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Bacteria-host interactions through bile acid 7-dehydroxylation

Applicant Hapfelmeier Siegfried
Number 180317
Funding scheme Sinergia
Research institution Institut für Infektionskrankheiten Universität Bern
Institution of higher education University of Berne - BE
Main discipline Interdisciplinary
Start/End 01.09.2018 - 31.08.2022
Approved amount 2'988'167.00
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All Disciplines (7)

Discipline
Interdisciplinary
Endocrinology
Physiology : other topics
Medical Microbiology
Molecular Biology
Clinical Nutritional Research
Experimental Microbiology

Keywords (12)

intestinal infection; intestinal homeostasis; spore germination; gnotobiotic mouse; bile acids; commensal organisms; metagenome; Clostridium scindens; human gut; obesity; 7-dehydroxylation; bile acid receptors

Lay Summary (German)

Lead
Durch die Produktion sekundärer Gallensäuren mit hormonähnlicher Funktion reguliert eine bislang nur oberflächlich charakterisierte Gruppe anaerober Dickdarmbakterien den menschlichen Stoffwechsel und das Immunsystem. Diese Forschungskooperation hat sich zum Ziel gesetzt die zugrundeliegenden biologischen Mechanismen aufzuklären.
Lay summary

Inhalt und Ziele des Forschungsprojekts 

Gallensäuren werden in der Leber als sogenannte primäre Gallensäuren produziert und in den Zwölffingerdarm sezerniert. Im Darm werden sie von verschiedenen Mikroorganismen in eine Vielzahl sekundärer Gallensäuren umgewandelt. Eine kleine Gruppe anaerober Dickdarmbakterien katalysieren die wohl bedeutendste dieser Reaktionen, die sogenannte 7-Dehydroxylierung. 7-dehydroxylierte Gallensäuren regulieren über spezifische Gallensäurerezeptoren unter anderem den menschlichen Energiestoffwechsel und Zellen des Immunsystems. Antibiotikatherapien, Fehlernährung und andere Faktoren, die die Besiedelung mit den nötigen Darmbakterien negativ beeinflussen, stehen unter dem Verdacht diesen wichtigen biochemischen Dialog zwischen Mensch und Mikroben zu stören, und dadurch die Entstehung von Fettleibigkeit, Diabetes, Atherosklerose und Darminfektionen zu begünstigen. Das Projekt hat zum Ziel die biologische Diversität und molekulare Mikrobiologie der 7-dehydroxylierenden Spezies im Darmökosystem besser zu charakterisieren. Ausserdem sollen die ursächlichen mechanistischen Zusammenhänge zwischen Störungen der Besiedelung mit 7-Dehydroxylieredenden Bakterien und Störungen des Energiestoffwechsels in Diabetes und Dickleibigkeit sowie des Immunsystems aufgeklärt werden. 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts 

Das Projekt dient der Grundlagenforschung und soll Wege aufzeigen wie bakterielle 7-Dehydroxylierung therapeutisch genutzt oder günstig beeinflusst werden könnte. Durch ein genaues Verständnis der zugrundeliegenden Biologie soll der Weg für künftige medizinische Anwendungen geebnet werden. 

Direct link to Lay Summary Last update: 30.07.2018

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Biogeography of microbial bile acid transformations along the murine gut
Marion Solenne, Desharnais Lyne, Studer Nicolas, Dong Yuan, Notter Matheus D., Poudel Suresh, Menin Laure, Janowczyk Andrew, Hettich Robert L., Hapfelmeier Siegfried, Bernier-Latmani Rizlan (2020), Biogeography of microbial bile acid transformations along the murine gut, in Journal of Lipid Research, 61(11), 1450-1463.
Molecular Physiology of Bile Acid Signaling in Health, Disease and Aging
Perino Alessia, Demagny Hadrien, Velazquez-Villegas Laura Alejandra, Schoonjans Kristina (2020), Molecular Physiology of Bile Acid Signaling in Health, Disease and Aging, in Physiological Reviews, physrev.00-physrev.00.
Generation of a fully erythromycin-sensitive strain of Clostridioides difficile using a novel CRISPR-Cas9 genome editing system
Ingle Patrick, Groothuis Daphne, Rowe Peter, Huang He, Cockayne Alan, Kuehne Sarah A., Jiang Weihong, Gu Yang, Humphreys Christopher M., Minton Nigel P. (2019), Generation of a fully erythromycin-sensitive strain of Clostridioides difficile using a novel CRISPR-Cas9 genome editing system, in Scientific Reports, 9(1), 8123-8123.
A novel conjugal donor strain for improved DNA transfer into Clostridium spp.
Woods Craig, Humphreys Christopher M., Rodrigues Raquel Mesquita, Ingle Patrick, Rowe Peter, Henstra Anne M., Köpke Michael, Simpson Sean D., Winzer Klaus, Minton Nigel P. (2019), A novel conjugal donor strain for improved DNA transfer into Clostridium spp., in Anaerobe, 59, 184-191.
In vitro and in vivo characterization of Clostridium scindens bile acid transformations
Marion Solenne, Studer Nicolas, Desharnais Lyne, Menin Laure, Escrig Stéphane, Meibom Anders, Hapfelmeier Siegfried, Bernier-Latmani Rizlan (2019), In vitro and in vivo characterization of Clostridium scindens bile acid transformations, in Gut Microbes, 10(4), 481-503.

Collaboration

Group / person Country
Types of collaboration
Emma Slack, ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Keystone Symposia on “Diabetes: glucose control and beyond” Talk given at a conference -to be updated- 27.01.2020 Santa Fe, New Mexico, United States of America Schoonjans Kristina;
Symposium Karolinska Institute “Molecular and Physiological Aspects of Diabetes and Obesity” Talk given at a conference -to be updated- 13.11.2019 Stockholm, Sweden Schoonjans Kristina;
Marabou Symposium on Nutrition and Stem Cell Integrity in Ageing Talk given at a conference -to be updated- 14.06.2019 Stockholm, Sweden Schoonjans Kristina;
Keystone Conferences: Microbiome: chemical mechanism and biological consequences Talk given at a conference Microbial bile acid transformation in vitro and in vivo 10.03.2019 Montreal, Canada Marion Solenne Anne Marie; Hapfelmeier Siegfried; Bernier-Latmani Rizlan;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Bile acids boost gut regeneration EPFL News International 2020
Media relations: print media, online media Fünf neue Sinergia-Projekte in Bern Universität Bern Media Relations German-speaking Switzerland International 2018

Associated projects

Number Title Start Funding scheme
160798 LRH-1, HCF-1, and MAF1 in liver metabolism, regeneration, and cancer 01.08.2015 Sinergia
166695 LRH-1 signaling in liver intermediary metabolism 01.08.2016 Project funding (Div. I-III)
147603 In vivo germination of Clostridium difficile endospores: where, when and how? 01.10.2013 Sinergia
189178 Dissecting the role of bile acid-Tgr5 signalling in stemness and gut specification 01.10.2019 Project funding (Div. I-III)

Abstract

It is becoming increasingly apparent that, in addition to their role in lipid digestion and removal of cholesterol, bile acids (BAs) play a crucial role as signaling molecules. They are transformed by the gut microbiota and, through enterohepatic recirculation and spill-over in the systemic circulation, reach target organs including the intestinal mucosa, the liver, brown and white fat depots, and immune cells. The microbial transformation of BAs in the gut is critical to BA-mediated signaling as it modifies their amount and affinity for specific BA receptors. A group of intestinal bacteria is of particular importance as it catalyzes the dehydroxylation of liver-derived (primary) BAs at the C7 position (i.e., 7-dehydroxylation, 7-DH-ion) and produces secondary BAs. Specific receptors for secondary BAs are associated with regulation of energy expenditure and glucose management, protection from liver steatosis and inflammation as well as improved glucose homeostasis after bariatric surgery. In addition, secondary BAs are also associated with protection from infection by specific intestinal pathogens (i.e., Clostridium difficile). Thus, through their action on primary BAs, 7-dehydroxylating (7-DH-ing) bacteria play an important role in health promotion and in the functioning of major physiological feedback loops in the body such as insulin response, satiety, and intestinal immunity. On the other hand, excessive abundance of secondary BAs, possibly linked to overabundance of 7-DH-ing bacteria correlates with an increased risk for colon cancer and cholesterol gallstone disease. Despite these potentially important roles in the mammalian host, the 7-DH-ing bacteria are poorly studied and much remains to be deciphered regarding their metabolism, diversity, abundance in the gut, and colonization dynamics in the host. We hypothesize that there is a direct link between the activity of these microorganisms and host health and set out to establish the existence of this connection. The major goal of the project is, therefore, to provide a thorough understanding of the microbiology of BA 7-DH-ing bacteria and their role in regulating host metabolism and controlling infection. Through the involvement of four applicants and one partner, this project takes an interdisciplinary approach to investigating the microbiology and genetics of 7-DH-ing bacteria, their abundance and diversity in the human and mouse gut, their colonization of the mouse gut, their role in regulating metabolism and immunity.The primary impact of this work is the refinement of the current understanding of the role of a highly relevant but still poorly characterized gut microbial group in host health. We expect to show that BA 7-DH-ing bacteria play a significant role in metabolic and immune function.
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