover

   Affiliation as printed

   Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany

   MHH - Medizinische Hochschule Hannover = Hannover Medical School (Carl-Neuberg-Straße 1, 30625 Hannover, - Germany)

9. Thomas Clavel Aachen Functional Microbiome Research Group Institute of Medical Microbiology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH Aachen, Aachen, Germany

   UKA - Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (Universitätsklinikum Aachen, AöR - Pauwelsstraße 30 - 52074 Aachen - Germany)