Metabolic HEALTH through nutrition, microbiota, and tryptophan bioMARKers
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, Phascolarctobacterium, Dialister, 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.
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.
|German Center for Neurodegenerative Diseases, "Deutsches Zentrum für Neurodegenerative Erkrankungen e. V." (DZNE)
|National Research Institute for Agriculture, Food and Environment, “Institut national de recherche pour l’agriculture, l’alimentation et l’environnement” (INRAE)
|University College Cork/Teagasc (UCC/Teagasc)
|Edmund Mach Foundation, “Fondazione Edmund Mach” (FEM)
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.
Author: Cowan CSM*, Hoban AE, Ventura-Silva AP, Dinan TG*, Clarke G*, Cryan JF*
Author: Oluwagbemigun K*, Buyken AE, Alexy U, Schmid M, Herder C, Nöthlings U*
Author: Anesi A*, Rubert J*, Oluwagbemigun K*, Orozco-Ruiz X*, Nöthlings U*, Breteler MMM*, Mattivi F*
Author: Estrada, S, Lu, R, Conjeti, S, Orozco‐Ruiz X*, Panos‐Willuhn J, Breteler MMB*, Reuter M.
Author: Oluwagbemigun K*, Anesi A*, Ulaszewska M*, Clarke G*, Alexy U, Schmid M, Roden M, Herder C, Mattivi F*, Nöthlings U*
Author: Cussotto S, Delgado I*, Anesi A*, Dexpert S, Aubert A, Beau C, Forestier D, Ledaguennel P, Magne E, Mattivi F*, Capuron L*
Author: Oluwagbemigun K*, O'Donovan AN, Berding K, Lyons K, Alexy U, Schmid M, Clarke G*, Stanton C*, Cryan J*, Nöthlings U*
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.