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

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.


Partner Organization Partner Country
UMRS 1166 University France
AMC Department of Internal and Vascular Medicine Netherlands



  • 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. 


Title: Depicting the composition of gut microbiota in a population with varied ethnic origins but shared geography
Author: 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)
Link: https://doi.org/10.1038/s41591-018-0160-1
Title: Gut microbiota of obese subjects with Prader-Willi syndrome is linked to metabolic health.
Author: 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.
Link: https://doi.org/10.1136/gutjnl-2019-319322
Title: Nonalcoholic Fatty Liver Disease: Modulating Gut Microbiota to Improve Severity?
Author: Aron-Wisnewsky J, Warmbrunn MV, Nieuwdorp M, Clément K. .
Link: https://doi.org/10.1053/j.gastro.2020.01.049
Title: Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders.
Author: 2. Aron-Wisnewsky J, Vigliotti C, Witjes J, Le P, Holleboom AG, Verheij J, Nieuwdorp M*, Clément K*.
Link: https://doi.org/10.1038/s41575-020-0269-9
Title: Fecal Microbiota Transplantation: a Future Therapeutic Option for Obesity/Diabetes?
Author: Aron-Wisnewsky J*, Clément K*, Nieuwdorp M*.
Link: https://doi.org/10.1007/s11892-019-1180-z
Title: Associations between gut 1 microbiota, faecal short chain fatty acids and blood pressure across ethnic groups: the HELIUS study.
Author: 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.
Link: https://doi.org/10.1093/eurheartj/ehaa704
Title: 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, 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., Op
Link: https://doi.org/10.1038/s41467-020-19589-w
Title: Protein Intake, Metabolic Status and the Gut Microbiota in Different Ethnicities: Results from Two Independent Cohorts
Author: 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*
Link: https://doi.org/10.3390/nu13093159
Title: Protein supplementation during an energy-restricted diet induces visceral fat loss and gut microbiota amino acid metabolism activation: a randomized trial.
Author: 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.
Link: https://doi.org/10.1038/s41598-021-94916-9
Title: Exploring Semi-Quantitative Metagenomic Studies Using Oxford Nanopore Sequencing: A Computational and Experimental Protocol.
Author: ): Alili R, Belda E, Le P, Wirth T, Zucker JD, Prifti E, Clément K.
Link: https://doi.org/10.3390/genes12101496
Title: 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.
Author: 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.
Link: https://doi.org/10.3390/nu13010063
Title: A Crucial Role for Diet in the Relationship Between Gut Microbiota and Cardiometabolic Disease
Author: Ilias Attaye, Sara-Joan Pinto-Sietsma, Hilde Herrema, Max Nieuwdorp
Link: https://doi.org/10.1146/annurev-med-062218-023720
Title: 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.
Author: Alili R, Belda E, Fabre O, Pelloux V, Giordano N, Legrand R, Bel Lassen P, Swartz TD, Zucker JD, Clément K.
Link: https://doi.org/10.3390/biomedicines10010016
Title: Introducing the Continuous Glucose Data Analysis (CGDA) R Package: An Intuitive Package to Analyze Continuous Glucose Monitoring Data
Author: Ilias Attaye, Eduard W J van der Vossen, Diogo N Mendes Bastos, Max Nieuwdorp, Evgeni Levin
Link: https://doi.org/10.1177/19322968211070293
Title: A systematic review and meta-analysis of dietary interventions modulating gut microbiota and cardiometabolic diseases - striving for new standards in microbiome studies
Author: 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
Link: https://doi.org/10.1053/j.gastro.2022.02.011
Title: Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism.
Author: ): 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; MetaCa
Link: https://doi.org/10.1136/gutjnl-2021-325753
Title: The human gut microbiota contributes to type-2 diabetes non-resolution 5-years after Roux-en-Y gastric bypass
Author: 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 Clément
Link: https://doi.org/10.1080/19490976.2022.2050635
Title: Dynamics of the normal gut microbiota: a longitudinal one-year population study in Sweden
Author: Lisa Olsson, Fredrik Boulund, Staffan, Muhammad Tanweer Khan, Anders Gummesson, Linn Fagerberg, Lars Engstrand, Rosie Perkins, Mathias Uhlén, Göran Bergström, Valentina Tremaroli, Fredrik Bäckhed
Link: https://doi.org/10.1016/j.chom.2022.03.002

Communication & Dissemination Activities

Target groupAuthorsMeans of communication
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 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 2019oral
King and Queen of NetherlandsNieuwdorp presentation for the king and queen and 100 guests at Royal Palace in Amsterdamoral
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


Project number:
Duration: 100%
Duration: 100 %
Project lead and secretary:
Fredrik Bäckhed