Understand and prevent production of microbially-produced pro-diabetic metabolites in different ethnic groups: impact of protein dietary changes

HDHL INTIMIC cofunded call “Interrelation of the Intestinal Microbiome, Diet and Health” (IM 2017)
Understand and prevent production of microbially-produced pro-diabetic metabolites in different ethnic groups: impact of protein dietary changes
Fredrik Bäckhed
University of Gothenburg


Partner Organization Partner Country
UMRS 1166 UniversityFrance
AMC Department of Internal and Vascular MedicineThe Netherlands

1. Overall project description

1.1 Summary

Metabolic disorders such as obesity and type 2 diabetes (T2D) represent a growing unmet clinical need. Accumulating evidence shows that the collection of microbes residing within the human intestinal tract influence host metabolism. Diet is one of the most important factors shaping the gut microbiome. So far, mainly microbial metabolism of dietary fibers has been studied, with less emphasis on dietary proteins. Here we investigated how existing metagenome data available from different ethnicities is associated with different dietary patterns and test how they respond to diets high and low in proteins. To this end, we first performed cross-sectional analysis of two European cohorts (MetaCardis, n = 1759; HELIUS, n = 1528). There was no significant association between protein intake (total, animal, or plant) with either gut microbiota alpha diversity or beta diversity, regardless of ethnicity, but daily intake of (animal) protein was associated with glucose and lipid metabolism and T2D, which was independent of ethnic background. Next, we performed a dietary intervention with high or low protein for 12 weeks to invesitage the effect on the microbiota in individuals of Caribbean or Caucasian descent as well as with or without T2D, but did not find any effect on weight, glucose and lipid metabolism, nor microbiota composition. However, we did observe a significant change in plasma metabolites eg phenylacetylglutamine was increased following high protein intake, whereas indole 3 propionic acid was increased inlow protein diet. Third, using bioreactors we observed that the gut microbiota is associated with altered production of amino acid derived metabolites, especially branched chain and aromatic amino acids. However, we did not observe strong effects of media containing low or high protein content, which may be explained by that the low-protein media may contain too high protein levels to detect a difference, or alternatively the chemical environment is different in the bioreactors. One main focus in the grant was to further explore how the gut microbiota produces imidazole propionate and we first validated our findings in different ethnicities. Finally, we adminsiteredoral histidine before and after oral antibiotics to individuals with or without T2D an surprisingly found that ImP levels increased after antibiotics, suggestig that the low diverse envrionment promote ImP production. In summary, we have found that dietary protein intake has no major impact on gut microbiota composition and that production of bioactive metabolites is determined by both microbial composition, chemical environment, and substrate availability. Exploring this interaction more closely may provide increased understanding for how gut microbiota affects protein metabolism and production of bioactive amino acid derived metabolites.

1.2 Highlights

The consortium has identified that diet, including animal protein, is associated with a small but significant effect on gut microbiota compositionFurthermore, we have demonstrated that the gut microbiota can produce bioactive metabolites from amino acids, but that these may not primarily originate from the diet, but rather by altered metabolic capacity in the microbiota.

Indeed, patients with type 2 diabetes have an altered microbiota that produce increased levels of imidazole propionate, which is confirmed in patients of different ethnicities. Interestingly, antibiotics change the dynamics in the gut leading to increased levels of imidazole propionate and we are currently exploring which bacteria that are responsible. Collectively, we found that protein composition (notably animal proteins) in human diet have a relatively small effect on gut microbiota composition, but that the gut microbiota in type 2 diabetes processes histidine alternatively, which may contribute to diabetes development both in subject with a Caucasian or Caribbean background. 

4. Impact

4.1 List of publications

AuthorsTitleYear, Issue, PPPartners NumberDoiPdf
Mélanie Deschasaux, Kristien E. Bouter, Andrei Prodan, Evgeni Levin, Albert K. Groen, Hilde Herrema, Valentina Tremaroli, Guido J. Bakker, Ilias Attaye, Sara-Joan Pinto-Sietsma, Daniel H. van Raalte, Marieke B. Snijder, Mary Nicolaou, Ron Peters, Aeilko H. Zwinderman, Fredrik Bäckhed (JPI HDHL Project Partner) and Max Nieuwdorp (JPI HDHL Project Partner)Depicting the composition of gut microbiota in a population with varied ethnic origins but shared geography2018 Oct;24(10):1526-15311 and 310.1038/s41591-018-0160-1
Olsson LM, Poitou C, Tremaroli V, Coupaye M, Aron-Wisnewsky J, Bäckhed F (JPI HDHL Project Partner), Clément K (JPI HDHL Project Partner), Caesar R. Gut microbiota of obese subjects with Prader-Willi syndrome is linked to metabolic health.69(7): 1229-12381 and 2
Aron-Wisnewsky J, Warmbrunn MV, Nieuwdorp M, Clément K. .Nonalcoholic Fatty Liver Disease: Modulating Gut Microbiota to Improve Severity? 2 and 310.1053/j.gastro.2020.01.049.
2. Aron-Wisnewsky J, Vigliotti C, Witjes J, Le P, Holleboom AG, Verheij J, Nieuwdorp M*, Clément K*. Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. 2,310.1038/s41575-020-0269-9
Aron-Wisnewsky J*, Clément K*, Nieuwdorp M*. Fecal Microbiota Transplantation: a Future Therapeutic Option for Obesity/Diabetes?2,310.1007/s11892-019-1180-z
Verhaar, B.J.H., Collard, D., Prodan, A., Levels, J.H.M., Zwinderman, A.H., Bäckhed, F*., Vogt, L., Peters, M.J.L., Muller, M., Nieuwdorp, M*., van den Born, B.J.H. Associations between gut 1 microbiota, faecal short chain fatty acids and blood pressure across ethnic groups: the HELIUS study.1,3
Molinaro, A*., Bel Lassen, P*., Henricsson, M*., Wu, H., Adriouch, S., Belda, E., Chakaroun, R., Nielsen, T., Bergh, P.O., Rouault, C., André, S., Marquet, F., Andreelli, F., Salem, J.E., Assmann, K., Bastard, J.P., Forslund, S., Le Chatelier, E., Falony, G., Pons, N., Prifti, E., Quinquis, B., Roume, H., Vieira-Silva, S., Hansen, T.H., Pedersen, H.K., Lewinter, C., Sønderskov, N.B.; MetaCardis Consortium, Køber, L., Vestergaard, H., Hansen, T., Zucker, J.D., Galan, P., Dumas, M.E., Raes, J., Oppert, J.M., Letunic, I., Nielsen, J., Bork, P., Ehrlich, S.D., Stumvoll, M., Pedersen, O., Aron-Wisneswky, J*., Clément, K*., Bäckhed, F*. Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology. 2020 Dec 21;11(1):6448.1,210.1038/s41467-020-19589-w
Pierre Bel Lassen, Ilias Attaye, Solia Adriouch, Mary Nicolaou, Judith Aron-Wisnewsky, Trine Nielsen, Rima Chakaroun, Emmanuelle Le Chatelier , Sofia Forslund, Eugeni Belda, Peer Bork, Fredrik Bäckhed*, Michael Stumvoll, Oluf Pedersen, Hilde Herrema, Albert K Groen, Sara-Joan Pinto-Sietsma, Aeilko H Zwinderman, Max Nieuwdorp, Karine Clement*Protein Intake, Metabolic Status and the Gut Microbiota in Different Ethnicities: Results from Two Independent Cohorts2021 Sep 10;13(9):31591,2,310.3390/nu13093159
Bel Lassen P, Belda E, Prifti E, Dao MC, Specque F, Henegar C, Rinaldi L, Wang X, Kennedy SP, Zucker JD, Calame W, Lamarche B, Claus SP, Clément K.Protein supplementation during an energy-restricted diet induces visceral fat loss and gut microbiota amino acid metabolism activation: a randomized trial.2021 Aug 2;11(1):15620210.1038/s41598-021-94916-9
): Alili R, Belda E, Le P, Wirth T, Zucker JD, Prifti E, Clément K. Exploring Semi-Quantitative Metagenomic Studies Using Oxford Nanopore Sequencing: A Computational and Experimental Protocol.2021 Sep 25;12(10):1496210.3390/genes12101496
Dao MC, Thiron S, Messer E, Sergeant C, Sévigné A, Huart C, Rossi M, Silverman I, Sakaida K, Bel Lassen P, Sarrat C, Arciniegas L, Das SK, Gausserès N, Clément K, Roberts SB.Cultural Influences on the Regulation of Energy Intake and Obesity: A Qualitative Study paring Food Customs and Attitudes to Eating in Adults from France and the United States.Dec 28;13(1):63210.3390/nu13010063
Ilias Attaye, Sara-Joan Pinto-Sietsma, Hilde Herrema, Max Nieuwdorp A Crucial Role for Diet in the Relationship Between Gut Microbiota and Cardiometabolic Disease2020 Jan 27;71:149-161310.1146/annurev-med-062218-023720
Alili R, Belda E, Fabre O, Pelloux V, Giordano N, Legrand R, Bel Lassen P, Swartz TD, Zucker JD, Clément K.Characterization of the Gut Microbiota in Individuals with Overweight or Obesity during a Real-World Weight Loss Dietary Program: A Focus on the Bacteroides 2 Enterotype.2022, 10(1), 162 10.3390/biomedicines10010016
): Ilias Attaye, Eduard W J van der Vossen, Diogo N Mendes Bastos, Max Nieuwdorp, Evgeni LevinIntroducing the Continuous Glucose Data Analysis (CGDA) R Package: An Intuitive Package to Analyze Continuous Glucose Monitoring Data2022 Jan 19;19322968211070293310.1177/19322968211070293
Ilias Attaye, Moritz V Warmbrunn, Aureline N A F Boot, Suze C van der Wolk, Barbara A Hutten, Joost G Daams, Hilde Herrema, Max Nieuwdorp A systematic review and meta-analysis of dietary interventions modulating gut microbiota and cardiometabolic diseases - striving for new standards in microbiome studies2022 Feb 10;S0016-5085(22)00138-X310.1053/j.gastro.2022.02.011
): Belda E, Voland L, Tremaroli V, Falony G, Adriouch S, Assmann KE, Prifiti E, Aron-Wisnewsky J, Debédat J, Le Roy T, Nielsen T, Amouyal C, André S, Andreelli F, Blüher M, Chakaroun R, Chilloux J, Coelho LP, Dao MC, Das P, Fellahi S, Forslund S, Galleron N, Hansen TH, Holmes B, Ji B, Krogh Pedersen H, Le P, Le Chatelier E, Lewinter C, Mannerås-Holm L, Marquet F, Myridakis A, Pelloux V, Pons N, Quinquis B, Rouault C, Roume H, Salem JE, Sokolovska N, Søndertoft NB, Touch S, Vieira-Silva S; MetaCardis Consortium, Galan P, Holst J, Gøtze JP, Køber L, Vestergaard H, Hansen T, Hercberg S, Oppert JM, Nielsen J, Letunic I, Dumas ME, Stumvoll M, Pedersen OB, Bork P, Ehrlich SD, Zucker JD, Bäckhed F*, Raes J, Clément K.Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism.epublished ahead of print1,2 10.1136/gutjnl-2021-325753
Jean Debédat, Tiphaine Le Roy, Lise Voland, Eugeni Belda, Rohia Alili, Solia Adriouch, Pierre Bel Lassen, Kazuyuki Kasahara, Evan Hutchison, Laurent Genser, Licia Torres, Camille Gamblin, Christine Rouault, Jean-Daniel Zucker, Nathalie Kapel, Christine Poitou, Geneviève Marcelin, Federico E. Rey, Judith Aron-Wisnewsky & Karine ClémentThe human gut microbiota contributes to type-2 diabetes non-resolution 5-years after Roux-en-Y gastric bypassepublished210.1080/19490976.2022.2050635
Lisa Olsson, Fredrik Boulund, Staffan, Muhammad Tanweer Khan, Anders Gummesson, Linn Fagerberg, Lars Engstrand, Rosie Perkins, Mathias Uhlén, Göran Bergström, Valentina Tremaroli, Fredrik BäckhedDynamics of the normal gut microbiota: a longitudinal one-year population study in SwedenIn Press1

4.2 Presentation of the project

Target groupAuthorsMeans of communicationHyperlinkPdf
trainees in metabolism and NutritionJean Débedat (presenter), Karine Clement; Causal role of the intestinal microbiota in the modulation of carbohydrate and weight phenotypes after bariatric surgery in mice » Congres of CMDO, Canada 2019oral
scientistsJean Debedat (presnenter), Karine Clement; ausal role of the intestinal microbiota in the modulation of carbohydrates and weight phenotypes after bariatric surgery in mice. French Association for the Study of Diabetes (SFD).March 2019oral
scientistsPierre Bel Lassen Doctoral school days (scientific audience, Paris 2019): Microbially produced Imidazole propionate: a risk marker for Type 2 diabetes in humans? May 2019
scientistsFredrik Backhed Netherlands Gut Day 5 december 2019oral
King and Queen of NetherlandsNieuwdorp presentation for the king and queen and 100 guests at Royal Palace in Amsterdam oral
scientistsKarine Clément “Malnutrition” and gut microbiota in the modern world; lesson from current knowledge in diabetes and metabolic diseases”. FENS, October 2019video
scientistsMicrobiome and Metabolic Diseases? The Korean Society international conference “Nutrition and the microbiome for human health; current understanding and future perspective, November 6, 2020; > 500 attendees. Onlineonline
scientistsLe microbiote intestinal est-il important pour la résolution du diabète post-chirurgie bariatrique ? French Society of Nutrition, November 25-27, 2020. Online > 200 attendeesonline
scientistsGut Microbiome and NAFLD/NASH; Dutch Diabetes Academy. December, 1st 2020online

4.3 List of submitted patents and other outputs

Patent licencePartners involvedYearInternational eu or national patentCommentPdf

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This project has received funding from the European Union’s
H2020 Research and Innovation Programme under grant agreement n.696300

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