Campus Buch ECRC

Forslund Lab

Host-microbiome factors in cardiovascular disease

Profil

Many disease-related conditions in humans – such as the progression of or recovery from cardiovascular or metabolic diseases – influence gene expression, immune status, and the composition of the gut’s microbiome. All of these characteristics can be determined using high-throughput methods.

The goal of our group's work is to create data-based models that show how the human host and the microbiome develop together under different conditions toward health or disease. In order to be able to interpret and make use of all this data, we have to distinguish between causality and correlation, and also between effects that result from treatment and those that result from the disease.

To achieve this, we are analyzing data gained using high-throughput methods from human hosts and microbiome, taking into account metadata on disease development, nutrition, and lifestyle. The goal is to achieve a highly accurate, quantitative understanding of host-microbiome interaction that can be translated into personalized therapies for the future.

Team

Research

Today most healthy lifetime lost is due to the comorbidity nexus of cardiovascular and metabolic diseases. These are complex, involving factors of host genetics, diet and lifestyle interacting with features of the human microbiota. Progression and treatment prognosis is individually variable and reflects confounding impact of treatment regimes and indirect correlates of risk and protective factors. Mechanisms in particular involve circulating metabolite and lipid levels reflecting microbial action on nutrients from host diet, as well as complex action and reaction by the immune system.

Many questions remain unanswered qualitatively regarding the host-microbiome interaction space in the progression or reversal of disease. More importantly, high-fidelity quantitative understanding, which could be translated into personalized intervention regimes, is currently not available. The mission of the Forslund lab at the ECRC (joint cooperation of Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité Universitätsmedizin Berlin) is to provide this. We conduct integrative analysis of high-throughput host (metabolomic, immunomic, transcriptomic) and microbiome (metagenomic, metatranscriptomic) big data spaces, under constraints from clinical, dietary and lifestyle metadata, to try to model outcome of disease progression of treatment.

The following thus are our core activities:

Multi-omics clinical cohort studies

Systems medical analysis requires large-scale data collection from clinical cohorts. As previously reported, demographics of sampling and treatment regimes, alongside intrinsically high inter-individual variability, each may substantially bias such data, so we have particular interest in strategies for managing such bias. In particular, we seek to initiate and participate in longitudinal and interventional cohort studies to complement, enrich and synergize with existing cross-sectional/case-control datasets. Technical variability and the human factor makes standardized practices for sampling, enrolment, phenotyping, logistics and processing central to the effort of being able to usefully integrate data at high fidelity. Drawing on experiences from several international research consortia and best practices established together with our collaboration partners, we consider this a major focus.

High-throughput measurement of host and microbiota

Working with core facility actors for those procedures already standardized, we can process biosamples using a variety of methods, with a particular focus on gut microbiotal quantification using deep shotgun sequencing. With these platforms established, we welcome collaborations also in pursuit of scientific and medical questions outside of our core interests, locally and globally. This also includes adding dimensions of microbiome analysis to study cohorts where such provides a meaningful extension, and we are looking into analogous methods for analysis of e.g. host immune cell populations.

Bioinformatics and systems biology

Central to our platform is the computational analysis of high-dimensional biological (“-omics”) data, especially integrating multiple data types while controlling for complex confounder profiles. Vast amounts of work done by researchers world-wide languish in “data tombs” after initial publication; we seek to remedy this waste by systematically contrasting new findings to this background. These efforts, as well as the statistical analysis and modeling of data from new cohort studies, requires substantial software infrastructure as well as the application of machine learning, data alchemy and visualization approaches. Here we develop, benchmark and deploy software tools as needed to accomplish our aims. Moreover, all such analysis is built on a foundation of detailed and systematic annotation of human, animal and microbial biological parts, especially annotation of the genetic basis for functional pathways and processes. Where most expedient, we contribute ourselves to these annotations by mobilizing and developing techniques from evolutionary bioinformatics. With these platforms in place, we are also happy to act as computational partners in collaborative projects.

Validation and translational applications

Ultimately our mission as part of the ECRC is to facilitate the eventual translation of basic science findings into diagnostic, prognostic and therapeutic tools. For this purpose, we work closely with experimentalist collaborators, including model system experts at the MDC, seeking to validate key findings at the highest level of certainty. This involves techniques such as comparative interventions in germ-free or otherwise controlled animals, and the trialing of interventions in human volunteers. We are further very happy to work with industry partners (e.g. pharmaceutical, probiotic manufacturers, manufacturers of testing kits) in discovery or optimization of compounds, agents or techniques.

Clinical trials

XCVD study (late planning phase:)

Sex-hormone-differential host-microbiome cardiovascular risk – a longitudinal cohort approach

We will initiate the XCVD study soon, a cohort study that aims to investigate the influence of sex hormones on the gut microbiome, immune system and on the possible development of cardiovascular risk factors in a transgender cohort under hormonal transition. This will be a multicenter study with several partner institutions in Berlin, Leipzig and Odense/Denmark. Please find more information here soon.

NAMS study - Nutritional Approaches in Multiple Sclerosis

Within the last years, the potential role of the gut and gut microbiome in the pathogenesis of multiple sclerosis has gained attention. The NAMS study, a randomized-controlled trial, investigates the efficacy of fasting and ketogenic diets in patients with MS. The Forslund lab as a collaboration partner in the NAMS study aims to analyze stool samples of the study participants to understand, whether the dietary interventions have an impact on the gut microbiome composition and whether changes in the gut microbiome are associated with clinical outcomes. The NAMS study has its last patient out in September 2021 and does not recruit any more. Analysis will start soon.

KFO 339 Food allergy and tolerance (Food@)

A1- Induce oral tolerance to hen's egg, cow's milk, peanut and hazelnut in infants with eczema in a randomized placebo controlled study.

Interview with Prof. Dr. Kirsten Beyer RBB Praxis (German)

ICD-Code

  • T78.1 - Sonstige Nahrungsmittelunverträglichkeit, anderenorts nicht klassifiziert
  • L20.9 - Atopisches [endogenes] Ekzem, nicht näher bezeichnet

Inclusion Criteria

Gender

All

Additional Inclusion Criteria
  • Infants, age 4-8 months
  • eczema
  • signed informed consent of parents

Exclusion Criteria

  • previous consumption of hen´s egg, peanut or hazelnut
  • doctor´s diagnosed wheat allergy (matrix of the study product contains wheat)
  • severe diseases (cardiac, congenital)
  • participation in another interventional trial.

A2 - Tolerance induction through non-avoidance to prevent persistent food allergy

Scientific Short Description

Background: Peanut (PN) and tree nuts (TN) are among the most frequent elicitors of food allergy (FA) and can lead to life-threatening reactions. Allergic patients should strictly avoid the offending food independently of their individual threshold that triggered the allergic reaction, whereas sensitized patients without any allergic symptoms during the oral food challenge (OFC) should frequently consume the allergen to avoid re-development of FA. While most of the patients with cow's milk and hen's egg allergy gain oral tolerance over time, PN and TN allergy usually persists into adulthood. This difference might be explained by a constant oral exposure to low amounts of cow's milk or hen's egg in the diet, whereas for PN and TN this seems to be unlikely. Whether the current advice of strict allergen avoidance promotes persistence of FA is unknown, as the underlying mechanism of natural tolerance development is still not understood.
Aims: We aim to investigate the impact of allergen avoidance on natural tolerance development of PN and TN allergy in a randomized trial. We hypothesize that allergic patients who regularly consume the allergen below the individual threshold are more likely to gain tolerance than patients who strictly avoid PN or TN. We further hypothesize that allergen consumption below the individual threshold is safe. PN and TN sensitized but tolerant subjects will be included in an observational cohort, as we hypothesize that regular allergen consumption in these patients prevents the re-development of FA. Independently of the clinical outcome, the results will be helpful for future treatment of FA. The quality of life of patients will be assessed. Moreover, providing biosamples for the mechanistic projects within this clinical research unit will help to understand the mechanism of FA and tolerance development.
Methods: To test our hypotheses PN and TN sensitized children and adults undergo OFCs to determine their clinical reactivity. Peanut and tree nut allergic patients who tolerate at least 0.1 g of food protein will be randomized 1:1. One group will strictly avoid PN or TN whereas the other group will introduce products with low amounts of PN or TN on a regular basis into their diet for one year. One year after our dietary intervention, patients will be re-evaluated and a second OFC will be performed to determine the development of clinical tolerance (primary endpoint) and the threshold. Subjects with tolerance to PN or TN at baseline are advised to regularly consume the food and are observed for one year. The maintenance of clinical tolerance to peanut and tree nut will be assessed one year after initial OFC. Of all participants, blood, stool and dust samples as well as skin swabs will be obtained for mechanistic studies. Furthermore, questionnaires on quality of life will be obtained throughout the study.
Conclusion: This work will help to determine whether the current dietary advice for patients with FA is still up to date. Most importantly, we will obtain biological samples for the mechanistic projects to investigate the mechanisms of tolerance development.

ICD-Code

  • T78.1 - Sonstige Nahrungsmittelunverträglichkeit, anderenorts nicht klassifiziert

Erdnuss- und Baumnussallergie

HYPRO

Scientific Short Description

High blood pressure is a major risk factor for cardiovascular events, including stroke, heart and kidney failure. Typical anti-hypertensive drugs target vessels, the kidneys or the heart. Here we propose a randomized, placebo-controlled study to test the blood pressure-lowering effect of a probiotic in 110 patients with grade 1 hypertension. In addition, we will investigate glucose variability, fecal bacterial metabolome, peripheral blood effector T cell frequencies (%) and health-related quality of life.

ICD-Code

I10 - Essentielle (primäre) Hypertonie

Low-to-moderate Risk Grade 1 Hypertension

Inclusion Criteria

Age

50 - 80

Gender

All

Additional Inclusion Criteria

  • Men and postmenopausal women (50-75 years)

  • Treated or untreated grade 1 hypertension (resting office blood pressure >140/90 mmHg)

  • BMI 18.5 - 34.9 kg/m^2

Exclusion Criteria

  • Secondary causes of hypertension

  • Known target organ damage

  • 10 years cardiovascular risk score of >20%

  • Diabetes

  • Established cardiovascular or renal disease

  • Other serious diseases

  • Recent use of antibiotics

  • Specialized diets, e.g. use of probiotics

 

 

Work with us

Who are you?

  • Are you a student looking to do an internship, degree project or PhD studentship, or a doctor of philosophy or medicine looking to do a post-doctoral project? Whether you come from a computational background looking to apply your skills to biological and medical problems, or from a molecular biology, microbiology or medical background looking to learn high-throughput computational biology techniques, approach us to discuss ideas.
  • Are you a clinician or experimentalist with an idea, cohort, set of samples or pile of data looking for help to bring it all the way to a translatable and published finding? Approach us for a collaboration, where we will together identify the most synergistic use of our respective skills and resources for furthering knowledge and empowering medicine.
  • Are you a scientific leader looking to bring together a consortium of partner labs for addressing a topic thematically aligned with our focus areas, or where our contribution would be a good fit? Approach us for participation at any stage of the process, from planning to grant writing to execution.
  • Are you an investor or industry actor with a potentially marketable product, but concerns remaining in the way of its maturation? Approach us for discussing these ideas (in formal confidence as needed) and perhaps plan a strategy together for working through those remaining hurdles.

Fairness, diversity, transparency and accountability in the pursuit of knowledge

The Forslund lab as an ECRC actor adheres to the MDC principles of responsible research, good scientific practice, openness and transparency. We are dedicated to setting a good example as a scientific environment where talented students, researchers and collaborators can flourish, grow and succeed independently of their national or ethnic background, functional variation, sex/gender identity/alignment/orientation, family configuration, or other such feature of their persons or contexts. This involves enthusiastic adherence to MDC goals of promoting work-life balance, and an intention to pursue direct and explicit communication of needs, expectations and intentions. Beyond the baseline provided by our host institution, the lab has its own Code of Conduct addressing many of these topics, to which all members are required to commit during their time with us.