intestinal inflammation; commensal microbial mutualism; metabolite flux; microbiota; germ free; isobiotic; colonisation resistance; animal models; gnotobiotic ; metabolomics; mucosal immunity; Salmonella typhimurium
Hausmann Annika, Böck Desirée, Geiser Petra, Berthold Dorothée L., Fattinger Stefan A., Furter Markus, Bouman Judith A., Barthel-Scherrer Manja, Lang Crispin M., Bakkeren Erik, Kolinko Isabel, Diard Médéric, Bumann Dirk, Slack Emma, Regoes Roland R., Pilhofer Martin, Sellin Mikael E., Hardt Wolf-Dietrich (2020), Intestinal epithelial NAIP/NLRC4 restricts systemic dissemination of the adapted pathogen Salmonella Typhimurium due to site-specific bacterial PAMP expression, in Mucosal Immunology
, 13(3), 530-544.
Wotzka Sandra Y., Kreuzer Markus, Maier Lisa, Arnoldini Markus, Nguyen Bidong D., Brachmann Alexander O., Berthold Dorothée L., Zünd Mirjam, Hausmann Annika, Bakkeren Erik, Hoces Daniel, Gül Ersin, Beutler Markus, Dolowschiak Tamas, Zimmermann Michael, Fuhrer Tobias, Moor Kathrin, Sauer Uwe, Typas Athanasios, Piel Jörn, Diard Médéric, Macpherson Andrew J., Stecher Bärbel, Sunagawa Shinichi, et al. (2019), Escherichia coli limits Salmonella Typhimurium infections after diet shifts and fat-mediated microbiota perturbation in mice, in Nature Microbiology
, 4(12), 2164-2174.
Bansept Florence, Schumann-Moor Kathrin, Diard Médéric, Hardt Wolf-Dietrich, Slack Emma, Loverdo Claude (2019), Enchained growth and cluster dislocation: A possible mechanism for microbiota homeostasis, in PLOS Computational Biology
, 15(5), e1006986-e1006986.
Furter Markus, Sellin Mikael E., Hansson Gunnar C., Hardt Wolf-Dietrich (2019), Mucus Architecture and Near-Surface Swimming Affect Distinct Salmonella Typhimurium Infection Patterns along the Murine Intestinal Tract, in Cell Reports
, 27(9), 2665-2678.e3.
Wotzka Sandra Y., Kreuzer Markus, Maier Lisa, Zünd Mirjam, Schlumberger Markus, Nguyen Bidong, Fox Mark, Pohl Daniel, Heinrich Henriette, Rogler Gerhard, Biedermann Luc, Scharl Michael, Sunagawa Shinichi, Hardt Wolf-Dietrich, Misselwitz Benjamin (2018), Microbiota stability in healthy individuals after single-dose lactulose challenge—A randomized controlled study, in PLOS ONE
, 13(10), e0206214-e0206214.
Uchimura Yasuhiro, Fuhrer Tobias, Li Hai, Lawson Melissa A., Zimmermann Michael, Yilmaz Bahtiyar, Zindel Joel, Ronchi Francesca, Sorribas Marcel, Hapfelmeier Siegfried, Ganal-Vonarburg Stephanie C., Gomez de Agüero Mercedes, McCoy Kathy D., Sauer Uwe, Macpherson Andrew J. (2018), Antibodies Set Boundaries Limiting Microbial Metabolite Penetration and the Resultant Mammalian Host Response, in Immunity
, 49(3), 545-559.e5.
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.
Miki Tsuyoshi, Okada Nobuhiko, Hardt Wolf-Dietrich (2017), Inflammatory bactericidal lectin RegIIIβ: Friend or foe for the host?, in Gut Microbes
, 9(2), 179-187.
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
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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.
Wotzka Sandra Y., Nguyen Bidong D., Hardt Wolf-Dietrich (2017), Salmonella Typhimurium Diarrhea Reveals Basic Principles of Enteropathogen Infection and Disease-Promoted DNA Exchange, in Cell Host & Microbe
, 21(4), 443-454.
Diard Médéric, Bakkeren Erik, Cornuault Jeffrey K., Moor Kathrin, Hausmann Annika, Sellin Mikael E., Loverdo Claude, Aertsen Abram, Ackermann Martin, De Paepe Marianne, Slack Emma, Hardt Wolf-Dietrich (2017), Inflammation boosts bacteriophage transfer between Salmonella spp., in Science
, 355(6330), 1211-1215.
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.
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.
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.
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.
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
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Macpherson Andrew J, McCoy Kathy D (2015), Independence Day for IgA., in Immunity
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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
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Macpherson A J, McCoy K D (2015), Standardised animal models of host microbial mutualism., in Mucosal immunology
, 8(3), 476-86.
Macpherson Andrew J, Köller Yasmin, McCoy Kathy D (2015), The bilateral responsiveness between intestinal microbes and IgA., in Trends in immunology
, (8), 460-70.
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.
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.
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.