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 will investigate 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. Second, to clarify these responses in detail we will use bioreactors and investigate how microbiomes from patients and healthy controls respond to high/low protein diets as well as aromatic amino acids with the hypothesis that the microbiome produces bioactive compounds. We have identified one metabolite, imidazole propionate (ImP) from histidine, which is increased in blood of subjects with prediabetes and T2D. Further experiments have demonstrated that ImP can directly impair insulin sensitivity. Thus, we will investigate whether a low-protein diet (thus low in histidine) improves metabolism, alters the microbiota and reduces diabetogenic metabolites such as ImP in T2D patients of different ethnicities. Finally, we will confirm if the microbiome produces ImP in humans using isotope-labelled histidine.

1.2 Highlights

The consortium published a paper in Nature Communication confirming that the microbial metabolite imidazole propionate is associated with type 2 diabetes and that production of the metabolite is not affected by dietary intake of histidine, but rather an altered microbiota in metabolic disesae.

We are also proud that we managed to continue clinical work during the pandemic and finish the clinical intervention study on high and low protein diets in subjects with different ethnicities. Samples are being extracted/sequenced. 


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 geography10.1038/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.
3. Aron-Wisnewsky J, Warmbrunn MV, Nieuwdorp M, Clément K. .Nonalcoholic Fatty Liver Disease: Modulating Gut Microbiota to Improve Severity? 10.1053/j.gastro.2020.01.049.
2. Aron-Wisnewsky J, Vigliotti C, Witjes J, Le P, Holleboom AG, Verheij J, Nieuwdorp M ( JPI HDHL Project Partner), Clément K ( JPI HDHL Project Partner). Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. 10.1038/s41575-020-0269-9
Aron-Wisnewsky J, Clément K (JPI HDHL Project Partner), Nieuwdorp M (JPI HDHL Project Partner). Fecal Microbiota Transplantation: a Future Therapeutic Option for Obesity/Diabetes?10.1007/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.
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.

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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