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Intermicrobial and host-microbial interactions that determine the trajectory of mammalian microbial colonization in early life

Applicant Macpherson Andrew
Number 177164
Funding scheme Sinergia
Research institution Universität Bern
Institution of higher education University of Berne - BE
Main discipline Interdisciplinary
Start/End 01.05.2018 - 30.04.2022
Approved amount 2'792'796.00
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All Disciplines (3)

Discipline
Interdisciplinary
Immunology, Immunopathology
Experimental Microbiology

Keywords (7)

colonisation; metabolome; metabolic flux analysis; gnotobiology; computational modelling; microbiota; neonate

Lay Summary (German)

Lead
Prof. Andrew Macpherson
Lay summary

Menschen und andere Säugetiere leben mit einer beachtlichen Anzahl an gutartigen Bakterien im Darm und auf anderen Körperoberflächen (die Mikrobiota). Diese gutartigen Bakterien schaden uns nicht, sondern helfen uns bei der Verdauung, versorgen uns mit wichtigen Nährstoffen und verhindern, dass krankheitserregende Bakterien in unseren Körper gelangen. Die Körperoberflächen von Babys sind bei der Geburt noch frei von Mikroben, werden aber direkt nach der Geburt besiedelt (meistens von Bakterien, die auch im Geburtskanal der Mutter zu finden sind). In Neugeborenen ist die Bakterienpopulation noch sehr instabil, mit verschiedenen Spezies, die in einer zeitlich bestimmten Abfolge erscheinen, bis im Laufe der ersten Jahre eine relativ stabile Zusammensetzung erreicht wird. Wie die genaue Entwicklung der Mikrobiota in frühen Jahren genau verläuft ist bisher unbekannt. Dies ist jedoch wichtig, da Unterernährung und schlechte Entwicklung die Folge von einer Mikrobiota sein können, die nicht richtig reifen kann.

In diesem Projekt werden wir die Mechanismen untersuchen, die dazu führen, dass verschiedene Arten von Mikroben einander bei neugeborenen Mäusen in ihrer Präsenz folgen. Die Arbeit wird das Manipulieren der möglichen Abfolgen bei Mäusen, das Bestimmen der verschiedenen Chemikalien, die zwischen verschiedenen Arten von Mikroben und dem Tier, in dem sie leben, ausgetauscht werden, sowie das Definieren derjenigen Gene, die von den Mikroben exprimiert werden müssen, um Kolonisierung in verschiedenen Stadien zu erreichen, umfassen.

Ziel ist es, den Prozess gut genug zu verstehen, um ihn mit Computern zu simulieren und vorherzusagen, wie wir die Abfolge der Mikroben in Bezug auf die menschliche Gesundheit manipulieren können.

Direct link to Lay Summary Last update: 16.01.2018

Responsible applicant and co-applicants

Employees

Publications

Publication
Co‐catabolism of arginine and succinate drives symbiotic nitrogen fixation
Flores‐Tinoco Carlos Eduardo, Tschan Flavia, Fuhrer Tobias, Margot Céline, Sauer Uwe, Christen Matthias, Christen Beat (2020), Co‐catabolism of arginine and succinate drives symbiotic nitrogen fixation, in Molecular Systems Biology, 16(6), 9419.
Antibodies Set Boundaries Limiting Microbial Metabolite Penetration and the Resultant Mammalian Host Response
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.

Associated projects

Number Title Start Funding scheme
183501 Installing a Hyperion CyTOF mass cytometry platform for high-dimensional single cell analysis at the University of Bern 01.10.2019 R'EQUIP

Abstract

Background:Development of the young mammal is punctuated by the life-events of birth and weaning. Between these is the intimate period of lactation, where the mother provides her offspring with nutrition, immune memory and innate protection from pathogens, whilst an ecological succession of microbes colonizes the open niches of the neonate. This is a time of great instability of the microbial consortia, yet their composition and function has immediate and long-term consequences for health. The successive microbial trajectory is intimately linked with nutrition and multidimensional microbial-host interactions, yet undernutrition cannot be ascribed solely to food insecurity and the mechanisms involved are acknowledged to be very poorly understood at a molecular level (1). It is also argued that knowledge of the details of microbial consortial formation as a starting-point for rational manipulation is one of the major unmet biomedical needs of our time (1, 2). Goals of the project and novel transdisciplinary approach: In this application, we will leverage gnotobiotic, metabolomic, genomic and computational approaches extending a proven transdisciplinary partnership to interrogate precisely controlled models of early-life intestinal microbial succession, to dissect out the different factors of host-microbial multidimensionality, and to identify specific nutritional factors that determine microbial performance in each niche. Our approach will be powered to define the microbial and host mechanisms involved for individual microbes with the objective of developing generalizable rules that can be tested for different combinations of microbial consortia.Overview of the research application: We will start from a high-resolution definition of the microbial and metabolome environment in different niches of the mouse intestine over the neonatal and suckling trajectory. This will be done under established conditions of a highly-stable gnotobiotic microbiota of 12 fully-sequenced members representative of early life consortia where the milk composition can be controlled according to the maternal strain. In-vivo replication/contraction rates of individual members and their transcriptomic profiles will be assessed across different intestinal niches and time, using metagenomic and metatranscriptomic techniques. To identify essential metabolic pathways involved in the blooms and contractions of specific microbes during the succession, we will use transposon mutagenesis to interrogate critical microbial pathways in gnotobiotic mice and combine this with the metabolomics data for predictive computational genome-scale modelling to generate hypotheses on species-specific metabolism and pathway redundancy. Key predictions will be tested in defined culture combinations and by stable isotope tracing in vivo. Biomedical impact: By understanding high-resolution niche-specific metabolic interactions and windows of opportunity for microbial immigration and flexible consortia formation during succession we can start to formulate specific models as well as general rules that provide a framework for translational manipulation of the early-life microbiota. This has the potential to benefit colonization resistance against pathobionts and energy available for the host.
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