2023

In November 2023, Dr Johannes Meiser, Director of the LIH Department of Cancer Research and leader of the Cancer Metabolism Group, secured a 2 million euro grant from the prestigious European Research Council (ERC). This historic milestone marked LIH’s first-ever receipt of the ERC grant. The ERC, known for its stringent evaluation process based on scientific excellence, not only supports innovative research projects but also recognises exceptional Principal Investigators addressing significant scientific challenges at a mechanistic level.

Dr Meiser’s innovative research, funded in part by the FNR ATTRACT grant, has already revealed the phenomenon of formate overflow, a metabolic process playing a pivotal role in cellular adaptation along the metastatic cascade. Under the project named 4M8, Dr Meiser’s research will dissect formatedependent effects on cells, unravel intrinsic mechanisms relaying the formate signal promoting metastasis, and explore therapeutic strategies targeting formate for cancer cell eradication. This ERC grant positions the LIH to take a significant step forward in their research, offering the potential for groundbreaking treatments in the challenging realm of metastatic cancer, the leading cause of cancer-related deaths.

Launched in Luxembourg on April 27th, 2023, the Clinnova project represents a collaborative effort among clinicians and researchers from Luxembourg, France, Germany, and Switzerland. The initiative is supported by key entities, including the Luxembourg National Research Fund, to revolutionise healthcare through data-enabled precision medicine. Led by the LIH and with a total budget of EUR 50 million, the project focuses on developing AI algorithms to aid physicians in precise treatment decisions for diseases like inflammatory bowel disease, rheumatoid diseases, and multiple sclerosis.

Clinnova addresses the challenge of prescribing the right drug to the right patient by focusing on data quality and standardisation. The project also aims to bridge the gap between biomedical research and healthcare by enhancing infrastructure in Luxembourg and federating precision health data across borders. Through its partnerships, Clinnova envisions building a federated precision health network across Europe. This initiative aligns with Luxembourg’s national priorities, receiving strong support from the Ministry of Health and contributing significantly to the country’s research environment on a global scale.

In February, the LIH communicated its repositioning as a leading European institute for precision health, dedicated to translating research findings into tangible benefits for patients. Born from the 2015 merger of the former Centre de Recherche Publique de la Santé (CRP-Santé) and the Integrated Biobank of Luxembourg (IBBL), the LIH encompassed the Department of Cancer Research (DoCR), the Department of Infection and Immunity (DII), the Department of Precision Health (DoPH), and the Translational Medicine Operations Hub (TMOH). Evolving towards a more patient-oriented role, the LIH is committed to utilising knowledge and technology to directly impact people’s health.

The institute’s repositioning and updated brand strategy were widely disseminated through a comprehensive mass communication campaign across Luxembourg. Dominique Hansen, former Chief Communication Officer, emphasized the relevance of the LIH’s research on cancer and immunological disorders for the general public. The campaign featured posters, QR codes linking to videos showcasing collaborative projects with Luxembourg hospitals, and a revised logo symbolising the close relationship with clinicians and patients.

Arnaud D’Agostini, Head of Marketing and Communication, underscored the shift in perception, portraying scientists as strategic partners in modern-day healthcare, working collaboratively to translate research into tangible solutions for patients. The campaign centred around the patient as the ultimate beneficiary of the LIH’s translational research activities, reflecting a collaborative and caregiving aspect in the institute’s identity.

In February 2023, Prof Ulf Nehrbass, CEO of the LIH, and Prof Aline Muller, CEO of the LISER, convened at the LIH’s premises in Strassen to finalise the framework agreement for the establishment of the joint Socio-Economic and Environmental Health and Health Services (CARES) research group.

The collaborative efforts between the LIH and the LISER materialised in the creation of the inter-institutional CARES research group, aimed at bolstering research synergies. Operating under the aegis of the LIH’s Department of Precision Health (DoPH), CARES serves as a catalyst for joint research initiatives, spanning health economics, health services research, public health, and environmental health. The group actively stimulates collaborations, organising events, and seminars to foster a dynamic research environment.

Under the leadership of Dr Maria Ruiz-Castell and Prof Marc Suhrcke, the CARES group seeks to understand the complex dynamics that impact health and well-being by undertaking research on health disparities, environmental health risks and healthcare system challenges. This interdisciplinary initiative leverages complementary expertise in health economics, public health, environmental health and epidemiology to develop innovative prevention strategies.

Picture:
Prof Ulf Nehrbass, CEO of LIH
Prof Aline Muller, CEO of LISER

In April 2023, a collaborative effort between the LIH Cancer Metabolism Group, the University of Sheffield and the Karolinska Institute in Sweden, unveiled an innovative strategy in the fight against cancer. Focusing on one-carbon (1C) metabolism, a pivotal pathway for DNA synthesis and repair, the researchers discovered that cancer cells, driven by an elevated demand for nucleotides, upregulated enzymes involved in this process. Paradoxically, this upregulation opened a potential vulnerability that could be targeted by the innovative small molecule TH9619, designed to selectively eliminate cancer cells by targeting enzymes associated with 1C metabolism.

The study, led by Dr Johannes Meiser and Dr Nicole Kiweler, elucidated the mechanism behind TH9619’s efficacy. By inducing the accumulation of the 1C metabolism intermediate 10-formyl-tetrahydrofolate, TH9619 created a “folate trap,” starving cancer cells of essential tetrahydrofolate needed for DNA synthesis and repair, ultimately leading to their demise.

“This folate trapping mechanism differs from other 1C metabolism inhibitors and anti-folates, making TH9619 a promising new candidate for cancer treatment. This new approach to attack cancer cells could potentially also be used in combination with existing treatments to enhance their effectiveness”
Dr Johannes Meiser and Dr Nicole Kiweler

In August 2023, a collaborative effort led by Prof Michel Mittelbronn, Head of the National Centre of Pathology at the Laboratoire Nationale de Santé and the Luxembourg Centre of Neuropathology at the LIH, uncovered a key defence mechanism employed by certain tumours to become resistant to treatment.

Prof Mittelbronn explained that the GDF-15 cytokine, abundantly secreted by solid tumours like melanoma, liver cancer, and bladder cancer, inactivates the immune system, thus strategically blocking its action. By preventing T lymphocytes, the immune system’s infantry, from infiltrating the lesion, GDF-15 disrupts the natural defence mechanism against malignant tumours. Furthermore, the study revealed a significant negative correlation between GDF-15 expression and the presence of T lymphocytes in the tumour environment, with patients having a high level of GDF-15 experiencing earlier mortality.

This discovery enhances the potential success of current immunotherapies, underscoring the importance of understanding how malignant cells shield themselves to effectively combat cancer.

In June 2023, the Tumour Stroma Interactions (TSI) group of the LIH Department of Cancer Research (DoCR) achieved a groundbreaking milestone in cancer treatment. Drs Jérôme Paggetti, Etienne Moussay and Anne Largeot explored the inhibition of mRNA translation in chronic lymphocytic leukaemia (CLL) cells, focusing on oncogenes like MYC. Their findings unveiled the potential of the drug FL3 in inhibiting MYC translation through a newly elucidated mechanism, providing promising therapeutic options for CLL patients.

CLL, the most prevalent form of leukemia, is characterised by the abnormal accumulation of dysfunctional B lymphocytes. The study targeted the translation of oncogenes within CLL cells, aiming to rewire their metabolism and curb their proliferative capacity. The synthetic flavagline FL3, known for inducing cancer cell death, demonstrated effectiveness in inhibiting translation and synthesis of proteins involved in crucial cellular processes. Patient-derived CLL cells exhibited higher sensitivity to FL3-induced death than healthy cells, emphasizing the drug’s selective impact on cancerous cells.

FL3’s specific targeting of prohibitins (PHBs), proteins directly involved in translation, was identified as a key mechanism. Disrupting the interaction between FL3 and PHBs hindered translation initiation, impeding cancer cell growth. In vivo experiments on mice substantiated the drug’s efficacy, showcasing reduced CLL cells in the spleen and improved survival rates. Importantly, FL3 selectively targeted malignant CLL cells without affecting healthy B cells, offering a promising strategy for selectively combating cancerous cells.

Combining FL3 with anti-PD1 immunotherapy enhanced outcomes, suggesting the drug’s potential in boosting antitumour immunity. The study, titled “Inhibition of MYC Translation through Targeting of the Newly Identified PHBeIF4F Complex as Therapeutic Strategy in CLL”, not only earned a place in the prestigious journal Blood but also graced its cover page. This groundbreaking research, made possible through support from various funding sources, opens new avenues for CLL treatment and holds translational significance in addressing relapse and resistance to current therapies.

In December, a breakthrough study led by Dr Eric Van Dyck at the LIH uncovered a new role of the DAXX protein in preserving the integrity of our genetic material. This discovery has significant implications for cancers associated with DAXX alterations, providing potential insights and targeted therapeutic strategies, especially in understanding chromosomal instability in certain cancer types.

Within the intricate realm of genetics, Dr Van Dyck’s research focused on maintaining the integrity of specific chromosomal regions, such as centromeres, crucial for preventing cancerdriving chromosomal instability. Using paediatric glioma and pancreatic neuroendocrine tumour cell lines, the study revealed a novel function of the DAXX protein, highlighting its crucial role in preventing DNA damage and ensuring chromosome stability.

DAXX, known as a histone chaperone forming a complex with ATRX, was found to play a pivotal role in genome stability by preventing the accumulation of transcription-associated R-loops and DNA double-strand breaks at centromeres. Understanding how DAXX safeguards our genome could unlock potential avenues for treating cancers associated with DAXX alterations, such as paediatric glioma and pancreatic neuroendocrine tumours. This breakthrough not only expands our comprehension but also opens promising avenues for developing innovative therapies against diseases rooted in chromosomal instability.

In January, the LIH initiated Colive Cancer, a transformative study led by Dr Guy Fagherazzi from the LIH Department of Precision Health Deep Digital Phenotyping research unit. This project, conducted in collaboration with the Ministry of Health under the second National Cancer Plan, aims to enhance the quality and efficiency of the national cancer healthcare system by engaging directly with patients through an innovative online feedback system.

The importance of Colive Cancer is framed by the statistics from the National Cancer Registry and the European Cancer Information System, revealing approximately 3000 new cancer cases annually in Luxembourg, causing around 1100 deaths. Recognising the need for improvement in cancer care, the prioritises translational oncology, data digitalisation, and patient collaboration to enhance cancer diagnosis and treatment.

Colive Cancer, a key component of PNC2, is a pioneering online survey accessible via smartphone or laptop. Its patient-centric approach allows participants to share experiences and opinions on the healthcare system and overall quality of life. The survey covers various aspects, from diagnosis and treatment to care and support received, enabling direct patient feedback to shape improvements in the national cancer care system.

This project is a unique opportunity to improve the cancer care system in Luxembourg, thanks to direct inputs from the patients themselves! This patient-centred approach will allow us, for the first time in Luxembourg, to identify what works well, and also perhaps more importantly, what improvement targets to set for the National Cancer Plan”,
Dr Guy Fagherazzi, leader of the project

In May 2023, the LIH proudly announced the initiation of the ECHoS project, “Establishing of Cancer Mission Hubs: Networks and Synergies.” This three-year European consortium aligns with the Horizon Europe Mission on Cancer initiative, striving to enhance coordination in Research & Innovation (R&I) and Healthcare actions on cancer while integrating policy-making processes, ultimately fostering people-centric healthcare and research systems.

The consortium comprises over 58 leading organisations from governmental, healthcare, academic, and nonprofit sectors across 28 countries. The primary objective is to create National Cancer Mission Hubs (NCMHs) in each country, engaging a diverse range of stakeholders in collaborative initiatives and policy dialogues on cancer at national, regional, and local levels.

Driven by the ambitious goal of the Horizon Europe Mission on Cancer to “improve the lives of more than 3 million people by 2030 through prevention, cure, and better living for those affected,” ECHoS plays a crucial role in supporting this initiative. Dr Nikolai Goncharenko, Director of the National Institute of Cancer (INC) and national coordinator of the ECHoS project, emphasizes the importance of establishing networks and synergies in the fight against cancer. Luxembourg, represented by the INC and the LIH, is actively contributing to this project, aiming to promote collaboration at both the national and European levels. By redefining traditional research and health systems, ECHoS aims to create a brighter future in cancer care, reaching from individual citizens to European institutions, civil society, academia, public and private sectors.

The CraNE Joint Action-JA, funded under Europe’s Beating Cancer Plan (EBCP), aims to establish an EU Network of National Comprehensive Cancer Centres (CCCs) in every Member State by 2025. Aligned with the goal of ensuring 90% of eligible EU patients have access to high-quality cancer care by 2030, the initiative focuses on early detection, screening, diagnosis, treatment, and support, along with enhancing cancer research and professional training.

The National Institute of Cancer (INC) leads Work Package 6, implementing a national Comprehensive Cancer Care Network in lung cancer. The LIH actively participates in Work Package 7, defining standards for research, innovation, education, and integrating research and care for Comprehensive Cancer Centres. Participation in CraNE JA underscores Luxembourg’s commitment to improving cancer care and addressing EU disparities.

The kick-off meeting in November 2022, coordinated by the Slovenian National Institute of Public Health, initiated a twoyear project with 44 partners from 25 countries. Funded by the EU Health Program (EU4Health) 2021-2027 through the European Health and Digital Executive Agency (HaDEA), CraNE JA aligns with the broader mission of enhancing cancer care and collaboration across Europe.

The NORLUX Neuro-Oncology Laboratory at the LIH has secured funding from the EU-driven Horizon 2020 TRANSCAN-3 programme for the PLASTIG project. Titled “Tackling tumour heterogeneity and PLASTIcity as resistance mechanisms in Glioblastoma,” this multinational initiative aims to delve into the intricate resistance mechanisms of glioblastoma (GBM). GBM, the most aggressive primary brain tumour, presents significant challenges in treatment efficacy, with a survival rate of only 5.7% beyond five years.

“With GBM recurrence being an inevitable challenge for patients, and the prevalence of GBM expected to rise due to an aging population, the PLASTIG project represents a crucial step towards improving the understanding of treatment resistance mechanisms. Through its innovative research approach, we aim to unlock new avenues for effective treatments that could significantly affect the lives of GBM patients and their families”,
Dr Golebiewska, leader of the project

The PLASTIG consortium, including the Paris Brain Institute, the University of Freiburg, and the Royal College of Surgeons in Ireland, leverages interdisciplinary expertise in advanced computational approaches, single-cell analysis, and spatial image analysis. The project is financially supported by the EU-funded TRANSCAN-3 project, uniting 31 funding organisations from 20 countries, including Luxembourg’s National Research Fund (FNR), to promote high-impact translational cancer research through collaborative efforts.

In June 2023, the LIH celebrated the recognition of its cancer research initiatives with multiple projects securing funding through the 2023 call of the Télévie programme by the Belgian Fund for Scientific Research (FNRS). Of the 88 selected projects, five are led by the LIH in cancer research, while one involves the LIH as a partner. Additionally, three ongoing LIH projects received renewed funding for an additional two years.

PIANO (Exploration of spatial tumour heterogeneity in distinct groups of glioblastoma), led by Dr Eric van Dyck of the LIH’s Department of Cancer Research (DoCR), aims to link spatial changes in gene expression to tumour invasion, progression, and treatment response in glioblastoma.

RESTAGE (NR1D2 circadian clock gene as a target for reverting glioblastoma-associated immunosuppression via functional modulation of myeloid cells), is co-led by Drs Aurélie Poli and Alessandro Michelucci of the Neuro-Immunology research group. It investigates the potential of the nuclear receptor NR1D2 in myeloid cells as a target to enhance anti-tumour immunity in glioblastoma.

TNT2-CLL (Translation as novel Therapeutic target in CLL) and TiTLe (Role of AHR and HIF-1A in regulating Tregs suppressive ability in the tumour microenvironment of leukemia), led by Drs Jerome Paggetti and Etienne Moussay of the Tumour Stroma Interactions (TSI) group: the former focuses on understanding the role of prohibitins PHB and PHB2 in translation inhibition in Chronic Lymphocytic Leukemia (CLL) cells, with a particular emphasis on how the synthetic flavagline FL3 targets these proteins. The latter project explores the mechanisms by which transcription factors AHR and HIF-1a enhance the immunosuppressive capacity of regulatory T cells in CLL.

ACTICAM (Role of ICAM-1 in mediating actin remodelingdependent tumour immune evasion) led by Dr Clément Thomas of the Cytoskeleton and Cancer Progression group seeks to decipher molecular pathways underlying actin cytoskeleton remodelling during tumour cell recognition and killing by cytotoxic lymphocytes.

MOFIC (Deciphering the role of the microbiome-derived oncometabolite formate on the immune cell compartment in colorectal cancer), in collaboration with the University of Luxembourg, aims to elucidate the role of microbiome-derived oncometabolite formate in colorectal cancer.

Additionally, three ongoing LIH projects received renewed funding: IMPACT 21-2, EVceptor-2, and SUNRISE2. These projects cover diverse areas, including cancer immunotherapy, extracellular vesicles in leukaemia and lymphoma, and cancer cell propagation in glioblastoma.

In 2023, the TIME research group at the LIH showcased important advancements in the modulation of hypoxia within solid tumours. Hypoxia, marked by decreased oxygen pressure, profoundly influences the microenvironment of solid tumours, rendering them resistant to conventional cancer treatments. The research, led by Dr Bassam Janji, successfully demonstrated that targeting the HIF-1α gene associated with cancer cell adaptation to hypoxia not only inhibits tumour growth but also mobilizes cytotoxic immune cells to the cancerous tissue. These findings provide a promising avenue for enhancing the efficacy of existing anti-cancer treatments, particularly for melanomas resistant to traditional therapies.

Recognising the potential of this research, major pharmaceutical companies, including Roche Pharmaceuticals, extended their funding commitments to the project. This collaboration seeks to explore innovative therapeutic strategies, leveraging drugs that modulate hypoxia in combination with existing cancer treatment approaches. The TIME research group’s work promises to revolutionise anticancer care, offering new hope for patients facing resistant melanomas and challenging solid tumours.

In a study published in March 2023, researchers from the LIH and the University of Luxembourg delved into the manipulation of T cell metabolism to disrupt the function of autoreactive Th17 cells associated with autoimmune diseases. This exploration revealed promising insights into the intricate relationship between cellular metabolism and epigenetic modifications.

“The manipulation of metabolism in immune cells, especially T cells, is promising for interfering with inflammatory autoimmune diseases»,
explains Prof Dirk Brenner

T cells, crucial components of the immune system, safeguard the body against pathogens and combat cancer cells. However, Th17 cells, a specific type of T cell, have been implicated in autoimmune diseases. Diseases like multiple sclerosis, psoriasis, and inflammatory bowel disease have been linked to the overactivity of Th17 cells, prompting researchers to investigate the molecular and metabolic regulation of these cells. The study, led by Prof Dirk Brenner, employed sophisticated genetic techniques to alter glucose utilisation in T cells, revealing unexpected impacts on Th17 cell function without inducing an energy crisis. The research shed light on the connection between glucose metabolism and epigenetic modifications, particularly in altering gene expression related to disease-causing functions. This breakthrough offers promising prospects for developing targeted drugs to address autoimmune diseases and cancer, though further research is necessary to fully comprehend the relationship between general metabolic changes and specific epigenetic alterations in immune cells.

Parkinson’s disease (PD), a widespread neurodegenerative disorder affecting millions globally, is characterised by the degeneration of dopaminergic neurons, resulting in motor symptoms like tremors and slowness of movement. While the exact causes remain elusive, recent findings suggest a pivotal role of dysregulated immune pathways and microglia activation in PD.

In April, scientists led by Dr Alessandro Michelucci from the LIH Neuro-Immunology Group, presented a comprehensive review shedding light on the role of immune dysfunction in the development of Parkinson’s disease (PD). Focused on the PARK7/DJ-1 gene, the review underscores the crucial role of microglia as immune cells in the brain and the identification of neuroinflammatory and neurotoxic processes as key factors in advancing therapeutic targets for PD patients.

Frida Lind-Holm Mogensen, a PhD student in the group and the article’s first author, emphasised the importance of understanding microglia’s roles as recognising these processes is fundamental to developing therapeutic targets. The review outlined the association between mutations in the PARK7 gene and early-onset PD, with DJ-1 protein exhibiting neuroprotective functions and influencing microglia immune responses. Researchers are exploring compounds targeting DJ-1 to enhance its effects, exhibiting potential neuroprotective impacts that extend beyond neurons.

In August, a study featured as a cover story in the esteemed EMBO Molecular Medicine journal by the Nutrition, Microbiome, and Immunity Group at the Department of Infection & Immunity, unveiled the significant impact of a mother’s diet and gut bacteria composition on the immune development of her offspring. The study, led by Prof Dr Mahesh Desai, delved into the intricate relationship between diet, gut bacteria, and early-life immune system development.

The research focused on the influence of dietary fiber and the gut bacterium Akkermansia muciniphila on the development of the offspring’s immune system. Using a mouse model, scientists examined the effects of maternal fiber intake and the presence of A. muciniphila in the offspring’s gut microbiota. Results highlighted that a fiber-rich diet positively influenced microbial community and immune development during the weaning period. The presence of A. muciniphila in the offspring’s gut microbiota led to distinct alterations in innate and adaptive immune cell types, with effects varying based on maternal fiber intake. Notably, the study suggested a potential role of A. muciniphila in inducing colonic Th17 cells linked to autoimmune diseases.

Prof Mahesh Desai emphasised the study’s implications, stating,
”Our study demonstrates the significant impact of the maternal microbiome and dietary fiber intake on the postnatal development of the microbiome and immune system”,

Although conducted in a mouse model, the researchers anticipate substantial implications for human health, particularly as modern lifestyle practices disrupt the delicate balance between gut microbiota and immune function.

In September, the Nutrition, Microbiome, and Immunity research group at the LIH Department of Infection and Immunity unveiled compelling insights into the profound impact of a low-fiber diet on the gut microbiome and its link to food allergies. Led by Prof Mahesh Desai, the the study published in the prestigious journal Nature Microbiology demonstrated that a diet deficient in fiber leads to the proliferation of the mucolytic bacterium Akkermansia muciniphila in the gut, resulting in a compromised mucosal barrier, an inflammatory state, and heightened sensitivity to food allergens.

Using mouse models, the team compared the effects of fiber-free and fiber-rich diets on the gut microbiome. The results revealed an increase in mucolytic bacteria, especially A. muciniphila, in fiber-deprived mice, leading to altered immune responses and a predisposition to food allergies. The study highlighted previously undescribed innate immune pathways of allergen sensitisation in the large intestine, dependent on diet-induced changes in mucusdegrading bacteria. The presence of A. muciniphila emerged as a critical factor in exacerbating allergic symptoms in sensitized mice, irrespective of their diet, establishing its causal role in heightened allergen susceptibility induced by fiber deprivation.

“Understanding the role of the various components of the microbiome and how their functions are affected by external factors like diet therefore becomes the key to preventing and treating a broad range of afflictions, from food allergies to neurodegenerative diseases, thereby giving our work a highly translational dimension with an enormous therapeutic potential for many patients around the world”,
Prof Desai

In September a study addressing the escalating global challenge of allergies, was published. Under the leadership of Dr Annette Kuehn and Prof Markus Ollert, alongside Dr Maria Ruiz-Castell and Dr Guy Fagherazzi, the research provided profound insights transcending Luxembourg’s borders.

This groundbreaking study, a collaborative effort between the Department of Infection and Immunity (DII) and the Department of Precision Health (DoPH) at the LIH, delved into the allergy burden in the Luxembourg population. Employing cutting-edge technology to study IgE antibody signatures in human blood, the research generated a comprehensive dataset comprising 480,000 data points from 1,462 adult Luxembourg residents. The study was anchored in the European Health Examination Survey in Luxembourg (EHESLUX), led by Dr Maria Ruiz-Castell and Dr Guy Fagherazzi, which provided a solid foundation for this first-of-its-kind investigation.

The findings revealed the extensive impact of allergies, with over 42% of participants reporting diagnosed allergies, and a striking 44% testing positive for IgE antibodies indicative of allergic sensitisation. Tree pollens, grass pollens, and mites emerged as the most common sources of sensitisation. Notably, the youngest age group (25–34 years) exhibited the highest sensitisation rates and the greatest need for medical care, suggesting a connection between modern lifestyle, upbringing, living conditions, and the onset of chronic inflammation like allergies. The study thus underscored the necessity for tailored medical care and nationally planned interventions to alleviate the burden of allergies.

In March 2020, the World Health Organisation declared COVID-19 a global pandemic, caused by the SARS-CoV-2 virus. While some experienced severe illness, many reported mild-tomoderate symptoms. Later, individuals with COVID-19 reported gastrointestinal symptoms, prompting researchers from the LIH, in collaboration with the University’s Luxembourg Centre for Systems Biomedicine, to investigate the impact on the gut microbiome.

“Our study indicates that COVID-19’s influence on the infective competence of the gut microbiome may lead to a higher likelihood for other infections”,
Dr Guy Fagherazzi, study contributor

Severe infections were associated with persistent alterations to the gut microbiome for at least six months, potentially leading to bacterial, viral, or fungal co-infections. The findings indicate that COVID-19 influences the infective competence of the gut microbiome, raising the likelihood of other infections. Thus, the findings open new avenues for future research to track links to long-term effects of COVID-19 and explore whether changes in infective competence are common in viral and bacterial infections.

The COVID-19 pandemic has profoundly impacted global mental health, revealing both short and long-term psychological symptoms. The Digital Deep Phenotyping unit at the LIH conducted a pioneering study, led by Dr Gloria Aguayo, which analysed mental disorders as determinants of COVID-19 symptom trajectories. Their findings, published in March, highlight preexisting mental health conditions as a substantial risk factor.

Examining data from the Predi-COVID study, involving 791 adults, the research revealed a crucial link between regular use of psychotropic medication before infection and more severe COVID-19 symptoms. This association extended to a poorer overall prognosis, lack of recovery after two weeks, and a potential heightened risk of Long COVID. The researchers further identified four possible trajectories of COVID-19 severity, with a score reflecting the total number of symptoms. They showed that people that regularly used psychotropic medication before being infected, in particular antidepressants and anxiolytics, had a higher score and worse trajectory, exhibiting poorer recovery during the first two weeks after the infection. These insights emphasise the need to address mental health conditions during the pandemic, therefore helping to provide more tailored COVID-19 care.

The “COVIRNA” project, funded by the European Commission’s Horizon 2020 programme and led by the Cardiovascular Research Unit (CVRU) of the LIH, aimed to predict COVID-19 severity and identify patients at risk of post-COVID complications. Recognising the emergence of long-term health problems, including cardiovascular and neurological complications, the objective of the project was to provide a molecular diagnostic tool for tracking cardiovascular effects in those affected by “long-COVID.”

Conceived in response to the European Commission’s fast-track call for COVID-19 projects in March 2020, COVIRNA utilised the expertise of the CVRU in RNAs and cardiology to design a novel, micro RNA-based diagnostic tool allowing the stratification of patients according to anticipated severity of their symptoms. The consortium of 15 institutions across 12 European countries, previously collaborating within the EU-CardioRNA COST Action network, identified RNA molecules in the blood as predictive markers for severe health complications and mortality.

“Although we are still in the process of doing some validations before developing the final molecular diagnostic kit, we are confident that our new test will help personalise healthcare and improve the outcomes of COVID-19, particularly in patients developing the so-called long-COVID syndrome”,
Dr Yvan Devaux, COVIRNA project leader at the LIH

In a study published by the Deep Digital Phenotyping research unit in January 2023, researchers demonstrated the use of deep neural networks to predict the onset of neurodegenerative diseases, addressing the increasing threat to the older population’s health and quality of life. The study focused on understanding the complex prodromal phase and early onset factors crucial for disease prediction, risk minimisation, and promotion of protective factors.

”The added value of this study is that we present an advanced reproducible methodology, combining a novel approach with state-of-the-art techniques. This analysis can be applied in predictive studies on the general population and clinical cohorts, particularly those of neurodegenerative diseases. Moreover, deep neural networks have many potential applications in cohorts with rich and diverse epidemiological, clinical and image data, but also in those with missing data”,
Dr Gloria Aguayo, lead author

Both the “Société Francophone du Diabète” (SFD) and the “Société Luxembourgeoise de Diabétologie” (SLD) extended crucial support to the Deep Digital Phenotyping (DDP) research unit at the LIH Department of Precision Health (DoPH) for innovative projects.

The SFD granted EUR 30,000 for the SFDT1-IH clinical study, facilitating the development of a digital biomarker predicting the risk of hypoglycemia unawareness in type-1 diabetes patients. This research project, directed by Dr Guy Fagherazzi, leverages machine and deep learning algorithms such as TabTransformer. It was launched in March 2023 and will last for 18 months.

In parallel, the SLD awarded EUR 5,000 to the DDP research unit for the DIAVOX project, dedicated to developing and validating a vocal biomarker for real-time monitoring of diabetes-related distress in Luxembourg. Under the scientific leadership of Dr Fagherazzi, the project will apply advanced machine-learning algorithms to analyse data from the ongoing international Colive Voice cohort, currently including 842 participants with type 1 and type 2 diabetes.

Dr Guy Fagherazzi, Director of LIH’s Department of Precision Health and leader of the Deep Digital Phenotyping (DDP) unit, joined the team of the FragMent project led by Dr Camille Perchoux from LISER. The project, funded by the European Research Council, aims to assess the impact of the fragmentation of daily-life environment on stress in a Luxembourg-based cohort. In the study, stress, a global concern affecting mental and physical health, is being evaluated through self-reported measurements and vocal biomarkers, developed by the DDP team. Vocal biomarkers provide a quick, non-invasive method for stress assessment, which could be widely used to support stress prevention and be incorporated into public health prevention strategies. The collaborative effort between Dr Fagherazzi and Dr Perchoux explores efficient ways to assess stress in everyday life, contributing to advancements in stress monitoring.

In June, the LIH, through its Data Integration & Analysis (DIA) unit, joined the HiGHmed Consortium, a German medical informatics project uniting hospitals, academia, and industry partners. The project aims to improve access to medical patient data for research and healthcare.

The HiGHmed Consortium addresses challenges in managing diverse health data by building secure Data Integration Centres and developing interoperable digital solutions. These solutions support local and cross-institutional patient care and clinical research, with the ultimate goal of empowering physicians to make data-based, patient-centered decisions.

“Joining the HiGHmed Consortium is a strategic and logical decision for the LIH, as it is perfectly aligned with the objectives of the recently-launched CLINNOVA initiative and with our institute’s focus on supporting the integration of patient-derived data into our research and, ultimately, into current clinical practice”,
Dr Maximilian Fünfgeld, Chief Medical Information Officer at the LIH and leader of the Data Integration & Analysis (DIA) unit

HiGHmed, part of the German Medical Informatics Initiative, consists of 12 university hospitals and partners across Germany. The LIH, joining in the current funding phase (2023-2026), is the first international partner.

In July, the LIH and Expon Capital, a Luxembourg-based venture capital investment firm, joined forces to explore opportunities and synergies in scientific research and technological development within the digital health sector.

Luxembourg’s burgeoning health-tech scene, supported by government funding and national institutions like the Luxembourg National Research Fund, are positioning the country as an ideal hub for innovative health-tech companies, particularly in digital health. In line with this vision, the LIH, a leader in translational medicine and digital health, and Expon Capital, specialising in early and late-stage Venture Capital investment in European tech companies, signed a collaboration agreement.

The agreement focuses on identifying, developing, and implementing joint projects and activities. On Expon Capital’s side, these include supporting the LIH in organising hackathons and competitions, aiding spin-offs and start-ups, and providing assistance in science commercialisation activities. The LIH offers advisory and scientific support to Expon Capital and assists in developing a joint strategy to foster partnerships between digital health companies and the financial and investor community. This opportunity will help attract innovative e-health companies and unlock the potential of digital health and translational research in Luxembourg.

In January 2023, the first comprehensive evaluation of physical activity (PA) in Luxembourg, conducted by the Physical Activity, Sport and Health (PASH) Research Group led by Dr Laurent Malisoux at the LIH, aimed to assess the nation’s adherence to the World Health Organisation’s (WHO) PA guidelines. In 2021, Luxembourg officially embraced the WHO guidelines, recommending 150-300 minutes of moderate PA and 75-150 minutes of vigorous PA per week for adults. The study, led by Dr Paul Collings, obtained data from approximately 1100 adult participants who wore accelerometers on their wrists for a week as part of the ORISCAV-LUX 2 study on cardiovascular health risk. The findings indicated that over 98% of Luxembourg residents adhered to the WHO PA guidelines, comparable to countries like Finland and Germany. However, the study also revealed that despite high PA adherence, residents spent over 12 hours a day sitting, emphasising the challenge of sedentary behaviour in a modern, digitally-driven society.

The researchers, aware of the health risks associated with prolonged sedentary time, recommended public health initiatives in Luxembourg to encourage breaking up sedentary periods with low-intensity PA, particularly among individuals aged 50 and above. They underscored the potential health benefits of incorporating such activities without compromising work productivity, citing studies that support this approach. Additionally, the study suggested dedicating more time to PA in general, especially low-intensity activities, to address the paradoxical situation where high overall PA adherence coexists with extended sedentary periods among Luxembourg residents.

In February, Dr Maria Ruiz-Castell from the Socio-Economic, Environmental Health & Health Services (CARES) group, together with Dr Brice Appenzeller from the Human Biomonitroing Research Unit (HBRU), published a ground-breaking study revealing the cumulative impact of seemingly minor exposures on an individual’s health. Their approach based on hair analysis aimed to characterise the adult exposome of the general population of Luxembourg, considering a comprehensive range of environmental factors—chemical, lifestyle, psychosocial, and physical—that individuals encounter over their lifetimes.

The study, which analysed 175 environmental exposures, including a detailed list of chemical pollutants detectable in hair, shed light on correlations and patterns within specific groups (socio-economic status, age, gender, nationality, etc.). A concerning finding was the detection of EU-banned pesticides in many samples, highlighting the prolonged persistence of these harmful chemicals. Gender differences were observed, with higher concentrations of pollutants, especially pesticides and herbicides, in men, while women exhibited higher concentrations of micronutrients and lower alcohol consumption. Some exposures showed moderate correlations, reflecting lifestyle habits, such as the correlation between owning pets and exposure to anti-tick chemicals. This study signifies a shift towards understanding the complexity of the exposome, providing crucial insights into the long-term health effects of various environmental exposures.

“The adult exposome is complex and multidimensional with many components, which means that reducing environmental exposure to a few exposure components may only provide limited benefits. This complete overview will help to better interpret the role that the exposome plays on health”,
Dr Ruiz-Castell, leader of the study

In February 2023, the Luxembourg charity “OEuvre Nationale de Secours Grande-Duchesse Charlotte” generously supported the LIH’s PIANISSIMO project. Led by Drs Laurent Malisoux and Bernd Grimm, the initiative focuses on promoting physical activity in individuals with degenerative joint diseases. The project aims to develop Colive Move, a dedicated smartphone solution for patient education and data collection, investigating the real-world relationship between daily physical activity and pain. The project aligns with the institute’s priorities in digital health and preventive medicine, offering potential benefits for future translational research initiatives like CLINNOVA.

The HealthyW8 project, spearheaded by the LIH, was officially launched in June, marking a significant step towards advancing obesity prevention initiatives in Europe. Coordinated by the LIH, this Horizon Europe project will unfold over the course of 5 years and bring together expertise and resources from a diverse Europe-wide consortium. Acknowledging that traditional approaches to obesity prevention have had limited impact, HealthyW8 aims to revolutionise strategies by focusing on personalised interventions.

Dr Torsten Bohn and the consortium will target specific demographic groups at risk of transitioning from a healthy weight to overweight and obesity, including schoolchildren and their parents, young adults, and the elderly. The project entails over 40 pan-European pilot trials and long-term randomized control trials across various age groups. A key element of HealthyW8 is the development of the Healthy Lifestyle Recommender Solution (HLRS), a user-centred digital tool considering personal contexts, preferences, and emotional wellbeing to empower informed decisions about lifestyle factors. With a total budget of 10 million euros and the support of 24 entities from nine European countries, the project is expected to have a substantial impact on the fight against obesity.

Cardio-metabolic diseases, including diabetes, heart attack, and stroke, are influenced by known risk factors such as obesity and high blood pressure, although lifestyle choices are also emerging as an important element. In this context, the MET’HOOD project, initiated in 2021 by the LIH and the Luxembourg Institute of Socio-Economic Research (LISER), uniquely focused on the geographical environment’s impact on cardio-metabolic health in Luxembourg. The project aimed to analyse the long-term effects of residential neighbourhood characteristics and address social inequalities in order to inform urban policies supporting health equity.

Innovative research led by Dr Brice Appenzeller from the Human Biomonitoring research Unit (HBRU) discovered an association between chronic exposure to environmental pollutants and an increased risk of obesity, diabetes, and dyslipidemia. Published in November, the study involved an extensive investigation into the effects of pollutants, specifically polychlorinated biphenyls (PCBs) and various pesticides, on cardiovascular health. These pollutants, commonly found in the environment, homes, and food, were revealed to have significant associations with cardiovascular disease (CVD).

The project built on data from the NESCAV survey, a cross-sectional study conducted from 2007 to 2013 across Luxembourg and Belgium. Dr Feng-Jiao Peng, lead author of the publication and part of the Human Biomonitoring Research Unit, highlighted the study’s findings, showcasing associations between CVD risk factors and chronic environmental exposure to these pollutants in both Belgian and Luxembourgish adult populations.

“Ours was the first study to utilise hair samples to investigate CVD risk factors in relation to pollutant exposure. We were able to find an unprecedented association between CVD risk factors and chronic environmental exposure to currently used pesticides, which are still found in most countries. Our results show a clear need for further research into these associations to protect the welfare of citizens worldwide”,
Dr Appenzeller, leader of the HBRU group

In November, a collaborative study conducted by the French National Health and Safety Agency (ANSES), the LIH, and the French National Institute for the Industrial Environment and Risks (Ineris) revealed the efficacy of hair analysis in monitoring exposure to rapidly eliminated chemicals. Led by Claire Beausoleil, a toxicologist within ANSES, the study focused on substances like bisphenols, phthalates, and pesticides, commonly found in the environment or food but quickly eliminated from the body. Traditional blood or urine analyses faces challenges in assessing long-term exposure due to the substances’ rapid elimination and frequent re-exposure.

To address this, the scientists exposed rats to a mixture of 17 pollutants and analysed hair and urine samples. The results demonstrated a strong correlation between exposure dose and metabolite concentrations in the hair for 14 of the 17 substances. Notably, hair analysis proved to be a better method to assess exposure than blood analysis, as hair samples capture the exposure to pollutants over longer periods compared to blood samples.

In May, an international collaboration between researchers from Japan and Luxembourg, led by Professor Nobutaka Hattori from Juntendo University, resulted in the publication of a significant breakthrough in Nature Medicine. The research introduced a groundbreaking method, IP/RT-QuIC, capable of using pathological forms of the alpha-synuclein protein found in patients’ blood for the diagnosis of Parkinson’s disease and differentiation from other neurodegenerative motor disorders. The study addressed synucleinopathies, including Parkinson’s disease, Lewy body dementia, and multiple system atrophy, caused by abnormal aggregation of the alpha-synuclein protein.

The researchers, including scientists from the Luxembourg Centre for Systems Biomedicine (LCSB) at the University of Luxembourg, the LIH, and the Laboratoire National de Santé (LNS), collaborated to develop the innovative diagnostic method. IP/RT-QuIC involved immunoprecipitation and real-time quakinginduced conversion to detect alpha-synuclein seeds in the serum. Leveraging a unique longitudinal clinical and neuropathological database from Luxembourg, the researchers successfully detected alpha-synuclein seeds in the serum of 95% of patients with synucleinopathies. The method also revealed distinct patterns in the structure of these seeds, differentiating between diseases. This breakthrough opens the door to a simple blood test for the diagnosis of synucleinopathies, particularly Parkinson’s disease, representing a significant advancement in the field. Professor Rejko Krüger, director of Transversal Translational Medicine at the LIH and head of the Translational Neuroscience group at the LCSB, underlined the potential impact of a blood test for Parkinson’s disease, marking a major progress in diagnosis compared to the current reliance on clinical examinations.

In September 2023, Luxembourg marked a significant step in neurodegenerative disease care with the launch of the Réseau de compétences maladies neurodégénératives “ParkinsonNet Luxembourg” (RdC-MN). As a direct return on Luxembourg’s investment into the first National Centre for Excellence in Research for Parkinson’s disease (NCER-PD) supported by the FNR, the initiative aims to provide tailored and personalised care for individuals with neurodegenerative diseases, starting with Parkinson’s disease as a first use case. Led by Professor Rejko Krüger, the RdC-MN fosters collaboration among various healthcare professionals, facilitating improved communication and information exchange to enhance patient care. The network, initially focused on Parkinson’s disease, plans to expand to include additional healthcare professions and develop personalized treatment and prevention plans.

Luxembourg’s international recognition in the area of neurosciences, notably through the NCER-PD, highlights the success of 8 years of well-defined and excellent research programs. The NCER-PD programme generated new knowledge leading to earlier and better diagnosis of PD and to the implementation of precision medicine strategies. Additionally, the research results of NCER-PD opened new avenues for translational research, which will be explored in the upcoming years, using the vast amount of clinical data and samples collected thanks to the active participations of people with and without PD. NCER-PD will continue its clinical research activities by leveraging the strong alliance built between Luxembourgish research and healthcare institutions under the coordination of the LIH. The success of NCER-PD and of the ParkinsonNet concepts in Luxembourg points towards a promising model, with plans to gradually extend the initiative to comprehensively address other neurodegenerative diseases.

In an innovative study recently published in “Nature Communications,” scientists from the LIH and the Luxembourg Centre for Systems Biomedicine (LCSB) have unveiled noninvasive cellular immune biomarkers that could revolutionise early Parkinson’s disease diagnosis. Parkinson’s disease (PD), affecting around 10 million individuals globally, poses diagnostic challenges due to its slow onset and variable symptoms. The research reveals a direct link between disturbances in the peripheral immune system and PD, particularly in its early stages. This breakthrough, marking a major step forward in clinical diagnostics, involves analysing circulating immune cells in a patient’s blood sample, providing highly precise results within approximately five hours.

”Our work demonstrates, for the first time, a tangible connection between a disrupted peripheral immune system and a chronic brain disease like Parkinson’s. This could have far-reaching diagnostic implications, especially for patients without a defined genetic cause for their condition”,
Dr Feng Hefeng

The study builds on previous work on rare familial forms of Parkinson’s and explores immune system changes in individuals with the common sporadic form. The research team identified a specific subtype of immune cell, CD8 T lymphocytes with strong killing functions (CD8 TEMRA cells), elevated in number in patients with early-to-mid stage Parkinson’s compared to healthy individuals of the same age. The study underscores the power of translational research and interdisciplinary collaborations, setting the stage for a potential shift in Parkinson’s disease diagnosis.