HEALTHMARK

Metabolic HEALTH through nutrition, microbiota, and tryptophan bioMARKers

Project description

Background and aim

HEALTHMARK investigated the complex associations between diet, microbiota, tryptophan metabolites of microbial metabolism, and metabolic health in a set-up of identification, replication, and validation of associations. The project, organized in five work packages (WP) comprised two observational and two intervention studies.

In WP1, the University of Bonn (UB) using the DOrtmund Nutritional and Anthropometric Longitudinally Designed Study identified long-term body mass index trajectories and observed their association with cardiometabolic risk markers (CRM) such as interleukin-18. Besides, long-term overweight was associated with decreased levels of indole-3-acetic acid and several amino acids, including indole-3-carboxaldehyde were associated with elevated C-reactive protein (CRP). Finally, carbohydrate intake was associated with the relative abundance of some gut bacteria, PhascolarctobacteriumDialister, and Desulfovibrio.

In WP2, the German Center for Neurodegenerative Diseases, "Deutsches Zentrum für Neurodegenerative Erkrankungen e. V." (DZNE) using the Rhineland Study developed novel methods to automatically segment body fat distribution from MRI recordings. It was also observed that branched-chain amino acids (BCAA) and aromatic amino acids (AAA) metabolites are important biomarkers of some CRM and partial mediators of the association between visceral adipose tissue and CRM.

In WP3, the National Research Institute for Agriculture, Food and Environment, “Institut national de recherche pour l’agriculture, l’alimentation et l’environnement” (INRAE) using the Obesity Study measured plasma levels of tryptophan, and its metabolites, other AAA, and BCAA  before and after surgery-induced weight loss. Severe or morbid obesity was associated with increased ratio kynurenine/tryptophan, high plasma levels of 5-hydroxyindole- 3-acetic acid, and low plasma levels of tryptophan, serotonin, indole-3-propionic acid, indole-3-acetic acid, indole-3-lactic acid, and indoxyl sulfate. Moreover, kynurenine and tryptophan indole metabolites were associated with CRP and interleukin-6.

In WP4, the University College Cork/Teagasc (UCC/Teagasc) conducted a clinical investigation on the efficacy of probiotic Lactobacillus mucosae DPC6426 as a nutritional agent to modulate tryptophan metabolism and metabolic biomarkers in mildly hypercholesteremic adults. The counts of Lactobacillus increased in stool samples, but the probiotic had no effect on either total blood cholesterol or microbial diversity.

In WP5, the Edmund Mach Foundation, “Fondazione Edmund Mach” (FEM) developed and performed targeted metabolomic profiling of biofluids for the putative biomarkers of metabolic health for the WPs, 672 urine samples from WP1, 1000 plasma samples from WP2, and 104 plasma samples from WP3. FEM also built an in-house spectral library for structural elucidation and comparison of metabolites from these samples. Some samples also underwent untargeted metabolomics profiling.

Expected impact

HEALTHMARK characterized phenotypes of metabolic health and found specific biomarkers which could help to stratify populations. In addition, its focus on the development of adiposity phenotypes through tracking of body mass index from childhood to adulthood help identify early determinants of metabolic health. Furthermore, the project derived reliable biomarker signatures which could be helpful for monitoring key biological processes on the trajectory to metabolically driven diseases. The use of a number of human population studies allowed the study of tryptophan metabolites and microbial bioactives in a range of different biosamples (plasma and urine) and microbial composition (stool) in a population approach.

Metabolic markers that are modulated by diet are critical to tackling the ongoing public health problem of obesity in the population. HEALTHMARK yielded potential recommendations for dietary intake for strata of the population at risk for certain metabolic phenotypes from childhood through to adulthood. Examining dietary nutrients in relation to the microbiota could inform the development of gut microbiota–targeted dietary recommendations for disease prevention. This knowledge may also benefit industry partners who focus on the optimization of food and drink products. The methodological approaches developed under HEALTHMARK is also of great value to the assessment of metabolic health and disease. The metabolomics data produced at the project partner FEM (WP5) adopted technologies and workflows, which support interoperable bioscience data, making use of existing processing pipelines, in the context of open-source software for MS-based metabolomics experiments developed in-house. WP5 also ensured IP protection, which will foster future projects in the consortium and can assist others
who have to tackle similar questions. Furthermore, HEALTHMARK is strongly embedded in ongoing human studies, thus creating an added value with respect to availability of sample collection and biochemical measures such as concentration of selected metabolites and gut microbiota composition. Identical analytical procedures across studies also facilitated comparability across studies and strengthened the interpretation of findings.

Consortium

Partner Organization Partner Country
German Center for Neurodegenerative Diseases, "Deutsches Zentrum für Neurodegenerative Erkrankungen e. V." (DZNE) Germany
National Research Institute for Agriculture, Food and Environment, “Institut national de recherche pour l’agriculture, l’alimentation et l’environnement” (INRAE) France
University College Cork/Teagasc (UCC/Teagasc) Ireland
Edmund Mach Foundation, “Fondazione Edmund Mach” (FEM) Italy

Highlights

HEALTHMARK investigated the complex associations between diet, microbiota, tryptophan metabolites of microbial metabolism, and metabolic health in a set-up of identification, replication, and validation of associations. HEALTHMARK observed the association of long term body mass index, visceral adipose tissue and severe or morbid obesity with cardiometabolic risk markers. It also established the link of tryptophan and its metabolites, other aromatic amino acid metabolites and branched-chain amino acids with cardiometabolic risk markers. The project also observed the impact of dietary intake, particularly carbohydrate intake on the composition of the gut microbiome. In addition, probiotic Lactobacillus mucosae DPC6426 did not show effect on total blood cholesterol or gut microbial diversity. Finally, a validated state-of-the-art targeted metabolomic profiling method was used to quantify metabolites in the biofluids within the consortium.

Products

Title: Gutsy Moves: The Amygdala as a Critical Node in Microbiota to Brain Signaling
Author: Cowan CSM*, Hoban AE, Ventura-Silva AP, Dinan TG*, Clarke G*, Cryan JF*
Link: https://doi.org/10.1002/bies.201700172
Title: Developmental trajectories of body mass index from childhood into late adolescence and subsequent late adolescenceyoung adulthood cardiometabolic risk markers
Author: Oluwagbemigun K*, Buyken AE, Alexy U, Schmid M, Herder C, Nöthlings U*
Link: https://doi.org/10.1186/s12933-019-0813-5
Title: Metabolic profiling of human plasma and urine, targeting tryptophan, tyrosine and branched chain amino acid pathways.
Author: Anesi A*, Rubert J*, Oluwagbemigun K*, Orozco-Ruiz X*, Nöthlings U*, Breteler MMM*, Mattivi F*
Link: https://doi.org/10.3390/metabo9110261
Title: FatSegNet: A fully automated deep learning pipeline for adipose tissue segmentation on abdominal dixon MRI.
Author: Estrada, S, Lu, R, Conjeti, S, Orozco‐Ruiz X*, Panos‐Willuhn J, Breteler MMB*, Reuter M.
Link: https://doi.org/10.1002/mrm.28022
Title: Longitudinal investigation into the relationship of amino acids and indole metabolites with long-term body mass index and cardiometabolic risk markers in young individuals.
Author: Oluwagbemigun K*, Anesi A*, Ulaszewska M*, Clarke G*, Alexy U, Schmid M, Roden M, Herder C, Mattivi F*, Nöthlings U*
Link: https://doi.org/10.1038/s41598-020-63313-z
Title: Microbial tryptophan metabolites are differentially affected by inflammation in obesity
Author: Cussotto S, Delgado I*, Anesi A*, Dexpert S, Aubert A, Beau C, Forestier D, Ledaguennel P, Magne E, Mattivi F*, Capuron L*
Link: https://doi.org/10.3389/fimmu.2020.00557
Title: Long-term dietary intake from infancy to late adolescence is associated with gut microbiota composition in young adulthood.
Author: Oluwagbemigun K*, O'Donovan AN, Berding K, Lyons K, Alexy U, Schmid M, Clarke G*, Stanton C*, Cryan J*, Nöthlings U*
Link: https://doi.org/10.1093/ajcn/nqaa340

Reports


Endreport

HEALTHMARK observed biomarker signatures of metabolic health to be  tryptophan and its metabolites, other aromatic amino acid metabolites, branched-chain amino acids, and some gut bacteria. Some of these signatures could be modulated by diet and they may aid in monitoring key biological processes on the trajectory to metabolically driven diseases. The metabolomic profiling method in the project will support clinical and epidemiological investigation of several important biological questions and opening up new possibilities for nutritional studies aimed at understanding and preventing disease. Indeed, the set-up of identification, replication and validation of findings within HEALTHMARK gave rise to strong research findings in the area of microbiota-derived bioactive and metabolic health.

Target group Authors Means of communication Hyperlink Pdf
Scientists Cryan, J.F. (UCC/Teagasc),“The microbiome – A key regulator of brain & behaviour across the lifespan”, Santander Biomedical Lecture, Santander, Spain, March 2017 Special lecture    
Scientists Stanton, C. (UCC/Teagasc), “Gut microbiota in developing neonates”, 116th Abbott Nutrition Research Conference, Abott Nutrition Health Institute, Ohio, USA, April 2017 Presentation    
Scientists Stanton, C. (UCC/Teagasc) “Synbiotics effects on extra-intestinal targets”, International Scientific Association of Probiotics and Prebiotics, Chicago, USA, June 2017 Presentation    
Scientists, government representatives, industry, farmers Stanton, C. (UCC/Teagasc), “Microbiome-based solutions for early life nutrition”, Teagasc Authority Meeting, Kilkenny, Ireland, July 2017 Presentation    
Scientists Dinan, T. G (UCC/Teasgac), “Microbes and brain function”, FEMS (Federation of European Microbiological Societies) meeting, Valencia, Spain, July 2017 Presentation    
Scientists Cryan, J.F. (UCC/Teagasc), “Gut feelings: The microbiota as a key regulator of brain and behaviour across the lifespan”. International Society for Nutritional Psychiatry Research, Bethesda, USA, July 2017 Plenary lecture    
Academic Fallahghohroudy, A., Oluwagbemigun, K. (UB), “The relation between the dietary patterns (short-term and long-term) on the gut microbiota: systematic review”, Master course, project practical, Bonn, July 2017 Master’s course report    
Scientists Kloster, T., Oluwagbemigun, K. (UB), “The influence of the gut microbiota on blood lipids and short-chain fatty acids: a systematic review”, Master course, project practical, Bonn, July 2017 Master’s course report    
Scientists, industry Cowan, C. S. M., Dinan, T. G., Cryan, J.F. (UCC/Teagasc), “Towards psychobiotics: Microbiome, brain and behaviour”, Gut-Brain Axis Summit, San Francisco, C.A., August 2017 Presentation    
Physicians Cryan, J.F. (UCC/Teasgac), “A gut (microbiome) feeling about the brain” Nutricia Nutrition, Royal College of Physicians, London, November 2017 Presentation    
Scientists Mattivi, F., Nöthlings, U., Oluwagbemigun, K. (UB and FEM), "Gut microbiota and tryptophan metabolism - implications for human health", 9th Probiotics, Prebiotics & New foods, Nutraceuticals and Botanicals for Nutrition & Human and Microbiota Health. Rome; Italy, September 2017 Invited lecture    
Scientists Dinan, T. G. (UCC/Teagasc), “Psychobiotics”, 17th International Forum on Mood and Anxiety Disorders, Madrid, Spain, December 2017 Presentation    
General public & scientists Cowan, C.S.M., Hoban, A. E., Ventura-Silva, A. P., Dinan, T. G., Clarke, G., Cryan, J. F. (UCC/Teagasc), “BioEssays: Gutsy Moves: The Amygdala as a Critical Node in Microbiota to Brain Signaling”, December 2017 Video on microbiota & amygdala interactions to support review article published in BioEssays: youtube.com/watch?v=O5gvxVJjX18    
Scientists Cowan, C.S.M., Hoban, A. E., Ventura-Silva, A. P., Dinan, T. G., Clarke, G., Cryan, J. F. (UCC/Teagasc), “BioEssays: Gutsy Moves: The Amygdala as a Critical Node in Microbiota to Brain Signaling”, January 2018 Journal cover art    
Scientists Cowan, C.S.M., Dinan, T. G., Cryan, J. F. (UCC/Teagasc), “Gut-brain axis: Focus on the brain and behaviour.”, The 5th Nutrition Winter School, Levi, Finland, January 2018 Presentation    
Scientists, industry Cryan, J.F. (UCC/Teagasc),“New advances: Diet and microbiome.” International Life Science Institute – North America Annual Meeting, Bermuda, January 2018 Presentation    
Academic Petri N., Mattiivi F. (FEM), “Sviluppo e prima validazione di un metodo per la quantificazione dei metaboliti del triptofano nel plasma umano mediante cromatografia liquida abbinata a spettrometria di massa”, Master Thesis LM-61, University of Florence, February 2018 Master thesis    
Scientist Orozco-Ruiz X. (DZNE), “The Rhineland Study in DietBB: Prevalence and Characteristics of Metabolic Phenotypes”. The Symposium der Kompetenzcluster der Ernährungsforschung. Freising, Germany, March 2018. Presentation    
Scientists Orozco-Ruiz X. (DZNE), “Prevalence and characteristics of metabolic phenotypes: the Rhineland Study (Germany). European Congress of Epidemiology, Lyon, France, July 2018. Presentation    
Scientists Oluwagbemigun, K., (UB), “Developmental trajectories of body mass index from childhood into late adolescence and subsequent late adolescence young adulthood cardiometabolic risk markers”, 26th European Congress on Obesity, 29 April 2019. Poster    
Scientists Oluwagbemigun, K. (UB), “Longitudinal investigation into the relationship of amino acids and indole metabolites with long-term body mass index and cardiometabolic risk markers in young individuals”, DietBB annual meeting. 11 October 2019 Poster    
Scientist Orozco-Ruiz X. (DZNE), “Association of visceral and subcutaneous adipose tissue with metabolic health in the Rhineland Study”, DietBB annual meeting. 11 October 2019 Poster    
Scientists Capuron, L.. (INRAE), “Nutritional habits, obesity and neuropsychiatric symptoms”, International Society for Nutritional Psychiatry Research, London, UK, October 2019. Presentation    
Scientists Orozco-Ruiz X. (DZNE), “Association of Tryptophan, Tyrosine and Branched Chain Amino acids metabolites with abdominal obesity and cardiometabolic risk factors", CHARGE meeting, Hoston Tx, 29-31 January 2020 Poster    
Scientists Delgado, I., Capuron, L., (INRAE), “Adiposity-driven inflammatory mechanisms in obesity: role in neuropsychiatric comorbidities”, ECOICO Online 2020, via Zoom, September 2020 Presentation    
Scientists Orozco-Ruiz X. (DZNE), “Association of BCAAs and AAAs metabolites with abdominal fat and cardiometabolic risk factors”. DietBB annual meeting. 2 October 2020 Poster    
Scientists Anesi, A. (UB, FEM) “Metabolic profiling of human plasma and urine, targeting tryptophan, tyrosine and branched chain amino acid pathways”, Metabolomics 2020. October 27-29, 2020 Poster    
Scientists Cryan J.F. (UCC/Teagasc) “Microbiota and the Brain”, Online Retreats with the World Leaders (Italy), 2020 Workshop    
Scientists Cryan J.F. (UCC/Teagasc) “Microbiota-Gut Axis along human life, GMFH 2020 Wold Summit (Spain), 2020 Conference    
Scientists Cryan J.F. (UCC/Teagasc) “Gut microbiome, brain and behavior”, Molecular Mechanisms Linking the Microbiome and Human Health (USA), 2020 Conference    
Scientists Cryan J.F. (UCC/Teagasc) “A Gut Feeling about the Brain: Microbiome as a Key Regulator of Neurodevelopment and Behaviour”, Congresso Futuro Chile (Chile), 2020 Conference    
Scientists Cryan J.F. (UCC/Teagasc) “Gut Feelings: Diet-Microbiome-Gut- Brain axis”, Gran Sasso Forum (online), 2020 Seminar    
  Cryan J.F. (UCC/Teagasc) “Microbiome and Mental Health”, NYAS Webinar (online), 2020 Seminar    
Primary school students Cowan, C.S.M. (co-facilitated) (UCC/Teagasc), “Budding Biologist” workshop, UCC, Ireland, May 2017 Workshop    
General public Cryan, J.F. (UCC/Teagasc), “Feed your microbes – nurture your mind”, TEDx H’apenny Bridge, Dublin, June 2017 Presentation    
Primary school students Cowan, C.S.M. (co-facilitated) (UCC/Teagasc), “Microbe Magic” workshop, Local school, Ireland, November 2017 Workshop    
General public Cowan, C.S.M. (assisted) (UCC/Teagasc), "Science Week:" UCC open day, November 2017 Information stand    
General public Berding K. (UCC/Teagasc), “You are what you eat: Diet, Microbiota and Health”, World Microbiome Day (online) Seminar    
General public Berding K. (UCC/Teagasc), “Food, mood and microbes”, Conversation café, Cork, 2020 Round table discussion    

Subjects

Features

Project number:
HEALTHMARK
Duration: 100%
Duration: 100 %
2017
2021
Related subsidy round:
Project lead and secretary:
Prof Ute Nöthlings