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1. Kinetics of imidazole propionate from orally delivered histidine in mice and humans

Author

Warmbrunn, Moritz V., Attaye, Ilias, Horak, Anthony, Banerjee, Rakhee, Massey, William J., Varadharajan, Venkateshwari, Rampanelli, Elena, Hao, Youling, Dutta, Sumita, Nemet, Ina, Aron-Wisnewsky, Judith, Clément, Karine, Koopen, Annefleur, Wortelboer, Koen, Bergh, Per-Olof, Davids, Mark, Mohamed, Nadia, Kemper, E. Marleen, Hazen, Stanley, Groen, Albert K., van Raalte, Daniel H., Herrema, Hilde, Backhed, Fredrik, Brown, J. Mark, and Nieuwdorp, Max

Published
2024
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4. Protein supplementation changes gut microbial diversity and derived metabolites in subjects with type 2 diabetes

Author

Attaye, Ilias, Lassen, Pierre Bel, Adriouch, Solia, Steinbach, Emilie, Patiño-Navarrete, Rafael, Davids, Mark, Alili, Rohia, Jacques, Flavien, Benzeguir, Sara, Belda, Eugeni, Nemet, Ina, Anderson, James T., Alexandre-Heymann, Laure, Greyling, Arno, Larger, Etienne, Hazen, Stanley L., van Oppenraaij, Sophie L., Tremaroli, Valentina, Beck, Katharina, Bergh, Per-Olof, Bäckhed, Fredrik, ten Brincke, Suzan P.M., Herrema, Hilde, Groen, Albert K., Pinto-Sietsma, Sara-Joan, Clément, Karine, and Nieuwdorp, Max

Published
2023
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5. Microbially Produced Imidazole Propionate Is Associated With Heart Failure and Mortality

Author

Alves, Renato, Amouyal, Chloe, Andersson Galijatovic, Ehm Astrid, Andreelli, Fabrizio, Barthelemy, Olivier, Bastard, Jean-Philippe, Batisse, Jean-Paul, Berland, Magalie, Bittar, Randa, Blüher, Matthias, Bork, Peer, Bourron, Olivier, Camus, Mickael, Cassuto, Dominique, Ciangura, Cecile, Coelho, Luis Pedro, Collet, Jean-Philippe, Dumas, Marc-Emmanuel, Ehrlich, S. Dusko, Engelbrechtsen, Line, Fezeu, Leopold, Forslund, Sofia, Fromentin, Sebastien, Galan, Pilar, Giral, Philippe, Gøtze, Jens Peter, Hansen, Torben, Hansen, Tue H., Hartemann, Agnes, Hartmann, Bolette, Hercberg, Serge, Holmes, Bridget, Holst, Jens Juul, Hornbak, Malene, Hoyles, Lesley, Hulot, Jean-Sebastien, Jaqueminet, Sophie, Kerneis, Mathieu, Khemis, Jean, Kozlowski, Ruby, Pedersen, Helle Krogh, Kuhn, Michael, Mannerås-Holm, Louise, Marko, Lajos, Martinez-Gili Robin Massey, Laura, Maziers, Nicolas, Medina-Stamminger, Jonathan, Moitinho-Silva, Lucas, Montalescot, Gilles, Moutel, Sandrine, Neves, Ana Luisa, Olanipekun, Michael, Oppert, Jean-Michel, Poitou, Christine, Pousset, Francoise, Pouzoulet, Laurence, Rouault, Christine, Silvain, Johanne, Vestergaard, Henrik, Molinaro, Antonio, Nemet, Ina, Bel Lassen, Pierre, Chakaroun, Rima, Nielsen, Trine, Aron-Wisnewsky, Judith, Bergh, Per-Olof, Li, Lin, Henricsson, Marcus, Køber, Lars, Isnard, Richard, Helft, Gerard, Stumvoll, Michael, Pedersen, Oluf, Smith, J. Gustav, Tang, W.H. Wilson, Clément, Karine, Hazen, Stanley L., and Bäckhed, Fredrik

Published
2023
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8. An Integrated Understanding of the Rapid Metabolic Benefits of a Carbohydrate-Restricted Diet on Hepatic Steatosis in Humans

Author

Mardinoglu, Adil, Wu, Hao, Bjornson, Elias, Zhang, Cheng, Hakkarainen, Antti, Räsänen, Sari M., Lee, Sunjae, Mancina, Rosellina M., Bergentall, Mattias, Pietiläinen, Kirsi H., Söderlund, Sanni, Matikainen, Niina, Ståhlman, Marcus, Bergh, Per-Olof, Adiels, Martin, Piening, Brian D., Granér, Marit, Lundbom, Nina, Williams, Kevin J., Romeo, Stefano, Nielsen, Jens, Snyder, Michael, Uhlén, Mathias, Bergström, Göran, Perkins, Rosie, Marschall, Hanns-Ulrich, Bäckhed, Fredrik, Taskinen, Marja-Riitta, and Borén, Jan

Published
2018
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10. The acute effect of metabolic cofactor supplementation: a potential therapeutic strategy against non‐alcoholic fatty liver disease

Author

Zhang, Cheng, Bjornson, Elias, Arif, Muhammad, Tebani, Abdellah, Lovric, Alen, Benfeitas, Rui, Ozcan, Mehmet, Juszczak, Kajetan, Kim, Woonghee, Kim, Jung Tae, Bidkhori, Gholamreza, Ståhlman, Marcus, Bergh, Per‐Olof, Adiels, Martin, Turkez, Hasan, Taskinen, Marja‐Riitta, Bosley, Jim, Marschall, Hanns‐Ulrich, Nielsen, Jens, Uhlén, Mathias, Borén, Jan, and Mardinoglu, Adil

Published
2020
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11. Microbially Produced Imidazole Propionate Is Associated With Heart Failure and Mortality

Author

Molinaro, Antonio, primary, Nemet, Ina, additional, Bel Lassen, Pierre, additional, Chakaroun, Rima, additional, Nielsen, Trine, additional, Aron-Wisnewsky, Judith, additional, Bergh, Per-Olof, additional, Li, Lin, additional, Henricsson, Marcus, additional, Køber, Lars, additional, Isnard, Richard, additional, Helft, Gerard, additional, Stumvoll, Michael, additional, Pedersen, Oluf, additional, Smith, J. Gustav, additional, Tang, W.H. Wilson, additional, Clément, Karine, additional, Hazen, Stanley L., additional, and Bäckhed, Fredrik, additional

Published
2023
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12. Cardiomyocyte-specific PCSK9 deficiency compromises mitochondrial bioenergetics and heart function

Author

Laudette, Marion, primary, Lindbom, Malin, additional, Arif, Muhammad, additional, Cinato, Mathieu, additional, Ruiz, Mario, additional, Doran, Stephen, additional, Miljanovic, Azra, additional, Rutberg, Mikael, additional, Andersson, Linda, additional, Klevstig, Martina, additional, Henricsson, Marcus, additional, Bergh, Per-Olof, additional, Bollano, Entela, additional, Aung, Nay, additional, Gustav Smith, J, additional, Pilon, Marc, additional, Hyötyläinen, Tuulia, additional, Orešič, Matej, additional, Perkins, Rosie, additional, Mardinoglu, Adil, additional, Levin, Malin C, additional, and Borén, Jan, additional

Published
2023
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13. Cardiomyocyte-specific PCSK9 deficiency compromises mitochondrial bioenergetics and heart function

Author

Laudette, Marion, Lindbom, Malin, Arif, Muhammad, Cinato, Mathieu, Ruiz, Mario, Doran, Stephen, Miljanovic, Azra, Rutberg, Mikael, Andersson, Linda, Klevstig, Martina, Henricsson, Marcus, Bergh, Per Olof, Bollano, Entela, Aung, Nay, Smith, J. Gustav, Pilon, Marc, Hyötyläinen, Tuulia, Orešič, Matej, Perkins, Rosie, Mardinoglu, Adil, Levin, Malin C., Borén, Jan, Laudette, Marion, Lindbom, Malin, Arif, Muhammad, Cinato, Mathieu, Ruiz, Mario, Doran, Stephen, Miljanovic, Azra, Rutberg, Mikael, Andersson, Linda, Klevstig, Martina, Henricsson, Marcus, Bergh, Per Olof, Bollano, Entela, Aung, Nay, Smith, J. Gustav, Pilon, Marc, Hyötyläinen, Tuulia, Orešič, Matej, Perkins, Rosie, Mardinoglu, Adil, Levin, Malin C., and Borén, Jan

Abstract

Aims Pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is expressed mainly in the liver and at low levels in the heart, regulates cholesterol levels by directing low-density lipoprotein receptors to degradation. Studies to determine the role of PCSK9 in the heart are complicated by the close link between cardiac function and systemic lipid metabolism. Here, we sought to elucidate the function of PCSK9 specifically in the heart by generating and analysing mice with cardiomyocyte-specific Pcsk9 deficiency (CMPcsk9−/− mice) and by silencing Pcsk9 acutely in a cell culture model of adult cardiomyocyte-like cells. Methods and results Mice with cardiomyocyte-specific deletion of Pcsk9 had reduced contractile capacity, impaired cardiac function, and left ventricular dilatation at 28 weeks of age and died prematurely. Transcriptomic analyses revealed alterations of signalling pathways linked to cardiomyopathy and energy metabolism in hearts from CM-Pcsk9−/− mice vs. wild-type littermates. In agreement, levels of genes and proteins involved in mitochondrial metabolism were reduced in CM-Pcsk9−/− hearts. By using a Seahorse flux analyser, we showed that mitochondrial but not glycolytic function was impaired in cardiomyocytes from CM-Pcsk9−/− mice. We further showed that assembly and activity of electron transport chain (ETC) complexes were altered in isolated mitochondria from CM-Pcsk9−/− mice. Circulating lipid levels were unchanged in CM-Pcsk9−/− mice, but the lipid composition of mitochondrial membranes was altered. In addition, cardiomyocytes from CM-Pcsk9−/− mice had an increased number of mitochondria–endoplasmic reticulum contacts and alterations in the morphology of cristae, the physical location of the ETC complexes. We also showed that acute Pcsk9 silencing in adult cardiomyocyte-like cells reduced the activity of ETC complexes and impaired mitochondrial metabolism. Conclusion PCSK9, despite its low expression in cardiomyocytes, contributes to cardiac me, QC 20230907

Published
2023
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14. Microbially Produced Imidazole Propionate Is Associated With Heart Failure and Mortality

Author

Molinaro, Antonio, Nemet, Ina, Bel Lassen, Pierre, Chakaroun, Rima, Nielsen, Trine, Aron-Wisnewsky, Judith, Bergh, Per Olof, Li, Lin, Henricsson, Marcus, Køber, Lars, Isnard, Richard, Helft, Gerard, Stumvoll, Michael, Pedersen, Oluf, Smith, J. Gustav, Tang, W. H.Wilson, Clément, Karine, Hazen, Stanley L., Bäckhed, Fredrik, Molinaro, Antonio, Nemet, Ina, Bel Lassen, Pierre, Chakaroun, Rima, Nielsen, Trine, Aron-Wisnewsky, Judith, Bergh, Per Olof, Li, Lin, Henricsson, Marcus, Køber, Lars, Isnard, Richard, Helft, Gerard, Stumvoll, Michael, Pedersen, Oluf, Smith, J. Gustav, Tang, W. H.Wilson, Clément, Karine, Hazen, Stanley L., and Bäckhed, Fredrik

Abstract

Background: Over the past years, it has become clear that the microbial ecosystem in the gut has a profound capacity to interact with the host through the production of a wide range of bioactive metabolites. The microbially produced metabolite imidazole propionate (ImP) is clinically and mechanistically linked with insulin resistance and type 2 diabetes, but it is unclear how ImP is associated with heart failure. Objectives: The authors aimed to explore whether ImP is associated with heart failure and mortality. Methods: ImP serum measurements in 2 large and independent clinical cohorts of patients (European [n = 1,985] and North American [n = 2,155]) with a range of severity of cardiovascular disease including heart failure. Univariate and multivariate Cox regression analyses were performed to delineate the impact of ImP on 5-year mortality in the North American cohort, independent of other covariates. Results: ImP is independently associated with reduced ejection fraction and heart failure in both cohorts, even after adjusting for traditional risk factors. Elevated ImP was a significant independent predictor of 5-year mortality (for the highest quartile, adjusted HR: 1.85 [95% CI: 1.20-2.88]; P < 0.01). Conclusions: The gut microbial metabolite ImP is increased in individuals with heart failure and is a predictor of overall survival.

Published
2023

15. Postprandial metabolism of apolipoproteins B48, B100, C-III, and E in humans with APOC3 loss-of-function mutations

Author

Taskinen, Marja-Riitta, primary, Björnson, Elias, additional, Matikainen, Niina, additional, Söderlund, Sanni, additional, Rämö, Joel, additional, Ainola, Mari-Mia, additional, Hakkarainen, Antti, additional, Sihlbom, Carina, additional, Thorsell, Annika, additional, Andersson, Linda, additional, Bergh, Per-Olof, additional, Henricsson, Marcus, additional, Romeo, Stefano, additional, Adiels, Martin, additional, Ripatti, Samuli, additional, Laakso, Markku, additional, Packard, Chris J., additional, and Borén, Jan, additional

Published
2022
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16. Ring Trial on Quantitative Assessment of Bile Acids Reveals a Method- and Analyte-Specific Accuracy and Reproducibility

Author

Haange, Sven-Bastiaan, primary, Till, Andreas, additional, Bergh, Per-Olof, additional, Fauler, Günter, additional, Gigl, Michael, additional, Löfgren-Sandblom, Anita, additional, Schaap, Frank G., additional, Clavel, Thomas, additional, Trautwein, Christian, additional, Fenske, Wiebke, additional, Kleigrewe, Karin, additional, Marschall, Hanns-Ulrich, additional, Olde Damink, Steven W. M., additional, Moustafa, Tarek, additional, von Bergen, Martin, additional, and Rolle-Kampczyk, Ulrike, additional

Published
2022
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17. 6α-hydroxylated bile acids mediate TGR5 signalling to improve glucose metabolism upon dietary fiber supplementation in mice

Author

Makki, Kassem, primary, Brolin, Harald, additional, Petersen, Natalia, additional, Henricsson, Marcus, additional, Christensen, Dan Ploug, additional, Khan, Muhammad Tanweer, additional, Wahlström, Annika, additional, Bergh, Per-Olof, additional, Tremaroli, Valentina, additional, Schoonjans, Kristina, additional, Marschall, Hanns-Ulrich, additional, and Bäckhed, Fredrik, additional

Published
2022
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18. Duodenal Anaerobutyricum soehngenii infusion stimulates GLP-1 production, ameliorates glycaemic control and beneficially shapes the duodenal transcriptome in metabolic syndrome subjects:a randomised double-blind placebo-controlled cross-over study

Author

Koopen, Annefleur, Witjes, Julia, Wortelboer, Koen, Majait, Soumia, Prodan, Andrei, Levin, Evgeni, Herrema, Hilde, Winkelmeijer, Maaike, Aalvink, Steven, Bergman, Jacques J. G. H. M., Havik, Stephan, Hartmann, Bolette, Levels, Han, Bergh, Per-Olof, van Son, Jamie, Balvers, Manon, Bastos, Diogo Mendes, Stroes, Erik, Groen, Albert K., Henricsson, Marcus, Kemper, Ellis Marleen, Holst, Jens, Strauch, Christopher M., Hazen, Stanley L., Backhed, Fredrik, De Vos, Willem M., Nieuwdorp, Max, Rampanelli, Elena, Koopen, Annefleur, Witjes, Julia, Wortelboer, Koen, Majait, Soumia, Prodan, Andrei, Levin, Evgeni, Herrema, Hilde, Winkelmeijer, Maaike, Aalvink, Steven, Bergman, Jacques J. G. H. M., Havik, Stephan, Hartmann, Bolette, Levels, Han, Bergh, Per-Olof, van Son, Jamie, Balvers, Manon, Bastos, Diogo Mendes, Stroes, Erik, Groen, Albert K., Henricsson, Marcus, Kemper, Ellis Marleen, Holst, Jens, Strauch, Christopher M., Hazen, Stanley L., Backhed, Fredrik, De Vos, Willem M., Nieuwdorp, Max, and Rampanelli, Elena

Abstract

Objective Although gut dysbiosis is increasingly recognised as a pathophysiological component of metabolic syndrome (MetS), the role and mode of action of specific gut microbes in metabolic health remain elusive. Previously, we identified the commensal butyrogenic Anaerobutyricum soehngenii to be associated with improved insulin sensitivity in subjects with MetS. In this proof-of-concept study, we investigated the potential therapeutic effects of A. soehngenii L2-7 on systemic metabolic responses and duodenal transcriptome profiles in individuals with MetS. Design In this randomised double-blind placebo-controlled cross-over study, 12 male subjects with MetS received duodenal infusions of A. soehngenii/ placebo and underwent duodenal biopsies, mixed meal tests (6 hours postinfusion) and 24-hour continuous glucose monitoring. Results A. soehngenii treatment provoked a markedly increased postprandial excursion of the insulinotropic hormone glucagon-like peptide 1 (GLP-1) and an elevation of plasma secondary bile acids, which were positively associated with GLP-1 levels. Moreover, A. soehngenii treatment robustly shaped the duodenal expression of 73 genes, with the highest fold induction in the expression of regenerating islet-protein 1B (REG1B)-encoding gene. Strikingly, duodenal REG1B expression positively correlated with GLP-1 levels and negatively correlated with peripheral glucose variability, which was significantly diminished in the 24 hours following A. soehngenii intake. Mechanistically, Reg1B expression is induced upon sensing butyrate or bacterial peptidoglycan. Importantly, A. soehngenii duodenal administration was safe and well tolerated. Conclusions A single dose of A. soehngenii improves peripheral glycaemic control within 24 hours; it specifically stimulates intestinal GLP-1 production and REG1B expression. Further studies are needed to delineate the specific pathways involved in REG1B induction and function in insulin sensitivity.

Published
2022

19. Duodenal Anaerobutyricum soehngenii infusion stimulates GLP-1 production, ameliorates glycaemic control and beneficially shapes the duodenal transcriptome in metabolic syndrome subjects: a randomised double-blind placebo-controlled cross-over study

Author

Koopen, Annefleur, Witjes, Julia, Wortelboer, Koen, Majait, Soumia, Prodan, Andrei, Levin, Evgeni, Herrema, Hilde, Winkelmeijer, Maaike, Aalvink, Steven, Bergman, Jacques J.G.H.M., Havik, Stephan, Hartmann, Bolette, Levels, Han, Bergh, Per-Olof, van Son, Jamie, Balvers, Manon, Bastos, Diogo Mendes, Stroes, Erik, Groen, Albert K., Henricsson, Marcus, Kemper, Ellis Marleen, Holst, Jens, Strauch, Christopher M., Hazen, Stanley L., Bäckhed, Fredrik, de Vos, Willem M., Nieuwdorp, Max, Rampanelli, Elena, Koopen, Annefleur, Witjes, Julia, Wortelboer, Koen, Majait, Soumia, Prodan, Andrei, Levin, Evgeni, Herrema, Hilde, Winkelmeijer, Maaike, Aalvink, Steven, Bergman, Jacques J.G.H.M., Havik, Stephan, Hartmann, Bolette, Levels, Han, Bergh, Per-Olof, van Son, Jamie, Balvers, Manon, Bastos, Diogo Mendes, Stroes, Erik, Groen, Albert K., Henricsson, Marcus, Kemper, Ellis Marleen, Holst, Jens, Strauch, Christopher M., Hazen, Stanley L., Bäckhed, Fredrik, de Vos, Willem M., Nieuwdorp, Max, and Rampanelli, Elena

Abstract

Objective Although gut dysbiosis is increasingly recognised as a pathophysiological component of metabolic syndrome (MetS), the role and mode of action of specific gut microbes in metabolic health remain elusive. Previously, we identified the commensal butyrogenic Anaerobutyricum soehngenii to be associated with improved insulin sensitivity in subjects with MetS. In this proof-of-concept study, we investigated the potential therapeutic effects of A. soehngenii L2-7 on systemic metabolic responses and duodenal transcriptome profiles in individuals with MetS.Design In this randomised double-blind placebo-controlled cross-over study, 12 male subjects with MetS received duodenal infusions of A. soehngenii/ placebo and underwent duodenal biopsies, mixed meal tests (6 hours postinfusion) and 24-hour continuous glucose monitoring.Results A. soehngenii treatment provoked a markedly increased postprandial excursion of the insulinotropic hormone glucagon-like peptide 1 (GLP-1) and an elevation of plasma secondary bile acids, which were positively associated with GLP-1 levels. Moreover, A. soehngenii treatment robustly shaped the duodenal expression of 73 genes, with the highest fold induction in the expression of regenerating islet-protein 1B (REG1B)-encoding gene. Strikingly, duodenal REG1B expression positively correlated with GLP-1 levels and negatively correlated with peripheral glucose variability, which was significantly diminished in the 24 hours following A. soehngenii intake. Mechanistically, Reg1B expression is induced upon sensing butyrate or bacterial peptidoglycan. Importantly, A. soehngenii duodenal administration was safe and well tolerated.Conclusions A single dose of A. soehngenii improves peripheral glycaemic control within 24 hours; it specifically stimulates intestinal GLP-1 production and REG1B expression. Further studies are needed to delineate the specific pathways involved in REG1B induction and function in insulin sensitivity.

Published
2022

20. 6α-hydroxylated bile acids mediate TGR5 signalling to improve glucose metabolism upon dietary fiber supplementation in mice.

Author

Makki, Kassem, Brolin, Harald, Petersen, Natalia, Henricsson, Marcus, Christensen, Dan Ploug, Khan, Muhammad Tanweer, Wahlström, Annika, Bergh, Per- Olof, Tremaroli, Valentina, Schoonjans, Kristina, Marschall, Hanns- Ulrich, and Bäckhed, Fredrik

Subjects
BILE acids, DIETARY fiber, GLUCOSE metabolism, DIETARY supplements, GASTRIC inhibitory polypeptide, HYPERGLYCEMIA, WESTERN diet
Published
2023
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21. Duodenal Anaerobutyricum soehngenii infusion stimulates GLP-1 production, ameliorates glycaemic control and beneficially shapes the duodenal transcriptome in metabolic syndrome subjects: a randomised double-blind placebo-controlled cross-over study

Author

Koopen, Annefleur, primary, Witjes, Julia, additional, Wortelboer, Koen, additional, Majait, Soumia, additional, Prodan, Andrei, additional, Levin, Evgeni, additional, Herrema, Hilde, additional, Winkelmeijer, Maaike, additional, Aalvink, Steven, additional, Bergman, Jacques J G H M, additional, Havik, Stephan, additional, Hartmann, Bolette, additional, Levels, Han, additional, Bergh, Per-Olof, additional, van Son, Jamie, additional, Balvers, Manon, additional, Bastos, Diogo Mendes, additional, Stroes, Erik, additional, Groen, Albert K, additional, Henricsson, Marcus, additional, Kemper, Ellis Marleen, additional, Holst, Jens, additional, Strauch, Christopher M, additional, Hazen, Stanley L, additional, Bäckhed, Fredrik, additional, De Vos, Willem M, additional, Nieuwdorp, Max, additional, and Rampanelli, Elena, additional

Published
2021
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22. Sphingosine 1-Phosphate Mediates Adiponectin Receptor Signaling Essential For Lipid Homeostasis And Embryogenesis

Author

Ruiz, Mario, primary, Devkota, Ranjan, additional, Panagaki, Dimitra, additional, Bergh, Per-Olof, additional, Kaper, Delaney, additional, Henricsson, Marcus, additional, Nik, Ali, additional, Petkevicius, Kasparas, additional, Höög, Johanna L., additional, Bohlooly-Y, Mohammad, additional, Carlsson, Peter, additional, Borén, Jan, additional, and Pilon, Marc, additional

Published
2021
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23. Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology

Author

Bel Lassen, Pierre, Nielsen, Trine, Bergh, Per-Olof, Rouault, Christine, André, Sébastien, Marquet, Florian, Andreelli, Fabrizio, Salem, Joe-Elie, Assmann, Karen, Bastard, Jean-Philippe, Forslund, Sofia, Le Chatelier, Emmanuelle, Falony, Gwen, Pons, Nicolas, Prifti, Edi, Quinquis, Benoit, Roume, Hugo, Vieira-Silva, Sara, Hansen, Tue, Pedersen, Helle Krogh, Lewinter, Christian, Sønderskov, Nadja, Vestergaard, Henrik, Raes, Jeroen, Nielsen, Jens, Bork, Peer, Ehrlich, S. Dusko, Pedersen, Oluf, Aron-Wisneswky, Judith, Clément, Karine, Bäckhed, Fredrik, Molinaro, Antonio, Lassen, Pierre, Henricsson, Marcus, Wu, Hao, Adriouch, Solia, Belda, Eugeni, Chakaroun, Rima, Nielse, Trine, Bergh, Christine, Rouault, Sébastien, Andr, Florian, Marquet, Fabrizio, Andreelli, Joe-Elie, Salem, Karen, Assmann, Jean-Philippe, Bastard, Sofia, Forslund, Emmanuelle, Le Chatelier, Gwen, Falon, Nicolas, Pons, Edi, Prift, Benoit, Quinquis, Hugo, Roume, Sara, Vieira-Silv, Tue, Hansen, Krogh, Pedersen, Christian, Lewinter, Nadja, The, Metacardis, Køber, Lars, Vestergaar, Henrik, Hansen, Torben, Zucker, Jean-Daniel, Galan, Pilar, Dumas, Marc-Emmanuel, Rae, Jeroen, Oppert, Jean-Michel, Letunic, Ivica, Nielse, Jens, Ehrlic, S, Stumvoll, Michael, Pederse, Oluf, Aron-Wisnewsky, Judith, Bäckhe, Fredrik, Sahlgrenska Center for Cardiovascular and Metabolic Research, Partenaires INRAE, Sahlgrenska University Hospital, Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche en Nutrition Humaine d'Ile-de-France (CRNH-IDF), Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Sorbonne Paris Nord, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université (SU), Medical Department III – Endocrinology, Nephrology, Rheumatology, Universität Leipzig [Leipzig], Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Centre d'Investigation Clinique de Paris Est, Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital Tenon [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Experimental and Clinical Research Center [Berlin, Germany], Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association-Helmholtz-Gemeinschaft = Helmholtz Association-Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Bacteriology, Université Catholique de Louvain (UCL), VIB-KU Leuven Center for Microbiology [Belgium], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Unité de modélisation mathématique et informatique des systèmes complexes [Bondy] (UMMISCO), Sorbonne Université (SU)-Universtié Yaoundé 1 [Cameroun]-Université Cadi Ayyad [Marrakech] (UCA)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de la francophonie pour l'informatique-Institut de Recherche pour le Développement (IRD [France-Nord]), Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Metabolism, Digestion and Reproduction, Imperial College London, National Heart and Lung Institute [London] (NHLI), Royal Brompton and Harefield NHS Foundation Trust-Imperial College London, Centre de Recherche en Nutrition Humaine - Ile de France (CRNH - IDF), Biobyte Solutions GMBH, Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Sorbonne Paris Nord, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Sahlgrenska Academy at University of Gothenburg [Göteborg], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Helmholtz-Gemeinschaft = Helmholtz Association-Helmholtz-Gemeinschaft = Helmholtz Association-Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Helmholtz-Gemeinschaft = Helmholtz Association, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Rega Institute for Medical Research [Leuven, België], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Université de Yaoundé I-Institut de la francophonie pour l'informatique-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cadi Ayyad [Marrakech] (UCA)-Sorbonne Université (SU)-Institut de Recherche pour le Développement (IRD [France-Nord]), Chalmers University of Technology [Göteborg], European Molecular Biology Laboratory [Heidelberg] (EMBL), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, HAL-SU, Gestionnaire, Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Nord-Institut National Agronomique Paris-Grignon (INA P-G)-Sorbonne Université (SU)-CETAF-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut de Recherche pour le Développement (IRD [France-Nord])-Institut de la francophonie pour l'informatique-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cadi Ayyad [Marrakech] (UCA)-Université de Yaoundé I-Sorbonne Université (SU), Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Auteur indépendant, Commission of the European Communities, and Universität Leipzig

Subjects
0301 basic medicine, Male, ACCURATE METHOD, endocrine system diseases, Metabolite, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Type 2 diabetes, GUT MICROBIOME, GLUCOSE, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, [CHIM] Chemical Sciences, Prediabetes, lcsh:Science, 2. Zero hunger, RISK, Multidisciplinary, biology, INSULIN SENSITIVITY, Imidazoles, HOMEOSTASIS MODEL ASSESSMENT, Middle Aged, 3. Good health, Multidisciplinary Sciences, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Science & Technology - Other Topics, Enterotype, Female, Adult, medicine.medical_specialty, Science, Carbohydrate metabolism, Microbiology, digestive system, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, INTESTINAL MICROBIOTA, Internal medicine, medicine, Humans, [CHIM]Chemical Sciences, Histidine, Author Correction, PHYSIOLOGY, Aged, Science & Technology, Bacteria, General Chemistry, Metabolism, medicine.disease, biology.organism_classification, Gastrointestinal Microbiome, MetaCardis Consortium, METAGENOME, INDIVIDUALS, 030104 developmental biology, chemistry, Diabetes Mellitus, Type 2, Cardiovascular and Metabolic Diseases, lcsh:Q, Bacteroides
Abstract

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism., Gut microbial metabolism of nutrients contributes to metabolic diseases, and the histidine metabolite imidazole propionate (ImP) is produced by type 2 diabetes (T2D) associated microbiome. Here the authors report that circulating ImP levels are increased in subjects with prediabetes or T2D in three European populations, and this increase associates with altered gut microbiota rather than dietary histidine.

Published
2020
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24. Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology

Author

Molinaro, Antonio, Bel Lassen, Pierre, Henricsson, Marcus, Wu, Hao, Adriouch, Solia, Belda, Eugeni, Chakaroun, Rima, Nielsen, Trine, Bergh, Per-Olof, Rouault, Christine, Andre, Sebastien, Marquet, Florian, Andreelli, Fabrizio, Salem, Joe-Elie, Assmann, Karen, Bastard, Jean-Philippe, Forslund, Sofia, Le Chatelier, Emmanuelle, Falony, Gwen, Pons, Nicolas, Prifti, Edi, Quinquis, Benoit, Roume, Hugo, Vieira-Silva, Sara, Hansen, Tue H., Pedersen, Helle Krogh, Lewinter, Christian, Sønderskov, Nadja B., Køber, Lars, Vestergaard, Henrik, Hansen, Torben, Zucker, Jean-Daniel, Galan, Pilar, Dumas, Marc-Emmanuel, Raes, Jeroen, Oppert, Jean-Michel, Letunic, Ivica, Nielsen, Jens, Bork, Peer, Ehrlich, S. Dusko, Stumvoll, Michael, Pedersen, Oluf, Aron-Wisneswky, Judith, Clement, Karine, Baeckhed, Fredrik, Molinaro, Antonio, Bel Lassen, Pierre, Henricsson, Marcus, Wu, Hao, Adriouch, Solia, Belda, Eugeni, Chakaroun, Rima, Nielsen, Trine, Bergh, Per-Olof, Rouault, Christine, Andre, Sebastien, Marquet, Florian, Andreelli, Fabrizio, Salem, Joe-Elie, Assmann, Karen, Bastard, Jean-Philippe, Forslund, Sofia, Le Chatelier, Emmanuelle, Falony, Gwen, Pons, Nicolas, Prifti, Edi, Quinquis, Benoit, Roume, Hugo, Vieira-Silva, Sara, Hansen, Tue H., Pedersen, Helle Krogh, Lewinter, Christian, Sønderskov, Nadja B., Køber, Lars, Vestergaard, Henrik, Hansen, Torben, Zucker, Jean-Daniel, Galan, Pilar, Dumas, Marc-Emmanuel, Raes, Jeroen, Oppert, Jean-Michel, Letunic, Ivica, Nielsen, Jens, Bork, Peer, Ehrlich, S. Dusko, Stumvoll, Michael, Pedersen, Oluf, Aron-Wisneswky, Judith, Clement, Karine, and Baeckhed, Fredrik

Abstract

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism. Gut microbial metabolism of nutrients contributes to metabolic diseases, and the histidine metabolite imidazole propionate (ImP) is produced by type 2 diabetes (T2D) associated microbiome. Here the authors report that circulating ImP levels are increased in subjects with prediabetes or T2D in three European populations, and this increase associates with altered gut microbiota rather than dietary histidine.

Published
2020

25. Antioxidants Promote Intestinal Tumor Progression in Mice

Author

Zou, Zhiyuan V., primary, Le Gal, Kristell, additional, El Zowalaty, Ahmed E., additional, Pehlivanoglu, Lara E., additional, Garellick, Viktor, additional, Gul, Nadia, additional, Ibrahim, Mohamed X., additional, Bergh, Per-Olof, additional, Henricsson, Marcus, additional, Wiel, Clotilde, additional, Akyürek, Levent M., additional, Bergo, Martin O., additional, Sayin, Volkan I., additional, and Lindahl, Per, additional

Published
2021
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26. Duodenal infusion of &lt;em&gt;Anaerobutyricum soehngenii&lt;/em&gt; ameliorates glycemic control and postprandial GLP-1 responses and alters the transcriptional profile of small intestine in subjects with metabolic syndrome.

Author

Koopen, Annefleur, primary, Rampanelli, Elena, primary, Witjes, Julia, additional, Wortelboer, Koen, additional, Majait, Soumia, additional, Prodan, Andrei, additional, Levin, Evgeni, additional, Herrema, Hilde, additional, Winkelmeijer, Maaike, additional, Aalvink, Steven, additional, Bergman, Jacques, additional, Havik, Stefan, additional, Hartmann, Bolette, additional, Levels, Johannes, additional, Bergh, Per-Olof, additional, Balvers, Manon, additional, Bastos, Diogo N. Mendes, additional, Stroes, Erik, additional, Groen, Albert, additional, Henricsson, Marcus, additional, Kemper, Marleen, additional, Holst, Jens, additional, Bäckhed, Fredrik, additional, de Vos, Willem, additional, and Nieuwdorp, Max, additional

Published
2020
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27. Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1

Author

Koh, Ara, Molinaro, Antonio, Ståhlman, Marcus, Khan, Muhammad Tanweer, Schmidt, Caroline, Mannerås-Holm, Louise, Wu, Hao, Carreras, Alba, Jeong, Heeyoon, Olofsson, Louise E., Bergh, Per-Olof, Gerdes, Victor, Hartstra, Annick, de Brauw, Maurits, Perkins, Rosie, Nieuwdorp, Max, Bergström, G. ran, Bäckhed, Fredrik, Vascular Medicine, AGEM - Digestive immunity, ACS - Diabetes & metabolism, AGEM - Endocrinology, metabolism and nutrition, Internal medicine, and Amsterdam Cardiovascular Sciences

Abstract

Interactions between the gut microbiota, diet, and the host potentially contribute to the development of metabolic diseases. Here, we identify imidazole propionate as a microbially produced histidine-derived metabolite that is present at higher concentrations in subjects with versus without type 2 diabetes. We show that imidazole propionate is produced from histidine in a gut simulator at higher concentrations when using fecal microbiota from subjects with versus without type 2 diabetes and that it impairs glucose tolerance when administered to mice. We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1). We also demonstrate increased activation of p62 and mTORC1 in liver from subjects with type 2 diabetes. Our findings indicate that the microbial metabolite imidazole propionate may contribute to the pathogenesis of type 2 diabetes. Imidazole propionate, a metabolite produced by the gut microbiota, is elevated in type 2 diabetes and can directly impair glucose tolerance and insulin signaling.

Published
2018
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28. Duodenal Anaerobutyricum soehngeniiinfusion stimulates GLP-1 production, ameliorates glycaemic control and beneficially shapes the duodenal transcriptome in metabolic syndrome subjects: a randomised double-blind placebo-controlled cross-over study

Author

Koopen, Annefleur, Witjes, Julia, Wortelboer, Koen, Majait, Soumia, Prodan, Andrei, Levin, Evgeni, Herrema, Hilde, Winkelmeijer, Maaike, Aalvink, Steven, Bergman, Jacques J G H M, Havik, Stephan, Hartmann, Bolette, Levels, Han, Bergh, Per-Olof, van Son, Jamie, Balvers, Manon, Bastos, Diogo Mendes, Stroes, Erik, Groen, Albert K, Henricsson, Marcus, Kemper, Ellis Marleen, Holst, Jens, Strauch, Christopher M, Hazen, Stanley L, Ba¨ckhed, Fredrik, De Vos, Willem M, Nieuwdorp, Max, and Rampanelli, Elena

Abstract

ObjectiveAlthough gut dysbiosis is increasingly recognised as a pathophysiological component of metabolic syndrome (MetS), the role and mode of action of specific gut microbes in metabolic health remain elusive. Previously, we identified the commensal butyrogenic Anaerobutyricum soehngeniito be associated with improved insulin sensitivity in subjects with MetS. In this proof-of-concept study, we investigated the potential therapeutic effects of A. soehngeniiL2-7 on systemic metabolic responses and duodenal transcriptome profiles in individuals with MetS.DesignIn this randomised double-blind placebo-controlled cross-over study, 12 male subjects with MetS received duodenal infusions of A. soehngenii/ placebo and underwent duodenal biopsies, mixed meal tests (6 hours postinfusion) and 24-hour continuous glucose monitoring.ResultsA. soehngeniitreatment provoked a markedly increased postprandial excursion of the insulinotropic hormone glucagon-like peptide 1 (GLP-1) and an elevation of plasma secondary bile acids, which were positively associated with GLP-1 levels. Moreover, A. soehngeniitreatment robustly shaped the duodenal expression of 73 genes, with the highest fold induction in the expression of regenerating islet-protein 1B (REG1B)-encoding gene. Strikingly, duodenal REG1Bexpression positively correlated with GLP-1 levels and negatively correlated with peripheral glucose variability, which was significantly diminished in the 24 hours following A. soehngeniiintake. Mechanistically, Reg1B expression is induced upon sensing butyrate or bacterial peptidoglycan. Importantly, A. soehngeniiduodenal administration was safe and well tolerated.ConclusionsA single dose of A. soehngeniiimproves peripheral glycaemic control within 24 hours; it specifically stimulates intestinal GLP-1 production and REG1Bexpression. Further studies are needed to delineate the specific pathways involved in REG1B induction and function in insulin sensitivity.Trial registration numberNTR-NL6630.

Published
2022
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29. Author Correction: Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology.

Author

Molinaro, Antonio, Bel Lassen, Pierre, Henricsson, Marcus, Wu, Hao, Adriouch, Solia, Belda, Eugeni, Chakaroun, Rima, Nielsen, Trine, Bergh, Per-Olof, Rouault, Christine, André, Sébastien, Marquet, Florian, Andreelli, Fabrizio, Salem, Joe-Elie, Assmann, Karen, Bastard, Jean-Philippe, Forslund, Sofia, Le Chatelier, Emmanuelle, Falony, Gwen, and Pons, Nicolas

Subjects
PROPIONATES, DIABETES, MICROBIAL ecology
Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20412-9. [ABSTRACT FROM AUTHOR]

Published
2020
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30. Oral histidine affects gut microbiota and MAIT cells improving glycemic control in type 2 diabetes patients.

Author

Warmbrunn MV, Attaye I, Aron-Wisnewsky J, Rampanelli E, van der Vossen EWJ, Hao Y, Koopen A, Bergh PO, Stols-Gonçalves D, Mohamed N, Kemper M, Verdoes X, Wortelboer K, Davids M, Belda E, André S, Hazen S, Clement K, Groen B, van Raalte DH, Herrema H, Backhed F, and Nieuwdorp M

Subjects
Humans, Middle Aged, Male, Female, Glycemic Control, Dietary Supplements, Case-Control Studies, Feces microbiology, Blood Glucose metabolism, Aged, Adult, Bacteria classification, Bacteria metabolism, Bacteria genetics, Administration, Oral, DNA Methylation, Histidine metabolism, Diabetes Mellitus, Type 2 microbiology, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 immunology, Gastrointestinal Microbiome drug effects, Mucosal-Associated Invariant T Cells immunology, Mucosal-Associated Invariant T Cells metabolism
Abstract

Amino acids, metabolized by host cells as well as commensal gut bacteria, have signaling effects on host metabolism. Oral supplementation of the essential amino acid histidine has been shown to exert metabolic benefits. To investigate whether dietary histidine aids glycemic control, we performed a case-controlled parallel clinical intervention study in participants with type 2 diabetes (T2D) and healthy controls. Participants received oral histidine for seven weeks. After 2 weeks of histidine supplementation, the microbiome was depleted by antibiotics to determine the microbial contribution to histidine metabolism. We assessed glycemic control, immunophenotyping of peripheral blood mononucelar cells (PBMC), DNA methylation of PBMCs and fecal gut microbiota composition. Histidine improves several markers of glycemic control, including postprandial glucose levels with a concordant increase in the proportion of MAIT cells after two weeks of histidine supplementation. The increase in MAIT cells was associated with changes in gut microbial pathways such as riboflavin biosynthesis and epigenetic changes in the amino acid transporter SLC7A5. Associations between the microbiome and MAIT cells were replicated in the MetaCardis cohort. We propose a conceptual framework for how oral histidine may affect MAIT cells via altered gut microbiota composition and SLC7A5 expression in MAIT cells directly and thereby influencing glycemic control. Future studies should focus on the role of flavin biosynthesis intermediates and SLC7A5 modulation in MAIT cells to modulate glycemic control.

Published
2024
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31. Duodenal Anaerobutyricum soehngenii infusion stimulates GLP-1 production, ameliorates glycaemic control and beneficially shapes the duodenal transcriptome in metabolic syndrome subjects: a randomised double-blind placebo-controlled cross-over study.

Author

Koopen A, Witjes J, Wortelboer K, Majait S, Prodan A, Levin E, Herrema H, Winkelmeijer M, Aalvink S, Bergman JJGHM, Havik S, Hartmann B, Levels H, Bergh PO, van Son J, Balvers M, Bastos DM, Stroes E, Groen AK, Henricsson M, Kemper EM, Holst J, Strauch CM, Hazen SL, Bäckhed F, De Vos WM, Nieuwdorp M, and Rampanelli E

Subjects
Blood Glucose metabolism, Blood Glucose Self-Monitoring, Clostridiales, Cross-Over Studies, Double-Blind Method, Glucagon-Like Peptide 1 metabolism, Glycemic Control, Humans, Insulin metabolism, Male, Transcriptome, Diabetes Mellitus, Type 2 drug therapy, Insulin Resistance, Metabolic Syndrome genetics
Abstract

Objective: Although gut dysbiosis is increasingly recognised as a pathophysiological component of metabolic syndrome (MetS), the role and mode of action of specific gut microbes in metabolic health remain elusive. Previously, we identified the commensal butyrogenic Anaerobutyricum soehngenii to be associated with improved insulin sensitivity in subjects with MetS. In this proof-of-concept study, we investigated the potential therapeutic effects of A. soehngenii L2-7 on systemic metabolic responses and duodenal transcriptome profiles in individuals with MetS., Design: In this randomised double-blind placebo-controlled cross-over study, 12 male subjects with MetS received duodenal infusions of A. soehngenii / placebo and underwent duodenal biopsies, mixed meal tests (6 hours postinfusion) and 24-hour continuous glucose monitoring., Results: A. soehngenii treatment provoked a markedly increased postprandial excursion of the insulinotropic hormone glucagon-like peptide 1 (GLP-1) and an elevation of plasma secondary bile acids, which were positively associated with GLP-1 levels. Moreover, A. soehngenii treatment robustly shaped the duodenal expression of 73 genes, with the highest fold induction in the expression of regenerating islet-protein 1B ( REG1B )-encoding gene. Strikingly, duodenal REG1B expression positively correlated with GLP-1 levels and negatively correlated with peripheral glucose variability, which was significantly diminished in the 24 hours following A. soehngenii intake. Mechanistically, Reg1B expression is induced upon sensing butyrate or bacterial peptidoglycan. Importantly, A. soehngenii duodenal administration was safe and well tolerated., Conclusions: A single dose of A. soehngenii improves peripheral glycaemic control within 24 hours; it specifically stimulates intestinal GLP-1 production and REG1B expression. Further studies are needed to delineate the specific pathways involved in REG1B induction and function in insulin sensitivity., Trial Registration Number: NTR-NL6630., Competing Interests: Competing interests: MN is in the scientific board of Kaleido Biosciences, Boston USA. WMDV is founder and in the board of A-mansia, Belgium. FB is in the scientific board of Metabogen AB, Sweden. MN and WMDV are founders and Scientific Advisory Board members of Caelus Pharmaceuticals, the Netherlands. SLH is a paid consultant for P&G and coinventor on pending and issued patents held by the Cleveland Clinic, and is eligible for receiving payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland HeartLab, Quest Diagnostics and P&G., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2022
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32. Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology.

Author

Molinaro A, Bel Lassen P, Henricsson M, Wu H, Adriouch S, Belda E, Chakaroun R, Nielsen T, Bergh PO, Rouault C, André S, Marquet F, Andreelli F, Salem JE, Assmann K, Bastard JP, Forslund S, Le Chatelier E, Falony G, Pons N, Prifti E, Quinquis B, Roume H, Vieira-Silva S, Hansen TH, Pedersen HK, Lewinter C, Sønderskov NB, Køber L, Vestergaard H, Hansen T, Zucker JD, Galan P, Dumas ME, Raes J, Oppert JM, Letunic I, Nielsen J, Bork P, Ehrlich SD, Stumvoll M, Pedersen O, Aron-Wisnewsky J, Clément K, and Bäckhed F

Subjects
Adult, Aged, Bacteria classification, Bacteria genetics, Bacteria isolation & purification, Bacteria metabolism, Cohort Studies, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 metabolism, Female, Histidine metabolism, Humans, Male, Middle Aged, Diabetes Mellitus, Type 2 microbiology, Gastrointestinal Microbiome, Imidazoles blood
Abstract

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism.

Published
2020
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