A central challenge in gut microbiome research is to understand how interactions between the individual microorganisms affect community assembly, dynamics and functionality. Gnotobiotic mice colonized with defined microbial communities have become essential tools to address this question. While a majority of studies uses human-derived bacteria, we have developed a model community consisting of twelve phylogenetically diverse bacteria isolated from mice. In addition, we have developed a comprehensive set of protocols and analysis tools, allowing us to study this community in its native murine host. This Oligo-Mouse-Microbiota (OMM12) is unique because it recapitulates central physiologic and functional traits of a complex mouse microbiome. Furthermore, the OMM12 exhibits long-term stability in gnotobiotic mice and its composition is reproducible among different animal facilities. Hence, this model is used by an increasing number of research groups world-wide.
Publications of resources and methods
Lamy-Besnier Q, Bignaud A, Garneau JR, Titecat M, Conti DE, Von Strempel A, Monot M, Stecher B, Koszul R, Debarbieux L, Marbouty M. Chromosome folding and prophage activation reveal specific genomic architecture for intestinal bacteria. Microbiome. 2023 May 19;11(1):111. doi: 10.1186/s40168-023-01541-x.
Brugiroux S, Berry D, Ring D, Barnich N, Daims H, Stecher B. Specific Localization and Quantification of the Oligo-Mouse-Microbiota (OMM12) by Fluorescence In Situ Hybridization (FISH). Curr Protoc. 2022 Sep;2(9):e548. doi: 10.1002/cpz1.548. PMID: 36094300
Eberl C, Ring D, Münch PC, Beutler M, Basic M, Slack EC, Schwarzer M, Srutkova D, Lange A, Frick JS, Bleich A, Stecher B. Reproducible Colonization of Germ-Free Mice With the Oligo-Mouse-Microbiota in Different Animal Facilities. Front Microbiol. 2020 Jan 10;10:2999.
Lagkouvardos I., Pukall R., Abt B., Foesel B.U., Meier-Kolthoff J.P., Kumar N., Bresciani A., Martínez I., Just S., Ziegler C., Brugiroux S., Garzetti D., Wenning M., Bui T.P., Wang J., Hugenholtz F., Plugge C.M., Peterson D.A., Hornef M.W., Baines J.F., Smidt H., Walter J., Kristiansen K., Nielsen H.B., Haller D., Overmann J., Stecher B., Clavel T. The Mouse Intestinal Bacterial Collection (miBC) provides host-specific insight into cultured diversity and functional potential of the gut microbiota. Nat Microbiol. 2016 Aug 8;1(10):16131. doi: 10.1038/nmicrobiol.2016.131. PMID: 27670113
A key challenge in microbiome research is to predict functionality of microbial communities based on community membership and (meta)-genomic data. As central microbiota functions are determined by bacterial community networks, it is important to gain insight into the principles that govern bacteria-bacteria interactions. Our well-characterized OMM12 model increasingly used to uncover various ecological phenomena of bacterial communities. We use bottom-up approaches to uncover the directionality of strain-strain interactions in mono- and pairwise co-culture experiments as well as in community batch culture. Metabolic network reconstruction in combination with metabolomics analysis of bacterial culture supernatants provides insights into the metabolic potential and activity of the individual community members. Thereby, we could show that the OMM12 interaction network is shaped by both exploitative and interference competition in vitro in nutrient-rich culture media and demonstrate how community structure can be shifted by changing the nutritional environment.
We studied how individual bacterial strains contribute to community formation, identified potential keystone species, and tested their effects in different environments. By removing one species at a time, we found that bacterial relationships change significantly depending on the region of the mouse gut and the type of culture medium used. Key mechanisms behind environment-specific keystone roles included exclusive use of certain sugars and production of bacteriocins (bacteria-killing compounds). Overall, our study shows that bacterial interactions depend heavily on both living (biotic) and non-living (abiotic) environmental factors. These findings challenge the idea of universal keystone species in the gut and emphasize that their roles and interactions are highly context-dependent.
Publications
Weiss AS, Niedermeier LS, von Strempel A, Burrichter AG, Ring D, Meng C, Kleigrewe K, Lincetto C, Hübner J, Stecher B. Nutritional and host environments determine community ecology and keystone species in a synthetic gut bacterial community. Nat Commun. 2023 Aug 8;14(1):4780. doi: 10.1038/s41467-023-40372-0.
Weiss, A.S., Burrichter, A., Durai Raj A.C., von Strempel A., Meng, C., Kleigrewe K., Münch P.C., Rössler L., Huber C., Eisenreich W., Jochum L.M., Göing S., Jung K., Lincetto C., Hübner J., Marinos G., Zimmermann, J., Kaleta C., Sanchez A., Stecher B. In vitro interaction network of a synthetic gut bacterial community. ISME (2022). doi: 10.1038/s41396-021-01153-z
In this project we use metabolic modelling, a mathematical strategy to calculate metabolite fluxes within cells, and metaproteomic data to understand the OMM12 metabolic network under different conditions. Metaproteomic data gives us a direct insight into the active part of the genomic potential that is expressed under different circumstances and reflects adaptation of bacteria to the biotic and abiotic environment. Mathematical strategies allow us to make predictions about metabolite flows that are not directly accessible to measure. We aim to generate context-specific models for OMM12 bacteria under in vitro and in vivo growth conditions and provide general access to them.
In the framework of “SPP2474: Illuminating gene functions in the human gut microbiome“: We also investigate the mechanisms underlying keystone functions in the gut. The gut microbiota is highly spatially structured, with microbes clustering in different gut regions, around dietary particles or within the host's mucus layer. This spatial organization is believed to cause different context-dependent ecological patterns by shaping microbial interactions. To address this, we will combine the OMM12 model with spatial cultivation methods and high throughput metaproteomics and metabolomics analysis. From generated data, we will uncover unknown gene functions and improve the functional annotation of understudied bacterial genomes using protein covariation analyses based on the generated data.
Defined communities to study the human neonatal gut microbiota: Building on our expertise, we now aim to generate a synthetic community to model the human neonatal gut microbiota (NeoSyn). The microbiota plays a crucial role in various aspects of early development and health. NeoSyn is intended to mimic the highly variable neonatal gut microbiome both functionally and taxonomically. The variations in the neonatal gut microbiome are driven by many different factors, such as the mode of delivery, the type of feeding or the use of medication (especially antibiotics). Using MiMiC (Kumar et al. 2021), a tool which aids the design of minimal microbial consortia based on the functional potential identified in a given metagenomic sample, we designed different variants of NeoSyns to mimic an infant's microbiota of vaginally-born and caesarean-born infants. This core composition can be complemented with additional species of interest to perform research specific experiments.