HDHL-INTIMIC Cofunded Call "Interrelation of the Intestinal Microbiome, Diet and Health"

Description of the call and funded projects

In January 2017, the first joint funding action of the ERA-Net Cofund “Interrelation of the INtesTInal MICrobiome, Diet and Health” (HDHL-INTIMIC) was launched by nine countries – Austria, Belgium, France, Germany, Israel, Italy, the Netherlands, Spain and Sweden. This Cofunded call for joint transnational research proposals aimed to gather new insights about the relationship of diet, intestinal microbiome and health.

- Call text.

In total 66 eligible proposals at the first stage were received, of which 28 consortia were invited to submit a full proposal by mid July 2017. After peer review of the full-proposals, the Call Steering Committee selected 11 proposals, based on the ranking list elaborated by the Scientific Evaluation Committee. These 11 selected projects are requesting a total of about 9,6 Mio. EUR, including Top-Up funding from the European Commission.

Early 2018, 43 research teams from eight countries, completed with nine additional research teams collaborating with them with own resources, will start working for the upcoming two to three years. Together with other actions of the ERA-Net, these projects should contribute to the development of new microbiome-based strategies and health promoting products for the prevention of lifestyle-related chronic diseases.

Funded projects

Di-Mi-Liv

Dietary modulation of intestinal microbiota as trigger of liver health: role of bile acids

WHAT: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Alterations of intestinal microbiota composition and associated impairments of intestinal barrier function are critical in the onset and progression of NAFLD. Recent data suggest a pivotal role of bile acids and microbial bile acid metabolism as mediators of gut-liver-crosstalk subsequently affecting NAFLD initiation and progression. Soluble fibers like oat ß-glucans bind bile acids and modulate intestinal microbiota composition and may thereby affect metabolic parameters and liver health. Furthermore, intervention trails suggest that manipulating intestinal microbiota composition through prebiotics may improve disease progression of NAFLD. However, the molecular mechanisms involved remain incompletely understood and established therapeutic strategies are still missing.

HOW: Di-Mi-Liv combines the complementary expertise of 5 groups with a strong background in various aspects of diet, liver disease, bile acids and intestinal microbiota. Through combining this expertise and combining clinical interventions with mouse models, the project aims to determine whether the interaction of bile acids and intestinal microbiota is critical for the initiating and progressing stages of NAFLD. Furthermore, it will be addressed whether this liver disease can be targeted through diet and more specifically with prebiotics, thereby improving disease progression and overall health.

WHO: The Di-Mi-Liv consortium consists of five funded partners and two collaborators, coordinated by Ina Bergheim, University of Vienna (Austria); email contact: ina.bergheim@univie.ac.at

The other funded consortium partners are Christian Trautwein (PI) and Kai Markus Schneider (Co-PI) , RWTH Aachen (Germany), Michael Trauner, Medical University of Vienna (Austria), Hanns-Ulrich Marschall, University of Gothenburg (Sweden) and Amélia Camarinha Silva, University of Hohenheim (Germany). The German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE) and University Clinic RWTH Aachen, Center for Translational & Clinical Research Aachen (both Germany) are collaborating in this project.

DiGuMet

Diet x gut microbiome-based metabotypes to determine cardiometabolic risk and tailor intervention strategies for improved health

WHAT: The human gut microbiota has been linked with incidence and progression of non-communicable diseases and their risk factors. Moreover, diet has been identified as an important modulator of microbiota composition and function, but responses vary between individuals. The underlying mechanisms of diet - microbiota interactions remain to be elucidated to provide a foundation for tailored dietary strategies for personalized precision nutrition. The aim of the DiGuMet project is to investigate how gut microbiota interact with diet and to identify the role of these interactions on cardiometabolic risk factors.

HOW: In this project the underlying mechanisms will be further dissected through extensive metabotyping using metagenomics and metabolomics combined with lifestyle data in a free-living prospective cohort subset. The hypothesis is that gut microbiota - diet interactions are a major determinant of the metabotypes and that distinct metabotypes could be reflected by predictive biomarkers. These biomarkers could then be used to tailor personalised dietary interventions to improve the molecular phenotypes among subjects at elevated risk of cardio vascular diseases. The hypothesis will be tested by conducting a dietary intervention rich in fermentable vs non-fermentable cereal fibres among subjects with signs of metabolic syndrome with distinct differences in their pattern of microbiota and microbiota-derived metabolites.

WHO: The DiGuMet consortium consists of three funded partners and two collaborators, coordinated by Prof. Rikard Landberg of Chalmers University of Technology (Sweden) email contact: rikard.landberg@chalmers.se

The other consortium partners are Cristina Andres-Lacueva, University of Barcelona (Spain) and Gabriele Riccardi, Federico II University (Italy). The Danish Cancer Society (Denmark) and Barilla G. e R. Filli (Italy) are collaborating in this project.

DIME

The role of diet-dependent human microbiome encoded T3SS-dependent effectors in modulating health

WHAT: Proteobacteria respond strongly to dietary changes and have been proposed as a diagnostic marker of dysbiosis (microbial imbalance). A unique feature of proteobacteria is the presence of secretion systems by which the so-called ‘effector-proteins’ can be injected into the host’s cytosol to interact with host proteins and modulate molecular pathways. DIME will investigate how diet-responsive commensal gut microbes modulate human health by injecting microbial proteins into human cells to affect regulation and metabolism.

HOW: DIME aims to analyze the protein-protein interaction network of effector proteins from commensal microbes with the human host interactome to understand which processes and disease modules are targeted by this underexplored molecular mechanism. First, effectors and secretion systems in microbial reference genomes and meta-genome datasets will be identified, especially those that change in response to certain diets. For these, open reading frames (ORFs) will be cloned or synthesized and then submitted to experimental and bioinformatic interaction mapping/prediction using high-quality pipelines. The resulting host-microbe interactome map will be analyzed to identify targets, processes, and disease modules that are perturbed by microbial effectors; for selected examples the molecular mechanism will be elucidated. It is expected that the mechanisms and the systems-level effector-host network will enable dietary or pharmaceutical interventions based on specific interference or secretion-blocking strategies.

WHO: The DIME consortium consists of three partners, coordinated by Pascal Falter-Braun, Helmholtz Zentrum München (Germany); email contact: pascal.falter-braun@helmholtz-muenchen.de

The other consortium partners are Thomas Rattei, University of Vienna (Austria) and Christine Brun, INSERM (France).

earlyFOOD

Long-term impact of gestational and early-life dietary habits on infant gut immunity and disease risk

WHAT: Man is colonized immediately upon birth by environmental microbes of primarily maternal origin. Initial colonization and transfer of maternal immunity through breastfeeding are believed to impact infant health at short- and long-term by conferring protection from infection and potentially resistance to metabolic and allergic diseases. The project proposes to assess the importance of dietary habits on maternal immunity (sIgA in gut microbiota and breast milk) and on neonatal colonization and installation of immunological tolerance by a novel high-throughput immune-metagenomic approach.

HOW: EarlyFOOD will integrate immuno-metagenomics, metabolomics and toxicological as well as epidemiological data, such as exposure to dietary-derived metabolites and pollutants as well as infectious events, antibiotics, allergens and air pollutants in a birth cohort of individuals living across Europe in environments of different biodiversity. The impact of gestational and early-life dietary habits on dysbiotic states of microbiota will be identified by biostatistical modelization of the risk of developing metabolic and allergic disease as well as neurobehavioral disorders. The program will identify predictive biomarkers and early-life preventive strategies for the growing epidemic of human metabolic and allergic diseases. Such advances may have important impact on public health and generate socio-economic benefits.

WHO: The earlyFOOD consortium consists of five partners, coordinated by Martin Larsen, Centre d’immunologie et des maladies infectieuses (France); email contact: martin.larsen@upmc.fr

The other consortium partners are Isabella Annesi-Maesano, UPMC (France), Bart Keijser, TNO (The Netherlands); Marta Schuhmacher, Universitat Rovira i Virgili (Spain) and Sandra Baldacci, CNR Institute of Clinical Physiology (Italy).

FATMAL

Identification of the molecular interplay between dietary fatty acids and gut microbiota in NAFLD

WHAT: Obesity promotes Non Alcoholic Fatty Liver Diseases (NAFLD) through mechanisms involving the gut microbiota. Cohorts of obese individuals (FLORINASH project under FP7&ROLIVER), in which a multilevel omics approach was used, allowed us to identify a specific microbiome architecture indicating novel molecular hypotheses to be validated. This was associated with hepatic insulin signaling perturbations, a transcriptomic profile indicative of NAFLD and triglyceride accumulation. On other cohorts transcriptomic analyses from intestinal biopsies and 16S sequencing of liver samples suggested: 1. impaired intestinal defense favoring translocation of bacteria towards the liver, inflammation and lipid deposition and 2. impaired intestinal and liver lipid metabolism. The interaction between dietary lipids and the gut microbiota in the etiology of NAFLD is unknown and could impair intestinal defense and lipid handling.

HOW: Using original and complementary models of genetically modified mice and germ-free mice colonized with human microbiota, FATMAL will study the impact of different lipid-enriched diets on: 1. gut microbiota and its causal role in liver disease; 2. intestinal immune- and non-immune defense systems; 3. translocation of bacteria towards the liver responsible for inflammation; 4. lipid handling processes in the liver and the intestine (bile acids/FXR and fatty acids/PPARa) and 5. gender by studying the role of the estrogen receptor a (ERa) in the gut microbiota/dietary lipids interplay.

WHO: The FATMAL consortium consists of four partners, coordinated by Rémy Burcelin, INSERM (France); email contact: remy.burcelin@inserm.fr

The other consortium partners are Sandrine Ellero-Simatos, INRA (France), Robert Caesar, Gothenburg University (Sweden) and Antonio Moschetta, University of Bari (Italy).

GUTMOM

Maternal obesity and cognitive dysfunction in the offspring: cause-effect role of the GUT MicrobiOMe and early dietary prevention

WHAT: Early life is fundamental for brain and microbiota development, as gut microbiota influences brain function. Maternal obesity affects maturation of gut microbiota and is an important predictor of cognitive dysfunction in the offspring. Cognitive decline through life is an increasingly invalidating condition, due to population ageing and the high frequency of predisposing factors (obesity, unhealthy diets). GUTMOM hypothesizes that the negative effects of maternal obesity on cognitive function in the offspring are partly mediated by the microbiota and its metabolites, offering the opportunity for non-invasive risk-screening and -reduction by tailored foods and diets, since earliest life stages.

HOW: GUTMOM will use two existing children cohorts to identify the gut bacteria and metabolites that are related to maternal obesity and offspring’s cognitive development in early, pre-scholar and scholar age. Animal models will be used to investigate cause-effect mechanisms, and develop tailored dietary interventions to counteract the effects of maternal obesity on the gut microbiota, improving offspring’s cognition.

WHO: The GUTMOM consortium consists of four funded partners and three collaborators, coordinated by Patricia Iozzo, Consiglio Nazionale delle Ricerche (Italy); email contact: patricia.iozzo@ifc.cnr.it

The other funded consortium partners are Sascha van Hijum, Radboud University Medical Center (The Netherlands), Mathias Schmidt, Max Planck Gesellschaft (Germany) and Consuelo Borrás, University of Valencia (Spain). The Istituto Superiore di Sanità (Italy), Mead Johnson Nutrition (The Netherlands) and the University of Helsinki (Finland) are collaborating in this project.

MeaTIc

Faecal Microbiome as determinant of the effect of diet on colorectal cancer risk: comparison of meat based versus pesco-vegetarian diets

WHAT: Colorectal cancer (CRC) is strongly affected by diet, with red and processed meat increasing the risk.

HOW: To understand the role of microbiome in this phenomena, MeaTic will study the gut microbiome profiles (metagenomics and metabolomics), and CRC biomarkers (genotoxicity, cytotoxicity, peroxidation in faecal water, lipid/glycemic indexes, inflammatory cytokines, oxidative stress) of healthy volunteers. These will be fed for 3 months with: a high-CRC risk diet (meat-based MBD), a normalized CRC risk diet (MBD plus alpha-tocopherol, MBD-T), a low-CRC risk diet (pesco-vegetarian, PVD) and examined at the beginning and at the end of the intervention. To study colon carcinogenesis, the same diets will be fed (3 months) to carcinogen-induced rats or to Pirc rats, mutated in Apc, the key gene in CRC. Faecal microbiome profiles will be correlated to carcinogenesis measuring preneoplastic lesions, colon tumors, and faecal and blood CRC biomarkers as in humans. Third, to further elucidate the mechanisms underlying the effect of different microbiomes in determining CRC risk, faeces from rats fed the experimental diets will be transplanted into carcinogen-induced germ-free rats, measuring how microbiome changes correlate with metabolome and disease outcomes. The results will provide fundamental insight in the role of microbiome in determining the effect of the diet, in particular red/processed meat intake, on CRC risk.

WHO: The MeaTIc consortium consists of five partners, coordinated by Carlotta De Filippo, National Research Council (Italy); email contact: carlotta.defilippo@ibba.cnr.it

The other consortium partners are Giovanna Caderni, University of Florence (Italy), Fabrice Pierre and Philippe Gérard, both INRA (France) and Jildau Bouwman, TNO (The Netherlands).

MEDIMACS

Impact of MEditerranean Diet, Inflammation and Microbiome on plaque vulnerability and microvascular dysfunction after an Acute Coronary Syndrome. A randomized, controlled, mechanistic clinical trial

WHAT: Coronary atherosclerosis is a leading cause of mortality and disability worldwide. Continuous efforts are needed to improve secondary prevention and understand the mechanism underlying disease progression. Based on primary prevention trials, a potential benefit of the Mediterranean diet after an acute coronary syndrome can be anticipated. The integrated microbiome-mediated/immunologic and metabolic pathways by which the Mediterranean diet modifies cardiovascular risk remain mostly unknown. Intestinal and oral dysbiosis is involved in the pathogenesis of atherosclerosis and microbiome dynamics may account for some of the observed benefits of Mediterranean diet.

HOW: The first objective of MEDIMACS is to evaluate the effects of a well-controlled Mediterranean diet intervention on atherosclerotic plaque vulnerability and coronary endothelial dysfunction after an episode of acute coronary syndrome. The second objective is to decipher the interplays among diet, microbiota, immunity and metabolism responsible for the observed effects. Therefore, a randomized mechanistic clinical trial, using state-of-the-art efficacy read-outs is proposed. This study will provide valuable insights to identify potential microbiome therapeutic targets for coronary artery disease.

WHO: The MEDIMACS consortium consists of four partners, coordinated by Francisco Fernández-Avilés, CIBER (Spain); email contact: faviles@redcardiovascular.com

The other consortium partners are Dominique Charron and Reem Al-Daccak, Université Paris-Diderot and INSERM (France), Uri Gophna, Tel Aviv University (Israel) and Edward Moore, University of Gothenburg (Sweden).

MICRODIET

Understand and prevent production of microbially-produced pro-diabetic metabolites in different ethnic group: impact of dietary change

WHAT: 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.

HOW: In this project it will be investigated how existing metagenome data available from different ethnicities is associated with different dietary patterns and tested how they respond to diets high and low in proteins. Second, to clarify these responses in detail bioreactors will be used and it will be investigated 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. One metabolite, imidazole propionate (ImP) from histidine has been identified, which is increased in blood of subjects with prediabetes and T2D. Further experiments have demonstrated that ImP can directly impair insulin sensitivity. In this project, it will be investigated 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, it will be confirmed if the microbiome produces ImP in humans using isotope-labelled histidine.

WHO: The MICRODIET consortium consists of three partners, coordinated by Fredrik Bäckhed, University of Gothenburg (Sweden); email contact: Fredrik@wlab.gu.se

The other consortium partners are Karine Clement, Université Pierre et Marie Curie (France) and Max Nieuwdorp, UvA-AMC (The Netherlands).

OCTOPUS

A sound microbiota in a sound body through apolipoprotein A-I and HDL: from mouse models to humans

WHAT: ApoA-I/HDL has been recognized to exert a beneficial role in cholesterol homeostasis and immunity, and, as a consequence, to be anti-atherogenic. The OCTOPUS project aims to demonstrate, for the first time, that apoA-I/HDL can also modulate intestinal homeostasis and microbiota composition and notably, that an apoA-I/HDL deficiency-driven dysbiosis can predispose to atherosclerosis development.

HOW: The OCTOPUS project originates from preliminary data elaborated by the Coordinator, and from published observations indicating that i) apoA-I deficient mice have an altered microbiota composition, enriched in choline-degrading bacteria; ii) gut microbiota can influence atherosclerosis development by metabolizing dietary choline. In this study it will be assessed to what extent different levels of apoA-I/HDL modulate gut microbiota composition, intestinal homeostasis/immunity, host metabolome and atherosclerosis development in atherosclerosis-prone, dyslipidemic mouse models and in two large human cohorts (PLIC, LURIC). In addition, microbiota from mice and humans with different levels of apoA-I/HDL will be transplanted in atherosclerosis-prone germ-free mice to mechanistically assess to what extent low apoA-I/HDL levels make the gut microbiota harmful for atherosclerosis development. The results obtained will potentially open a completely new scenario and shed light on an aspect of apoA-I/HDL biology that has not been investigated before.

WHO: The OCTOPUS consortium consists of four partners, coordinated by Giulia Chiesa, Università degli Studi di Milano (Italy); email contact: Giulia.Chiesa@unimi.it

The other consortium partners are Marcus Kleber, University of Heidelberg and Olivia Gräbner, Metabolomic Discoveries GmbH (both Germany) and Philippe Gérard, INRA (France).

TransMic

The transition from a traditional to a Western lifestyle and its effect on the interrelation between diet, gut microbiome and health

WHAT: Chronic diseases have increased to epidemic proportions in Western countries. The composition of the gut microbiota influences health and disease. The comprehensive, systems biology approach of the Human Functional Genomics Project (HFGP) offers unprecedented opportunities to unravel the effects of the gut microbiome on health and disease. Still, important gaps in our knowledge remain of how diet influences the composition of the microbiome and its effects on health. TransMic aims to fill these gaps by studying the effects of traditional versus modern ‘Western’ diets on gut microbiome and the functional consequences for health.

HOW: Data from cohorts from populations in different phases of the demographic transition from Tanzania, Burkina Faso and Europe will be used and analyzed using the comprehensive HFGP approach. In addition, a short dietary intervention will be performed switching young subjects from a Western to a traditional diet and vice versa. Omics-based data, including microbiome composition, genetics, transcriptome and lipidome will be related to functional data, such as immune responses. This large-scale analysis will provide important fundamental insights in the effects of diet on microbiome and health in general and the health effects of ‘westernization’ of diet in particular. It will thereby provide the necessary data for future innovative interventions to improve health, such as directed dietary microbiota modulation.

WHO: The TransMic consortium consists of three funded partners and one collaborator, coordinated by Mihai Netea and Quirijn de Mast, Radboud University Medical Center (The Netherlands); email contact: mihai.netea@radboudumc.nl or quirijn.demast@radboudumc.nl

The other consortium partners are Joachim Schultze, University of Bonn (Germany) and Paolo Lionetti, University of Florence (Italy). The Kilimanjaro Clinical Research Center (Tanzania) is collaborating in this project.