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The Host-Microbial Superorganism

English title The Host-Microbial Superorganism
Applicant Macpherson Andrew
Number 154414
Funding scheme Sinergia
Research institution Universität Bern
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.01.2015 - 31.12.2017
Approved amount 2'253'291.00
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Keywords (12)

intestinal inflammation; commensal microbial mutualism; metabolite flux; microbiota; germ free; isobiotic; colonisation resistance; animal models; gnotobiotic ; metabolomics; mucosal immunity; Salmonella typhimurium

Lay Summary (German)

Lead
Der Darm des Menschen enthält eine grosse Zahl von Mikroorganismen ("Mikrobiota"). Fortschritte in der analytischen Technik haben gezeigt, dass sich diese Mikrobiota aus 500-1000 verschiedenen Bakterienarten zusammensetzt. Die Zusammensetzung der Mikrobiota scheint grossen Einfluss auf die Verdauung zu haben und beeinflusst überraschender Weise auch auf die Reifung des Immunsystems, Autoimmunerkrankungen, entzündliche Darmerkrankungen, die Krebsenstehung und das "metabolische Syndrom".
Lay summary

Die kausalen Zusammenhänge konnten allerdings aufgrund der genetischen Heterogenität der Patienten, der Variabilität in der Mikrobiotazusammensetzung und der schieren Komplexität dieses 1000+1 Partner-Systems nicht schlüssig belegt werden. Deshalb hat das Sinergia Projekt " The Host-Microbial Superorganism " einen radikal anderen Ansatz gewählt. Hier werden genetisch identische Mäuse mit wenigen, dafür aber komplett definierten Stämmen der Darmmikrobiota stabil assoziiert. Diese "stable defined moderately diverse microbiota" (sDMDM) Mäuse stellen ein ideales Untersuchungsobjekt dar, weil das System genetisch homogen ist, weil jedes Individuum dieselbe Mikrobiota enthält und weil die vereinfachte Zusammensetzung detaillierte molekulare Analysen ermöglicht. Diese sDMDM Tiere werden nun eingesetzt um zu untersuchen wie die Mikrobiota-Bakterien Nährstoffe mit dem Wirt austauschen, wie sich das auf entzündliche Darmerkrankungen auswirkt und wie die Mikrobiota den Wirt vor Infektionen mit Krankheitserregern schützt.

Direct link to Lay Summary Last update: 16.12.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Divergent Roles of Interferon-γ and Innate Lymphoid Cells in Innate and Adaptive Immune Cell-Mediated Intestinal Inflammation
Brasseit Jennifer, Kwong Chung Cheong K. C., Noti Mario, Zysset Daniel, Hoheisel-Dickgreber Nina, Genitsch Vera, Corazza Nadia, Mueller Christoph (2018), Divergent Roles of Interferon-γ and Innate Lymphoid Cells in Innate and Adaptive Immune Cell-Mediated Intestinal Inflammation, in Frontiers in Immunology, 9, 1.
High-Quality Whole-Genome Sequences of the Oligo-Mouse-Microbiota Bacterial Community
Garzetti Debora, Brugiroux Sandrine, Bunk Boyke, Pukall Rüdiger, McCoy Kathy D., Macpherson Andrew J., Stecher Bärbel (2017), High-Quality Whole-Genome Sequences of the Oligo-Mouse-Microbiota Bacterial Community, in Genome Announcements, 5(42), e00758-17-e00758-17.
How nutrition and the maternal microbiota shape the neonatal immune system
Macpherson Andrew J., de Agüero Mercedes Gomez, Ganal-Vonarburg Stephanie C. (2017), How nutrition and the maternal microbiota shape the neonatal immune system, in Nature Reviews Immunology, 17(8), 508-517.
IFN-γ Hinders Recovery from Mucosal Inflammation during Antibiotic Therapy for Salmonella Gut Infection
Dolowschiak Tamas, Mueller Anna Angelika, Pisan Lynn Joanna, Feigelman Rounak, Felmy Boas, Sellin Mikael Erik, Namineni Sukumar, Nguyen Bidong Dinh, Wotzka Sandra Yvonne, Heikenwalder Mathias, von Mering Christian, Mueller Christoph, Hardt Wolf-Dietrich (2016), IFN-γ Hinders Recovery from Mucosal Inflammation during Antibiotic Therapy for Salmonella Gut Infection, in Cell Host & Microbe, 20(2), 238-249.
Our Mothers' Antibodies as Guardians of our Commensals.
Ganal-Vonarburg Stephanie C., Macpherson Andrew J. (2016), Our Mothers' Antibodies as Guardians of our Commensals., in Trends in Molecular Medicine, 22(9), 739-741.
The Liver at the Nexus of Host-Microbial Interactions.
Macpherson Andrew J., Heikenwalder Mathias, Ganal-Vonarburg S.C. (2016), The Liver at the Nexus of Host-Microbial Interactions., in Cell Host&Microbe, 20(5), 561-571.
The maternal microbiota drives early postnatal innate immune development.
Gomez de Agüero Mercedes, Ganal-Vonarburg Stephanie C., McCoy Kathy D., Macpherson Andrew J. (2016), The maternal microbiota drives early postnatal innate immune development., in Science, 1296-302(351), 1296-1302.
CD4 T cells are required for both development and maintenance of disease in a new mouse model of reversible colitis.
Brasseit J, Althaus-Steiner E, Faderl M, Dickgreber N, Saurer L, Genitsch V, Dolowschiak T, Li H, Finke D, Hardt W-D, McCoy K D, Macpherson A J, Corazza N, Noti M, Mueller C (2015), CD4 T cells are required for both development and maintenance of disease in a new mouse model of reversible colitis., in Mucosal immunology, (Sept 16), Epub.
Independence Day for IgA.
Macpherson Andrew J, McCoy Kathy D (2015), Independence Day for IgA., in Immunity, 43(3), 416-8.
Penetrability of the inner mucus layer: who is out there?
Li Hai, Limenitakis Julien P, Ganal Stephanie C, Macpherson Andrew J (2015), Penetrability of the inner mucus layer: who is out there?, in EMBO reports, 16(2), 127-9.
Standardised animal models of host microbial mutualism.
Macpherson A J, McCoy K D (2015), Standardised animal models of host microbial mutualism., in Mucosal immunology, 8(3), 476-86.
The bilateral responsiveness between intestinal microbes and IgA.
Macpherson Andrew J, Köller Yasmin, McCoy Kathy D (2015), The bilateral responsiveness between intestinal microbes and IgA., in Trends in immunology, 36(8), 460-70.
The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation.
Zaiss Mario M, Rapin Alexis, Lebon Luc, Dubey Lalit Kumar, Mosconi Ilaria, Sarter Kerstin, Piersigilli Alessandra, Menin Laure, Walker Alan W, Rougemont Jacques, Paerewijck Oonagh, Geldhof Peter, McCoy Kathleen D, Macpherson Andrew J, Croese John, Giacomin Paul R, Loukas Alex, Junt Tobias, Marsland Benjamin J, Harris Nicola L (2015), The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation., in Immunity, 43(5), 998-1010.
The outer mucus layer hosts a distinct intestinal microbial niche.
Li Hai, Limenitakis Julien P, Fuhrer Tobias, Geuking Markus B, Lawson Melissa A, Wyss Madeleine, Brugiroux Sandrine, Keller Irene, Macpherson Jamie A, Rupp Sandra, Stolp Bettina, Stein Jens V, Stecher Bärbel, Sauer Uwe, McCoy Kathy D, Macpherson Andrew J (2015), The outer mucus layer hosts a distinct intestinal microbial niche., in Nature communications, 6, 8292-8292.

Collaboration

Group / person Country
Types of collaboration
Swiss IBD Cohort Study PI: Gerhard Rogler, Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Mathias Heikenwälder (University of Munich, Germany) Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Bärbel Stecher (University of Munich, Germany) Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Jens Stein (TKI, University of Bern) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Christian von Mering (Institute of Molecular Life Sciences, UZH) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Jörg Stelling (Computer Science, ETH Basel) Switzerland (Europe)
- Publication
Prof. Manfred Kopf (ETH, Zürich) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. Rudolph Aebersold (ETH, Zürich) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Awards

Title Year
Bern Immunologie Club "Best Paper of the year 2016" 2017
Pfizer Research Prize Immunology 2017
Swiss Society for Gastroenterology Award 2016

Associated projects

Number Title Start Funding scheme
170084 Intestinal tissue resident memory T cells in inflammation and homeostasis 01.11.2016 Project funding (Div. I-III)
173338 Deciphering the initial steps that lead to Salmonella Typhimurium diarrhea 01.05.2017 Project funding (Div. I-III)
160262 Secretory IgA in host-microbial reciprocity 01.04.2015 Project funding (Div. I-III)
189277 Relapsing-remitting intestinal inflammation: the contribution of resident immune cells 01.11.2019 Project funding (special)

Abstract

Background. Humans and other animals coexist with ten times more microbes within the gastrointestinal tract and on other surfaces than there are cells in their bodies. Our tenet is that this mutualistic relationship must biomedically be considered as a host-microbial superorganism. Experiments with germ-free mice show that whilst mammalian life without commensal microbes is possible, it certainly is not normal. Comparison of germ-free and colonized animals by modern metabolomics methods shows that the effects of commensal microbes on the integration of microbial and host metabolism are pervasive throughout all body systems. There is good evidence from human and animal studies that commensal microbes shape human health, especially the susceptibility to allergy, autoimmunity, inflammatory bowel disease, neoplasia, heart disease, metabolic syndrome, obesity and hypertension. The human microbiota is extremely complex with over 1000 taxonomic variants: despite amazing insights into gene content and microbial metabolic gene frequencies, the human host is both genetically polymorphic AND there are inter- and intra-individual differences in microbial frequencies in the consortia. To understand gene-function relationships across the superorganism we need animal models standardised both in the host germline (isogenic) and for the microbiota (isobiotic). The problem facing biomedical science is that our current animal models fail to model the host-microbial superorganism accurately and reproducibly. Many vivaria have only an approximate knowledge of the diversity of the complex commensal microbiota in their animals, or very simple microbiotas (such as ASF) are unrepresentative of a natural situation. Objectives and Plan. The unique starting point for our research is a world-class facility to maintain defined microbiotas of different complexity in mice. We will extend our current gnotobiotic mouse strains with stable defined moderately diverse microbiota (sDMDM) to 4 lines (with up to 30 culturable fully sequenced microbial species, differently composed in each line) that fulfil a series of criteria of 'normality': specifically, the host-microbial metabolic interchange, immune system composition and the susceptibility to infectious and immune diseases will phenocopy animals with a diverse microbiota. These isobiotic microbiotas (where every animal carries an identical microbial consortium) can easily be converted between different mouse strains that have a defined genetic background (knockouts/transgenics) through experimental embryo transfer. This opens up standardised experiments in over 20'000 genetical strains of mice.We will move beyond ' who is there' to exploit the powerful tool of isobiotic animals through three types of functional assessment of the host-microbial handshake at a molecular level. 1. To follow how the metabolites and metabolic fluxes transit between microbes and the host, and how they originate from the metabolic contribution of particular members of the microbiota. 2. To define how susceptibility to disease models (intestinal inflammatory disease and autoimmunity) depends on the composition of the microbiota, and how this can be explained in terms of the metabolic activity of the microbes present. 3. How the normal community of microbes in the intestine exchanges molecules and limits the ability of a bacterial pathogen to flourish or to invade the body.Impact. The microbiota provides 'our other genome' and 90% of the cells in our bodies. Through the development of systems in which the impact of the prokaryotic part of the superorganism can be systematically understood in molecular terms - according to individual microbial members - we will overcome the overwhelming multidimensionality for later human research. Our outlook is to exploit these effects to benefit human health by rational microbial manipulation, to treat disease and obviate disease susceptibility.
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