© Ivan-balvan / Getty Images

Sleep apnea affects nearly one billion people worldwide and causes repeated episodes of oxygen deprivation during the night, known as intermittent hypoxia. A study conducted by scientists from the University of Grenoble Alpes, Inserm, and Grenoble Alpes University Hospital, published today in the journal Science Advances, shows that these episodes reorganize the liver’s biological clock, altering the daily rhythms of its metabolic activity. These findings shed light on a previously unknown aspect of the disease and could help to better target the optimal time for administering treatments to improve their effectiveness.

While the pathological consequences of intermittent hypoxia in sleep apnea are well documented, their impact on the body’s biological rhythms, governed by the circadian clock, remains largely unexplored.

In this study, scientists used a mouse model of chronic intermittent hypoxia to analyze the effects of this respiratory stress on the body over the entire day-night cycle. Focusing on the liver, the central organ of energy regulation, they combined transcriptomic, metabolomic, and physiological approaches to track adaptations in hepatic metabolic activity over time.

The results show that intermittent hypoxia not only alters certain major energy pathways orchestrated by the liver, such as glucose and lipid metabolism, but also profoundly reprograms their circadian organization. For example, metabolomic analysis reveals that nearly half of hepatic metabolites exhibit a 24-hour rhythm and that more than a third of them acquire a new rhythm under intermittent hypoxia. This redistribution of metabolic rhythms throughout the day reflects a genuine temporal reprogramming of hepatic activity and highlights a previously underestimated dimension of sleep apnea.

This research opens up new perspectives in chronomedicine. By reprogramming the liver’s metabolic rhythms, intermittent hypoxia could alter the body’s response to certain drugs, particularly those that affect blood sugar or lipid metabolism. Their effectiveness could therefore vary depending on the time of day, with optimal times for administration differing from those observed in people without this respiratory disorder. This highlights the importance of incorporating the temporal dimension into the management of sleep apnea.

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Many cases of sudden cardiac death could be avoided thanks to artificial intelligence. As part of a new study to be published in European Heart Journal, a network of artificial neurons imitating the human brain was developed by researchers from Inserm, Paris Cité University and the Paris public hospitals group (AP-HP), in collaboration with their colleagues in the USA. During the analysis of data from over 240 000 ambulatory electrocardiograms, this algorithm identified patients at risk of a serious arrhythmia that was capable of triggering cardiac arrest within the following 2 weeks in over 70% of cases.

Each year, sudden cardiac death is responsible for over 5 million deaths worldwide[1]. Many of these cardiac arrests occur out of the blue with no identifiable warning signs, striking individuals from the general population who do not always have a known history of heart disease.

Artificial intelligence could help to improve the anticipation of arrhythmias – unexplained heart rhythm disorders which, if severe, can cause fatal cardiac arrest – according to a new study led by a team of researchers from Inserm, Paris Cité University and the Paris public hospitals group (AP-HP), in collaboration with their colleagues in the USA.

As part of this study, a network of artificial neurons was developed by a team of engineers from the company Cardiologs (Philips group) in collaboration with the universities of Paris Cité and Harvard. What this algorithm does is imitate the functions of the human brain in order to improve the prevention of cardiac sudden death.

The researchers analysed several million hours of heartbeats thanks to data from 240 000 ambulatory electrocardiograms collected in six countries (USA, France, UK, South Africa, India and Czechia).

Thanks to artificial intelligence, the researchers were able to identify new weak signals that herald the risk of arrhythmia. They were particularly interested in the time needed to electrically stimulate and relax the heart ventricles during a complete cycle of cardiac contraction and relaxation.

“By analysing their electrical signal for 24 hours, we realised that we could identify the subjects susceptible of developing a serious heart arrhythmia within the next two weeks. If left untreated, this type of arrhythmia can progress towards a fatal cardiac arrest”, explains Dr Laurent Fiorina, first author of the study, researcher at the Paris Cardiovascular Research Centre (PARCC) (Inserm/Paris Cité University), cardiologist at Cardiovascular Institute Paris-Sud (ICPS) (Ramsay, Massy), and medical director in charge of artificial intelligence at Philips.

While the artificial neural network is still in the evaluation phase, it showed itself in this study to be capable of detecting at-risk patients in 70% of cases, and no-risk patients in 99.9% of cases.

In the future, this algorithm could be used to monitor at-risk patients in hospital. If its performances are refined, it could also be used in devices such as ambulatory Holters that measure blood pressure to reveal hypertension risks. It could even be used in smartwatches.

“What we’re proposing here is a paradigm change in the prevention of sudden death, comments Eloi Marijon, Inserm research director at PARCC (Inserm/Paris Cité University), professor of cardiology at Paris Cité University and head of the cardiology department at Georges Pompidou European Hospital AP-HP. Until now we’d been trying to identify patients at risk over the medium and long term, but were incapable of predicting what could happen in the minutes, hours or days that precede a cardiac arrest. Now, thanks to artificial intelligence, we can predict these events in the very short term and potentially take action before it’s too late.”

The researchers now wish to conduct prospective clinical studies to test the efficacy of this model under real-world conditions.

“It’s essential for this technology to be evaluated in clinical trials before being used in medical practice, insists Dr Fiorina. But what we’ve already shown is that AI has the potential to radically transform the prevention of serious arrhythmias.”

[1] https://www.thelancet.com/commissions/sudden-cardiac-death

MASH is a growing pandemic worldwide, with obesity and diabetes on the rise. It is also an area of significant unmet medical need. © François Pattou

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly referred to as nonalcoholic fatty liver disease (NAFLD), impacts roughly 30% of the global adult population. The disease spans from benign fat accumulation in the liver (steatosis) to its more severe form, metabolic dysfunction-associated steatohepatitis (MASH, formerly nonalcoholic steatohepatitis or NASH). MASH represents a dangerous progression, with the potential to cause cirrhosis, liver cancer, type 2 diabetes, and cardiovascular disease.

Despite its prevalence, MASH remains highly heterogeneous. Not all individuals follow the same clinical trajectory, and conventional treatment approaches often fail to account for these differences. Recognizing this gap, a groundbreaking study led by Prof. François Pattou and Prof. Stefano Romeo has redefined MASH by identifying two distinct subtypes with distinct risks and outcomes.

This transformative research, conducted at Lille University Hospital as part of the RHU PreciNASH project coordinated by Inserm, was made possible through collaboration with leading scientific teams from Inria, CNRS, the University of Lille, Lille University Hospital, and the Pasteur Institute of Lille, alongside international partners from Sweden, Italy, Belgium, and Finland. Published in Nature Medicine, the study marks a pivotal shift in the understanding and treatment of MASH.

Two Subtypes of MASH, Two Distinct Risk Profiles

The study identified and validated two distinct types of MASH based on histology and liver imaging, using data from European cohorts and the UK Biobank:

• Liver-Specific MASH: A genetically driven subtype with rapid progression of liver disease but a surprisingly low risk of cardiovascular complications.
• Cardiometabolic MASH: A high-risk profile linked to type 2 diabetes and cardiovascular diseases, alongside comparable liver disease progression.

What makes this discovery groundbreaking is that both subtypes exhibit similar histological features under the microscope or on imaging, making them indistinguishable using traditional diagnostic methods. However, their markedly different clinical outcomes underscore the critical need for advanced diagnostic tools and personalized interventions.

Transforming Diagnosis and Treatment

This study empowers clinicians to move beyond one-size-fits-all approaches to treating MASH. By leveraging simple clinical markers—age, BMI, HbA1c, LDL cholesterol, triglycerides, and ALT—patients can be stratified into specific subtypes, enabling tailored treatments:

• Liver-Specific MASH: Focus on therapies to halt liver damage and prevent progression to cirrhosis or liver cancer.
• Cardiometabolic MASH: Emphasize aggressive management of metabolic and cardiovascular risks alongside liver disease treatment.

“This research marks a turning point,” says Prof. François Pattou. “We now have a clear path to develop subtype-specific treatments that can improve patient outcomes.”

Why This Discovery Matters

MASH is the most severe manifestation of MASLD, with the potential for devastating health consequences. However, its heterogeneity has often been overlooked, leading to inconsistent treatment outcomes.

“This manuscript offers a transformative perspective on MASH and its heterogeneous outcomes,” notes an anonymous reviewer. “Thoughtfully conducted on large, well-characterized cohorts, it opens new doors for precision medicine in this field.”

The Science Behind the Subtypes

The study utilized data from the French ABOS cohort of 1,389 individuals with obesity and validated its findings across three European MASLD cohorts (Italy, Belgium, and Finland), comprising 1,099 participants, as well as imaging data (MRI) from over 6,000 UK Biobank participants. By integrating clinical traits with liver transcriptomics and plasma metabolomics, researchers uncovered distinct biological pathways driving each subtype.

“This discovery sheds light on why current treatments often yield inconsistent results,” explains co-lead researcher Prof. Stefano Romeo. “It was a true ‘eureka’ moment for our team.”

A New Era for MASH Treatment

This breakthrough highlights the urgent need for subtype-specific care, paving the way for innovative treatments and personalized medicine. Future research will explore how these subtypes respond to lifestyle interventions, pharmacological therapies, and other treatments in diverse populations.

“We’ve always known MASH was heterogeneous,” concludes Prof. Romeo. “Now, we finally have a roadmap to turn these insights into real-world solutions for patients.”

Nirsevimab is an antibody targeting the respiratory syncytial virus (RSV). Available in France since September 2023, it is indicated in neonates and infants for the prevention of bronchiolitis caused by RSV. © AdobeStock

Nirsevimab is an antibody targeting the respiratory syncytial virus (RSV). Available in France since September 2023, it is indicated in neonates and infants for the prevention of bronchiolitis caused by RSV. However, its widespread use raises the question of the emergence of resistance mutations. The POLYRES study, the largest prospective surveillance study of nirsevimab breakthrough infections to date, has just delivered its conclusions. This work, coordinated by Prof. Slim Fourati and Prof. Marie-Anne Rameix-Welti[1], was funded by the ANRS MIE with the support from the French Ministry of Higher Education and Research as part of the EMERGEN Consortium.[2] Scientists from AP-HP (including Henri Mondor University Hospitals), Inserm, Institut Pasteur and the Universities of Paris-Est-Créteil and Versailles-Saint-Quentin-en-Yvelines, members of the ANRS MIE virology network teams, have shown that nirsevimab resistance mutations in RSV are very rare. The results of this study have just been published in the Lancet Infectious Diseases on October 15, 2024.

Respiratory syncytial virus (RSV) is the main cause of bronchiolitis, a lower respiratory tract infection in infants. Two groups of RSV (RSV-A and RSV-B) circulate alternately or together. Every year, RSV is responsible for more than 33 million cases of bronchiolitis worldwide, leading to the deaths of 100,000 children, mainly in low-income countries. In France, the disease is responsible for around 480,000 cases a year. It is by far the most common cause of hospitalisation in children, leading to more than 26,000 paediatric hospitalisations every year. Nirsevimab, a new neutralising antibody* against the virus, became available in France in September 2023. This monoclonal antibody** targets a specific antigenic site (the epitope*** Ø) of the RSV surface F protein, which is involved in viral multiplication, and blocks the virus. Due to the genetically variable forms of RSV, there is a theoretical risk of the emergence of variants carrying mutations resistant to neutralisation by nirsevimab, even in the absence of selection pressure. This risk could increase with the widespread preventive use of nirsevimab. During the phase IIb/III clinical trials, only 48 RSVs infecting children treated with nirsevimab could be studied, and escape mutations^# were found in two of them.  The aim of the POLYRES study was to assess the risk of viral escape from nirsevimab in a large cohort using a large, multicentre, real-life observational study conducted during the 2023-2024 winter season.

The study included 695 RSV infected infants, 349 of whom had received nirsevimab prophylaxis. RSV-A was the most dominant circulating virus this season and was found in 86.6% of infected children. The teams analysed the characteristics of RSV-A and RSV-B in nasopharyngeal swabs collected as part of the children’s routine care. Full-length sequencing of the viral genome was conducted to identify potential mutations in the Ø site, the nirsevimab binding site (genotypic analysis^§ ). The ability of nirsevimab to inhibit viral multiplication in cell culture was also investigated (phenotypic analysis^¥ ). Analysis of 472 RSV-A viruses (half from treated children) revealed no nirsevimab resistance mutation in the Ø site of the F protein. Of the 73 children infected with RSV-B, 24 had received nirsevimab prophylaxis. In these 24 children, two isolates of RSV-B had resistance mutations to the antibody. One mutation has been described before and the other is described here for the first time.

“This study is the largest surveillance study of nirsevimab virological failures to date. It was made possible thanks to collaborative synergy with the consortium of virologists at the ANRS MIE. It is a nationwide project that will help identify the resistance phenomenon associated with the widespread use of the drug. This type of study is essential for analysing the evolutionary dynamics of viruses, in the light of existing medical solutions” explains Prof Marie-Anne Rameix-Welti, head of the National Reference Centre for Respiratory Infection Viruses at the Institut Pasteur, and head of the M3P unit (Institut Pasteur, Inserm U1173).

“The low prevalence of nirsevimab resistance mutations in treated patients is reassuring. However, escape mutations have been observed in a few RSV-Bs from treated patients, prompting caution and highlighting the importance of active molecular surveillance in the context of future wider global use of nirsevimab. These results are essential in the fight against this disease and in anticipating any form of resistance“, adds Prof Slim Fourati, Head of the Virology Unit-Respiratory Viruses, CHU Henri Mondor, Inserm U955.

In conclusion, the results of the POLYRES study support the continued use of nirsevimab for RSV prophylaxis in all newborns worldwide.

* Neutralising antibodies are specific antibodies that prevent infection by blocking the virus from entering the target cells. They do this by forming an antigen-antibody complex which inhibits the biological activity of the antigen (a substance foreign to the body capable of triggering an immune response aimed at eliminating it).

** Monoclonal antibodies consist of a single type of antibody (polyclonal antibodies have several types). They are used in medicine.

*** Part of a molecule recognised by an antibody.

^# Escape mutations enable the virus to thwart the action of antibodies in the human immune system.

• Genotypic tests are based on the identification of mutations that confer resistance to the virus.

^¥ Phenotyping, carried out using phenotypic tests, makes it possible to define the sensitive or resistant nature of the virus. This is done by culturing the virus in the presence of the antiviral being studied.

[1] Head of the National Reference Centre for Respiratory Infection Viruses at the Institut Pasteur and head of the M3P unit (Institut Pasteur, Inserm U1173)

[2] Coordinated by Santé publique France and ANRS MIE

Human kidney cross section on scientific background. 3d illustration © AdobeStock

The teams from the kidney transplantation department of Necker-Enfants Malades AP-HP hospital, Inserm and Paris Cité University, as part of the Paris Translational Research Center for Organ Transplantation (PARCC), coordinated by doctor Olivier Aubert and Professor Alexandre Loupy conducted a study on the benefit of liquid biopsy (cfDNA) as a technique for predicting kidney transplant rejection. This consists of detecting, in the blood of patients who have undergone a transplant, the DNA of their donor, with the aim of non-invasively predicting the rejection of the transplanted organ.

The results of this study were the subject of a publication published on June 2, 2024 in the journal Nature Medicine , accompanied by an editorial.

Allografts are the most commonly performed grafts, between two genetically different individuals of the same species. We speak of an allograft when the patient (or recipient) is grafted with cells from a healthy subject. Allograft rejection constitutes a major public health issue, which can have numerous consequences on the patient’s quality of life, even causing their death. Allograft rejections affect nearly 20% of patients in the following year.

The objective of this study is to show the usefulness of a liquid biopsy for kidney transplant patients. This technique consists of detecting, in the blood of patients who have undergone a transplant, the DNA of their donor, with the aim of predicting and non-invasively the rejection of the transplanted organ.

This study included nearly 3,000 kidney transplant patients from 14 transplant centers in Europe and the United States, all aged around 55 years, with a majority of men (61%). The cfDNA is integrated into a multimodal prediction ^algorithm¹ . Levels of cfDNA² ^have been shown to be strongly linked to different types of transplant rejection, including antibody-mediated rejection and T cell-mediated cellular rejection.

Thanks to this method, researchers will be able to determine, for each patient and in a non-invasive manner using a simple blood test, the probability of having a rejection of the transplanted organ. Additionally, analyzes revealed that adding cfDNA to existing monitoring models improves not only the detection of clinical rejections, but also subclinical rejections (not detectable with currently available tools), allowing for earlier therapeutic interventions. and more efficient.

Liquid biopsy, combining the usual transplant monitoring parameters with cfDNA, makes it possible to avoid unnecessary and invasive biopsies while detecting rejections more quickly with better precision. This approach can also reduce healthcare costs while considerably simplifying the care pathway for transplant patients. This non-invasive method offers a new way for monitoring transplant patients. Today, the liquid biopsy approach also extends to heart, lung and liver transplant recipients.

1. A type of artificial intelligence in which multiple data sources and numerous intelligent processing algorithms are combined to solve complex problems and achieve greater accuracy.

2. cfDNA levels indicate the intensity of inflammation and rejection of the transplanted organ.

© Adobe stock

Cardiovascular diseases represent the leading cause of death worldwide[1]. Preventing cardiovascular risk by identifying the people most susceptible to these diseases is a major public health challenge. In a new study in this field, researchers from Inserm, Université de Lorraine and Nancy Regional University Hospital opted to focus on arterial stiffness and how it changes with age, given that ageing is associated with a loss of arterial flexibility. Thanks to health data collected from over 1,250 Europeans, their research confirms that the stiffer the arteries, the greater the cardiovascular risk. The scientists suggest measuring arterial stiffness as a way to predict a patient’s cardiovascular risk, and emphasise the utility of a specific clinical tool called the Cardio-Ankle Vascular Index (CAVI). These findings have been published in eBioMedicine.

Cardiovascular risk is the probability of developing a cardiovascular disease or accident (problems affecting the heart and arteries). Finding a measurement that can predict this risk through the early detection of the factors that can influence it is a major challenge for research. The risk factors that are already well-known are high blood pressure, smoking, diabetes, high cholesterol, excess weight and sedentary lifestyle.

Previous studies have shown that ageing affects the flexibility of our arteries in that they become increasingly rigid over time. What is more, the scientific literature indicates that this phenomenon may be accelerated by other factors during ageing, such as hypertension or diabetes, and is associated with an increased cardiovascular risk. On the basis of these factors, it had been suggested that looking at arterial stiffness could be useful in preventing cardiovascular risk. However, testing for arterial stiffness is not on the list of recommended clinical practices.

In a new study, researchers from Inserm, Université de Lorraine and Nancy Regional University Hospital looked at a tool for measuring arterial stiffness called the Cardio-Ankle Vascular Index (CAVI), hypothesising that its use in clinical practice could predict patient cardiovascular risk.

The scientists were specifically interested in CAVI because of its accuracy, non-invasiveness and the fact that it is not influenced by blood pressure but reflects the structure of the artery itself. CAVI is measured using four cuffs – one around each arm and one around each ankle – assessing stiffness from the femoral artery to the tibial artery. A microphone is also placed on the heart. The tool measures the speed of blood flow and calculates an index: the higher the number, the stiffer the arteries[2].

During their research, the scientists followed 1,250 people from 18 European countries, all over the age of 40[3]. They provided their medical history and underwent a physical examination, including an assessment of their arterial stiffness using CAVI. They were then invited for a follow-up examination 2 years after the first measurement, and for some, up to 5 years after the first measurement. The aim of the follow-up was to assess the progression of the arterial stiffness and correlate this with the participants’ general state of health.

Thanks to their measurements, the researchers were able to observe that each one-point increase in CAVI, which corresponds to an approximate 10% increase in arterial stiffness, was associated with a 25% increased risk of a cardiovascular event in the years following the measurement.

The researchers also looked at what might influence arterial stiffness. They saw that age affected not just the CAVI value but also its progression, in that it increases more rapidly with age. They also observed the impact of blood pressure: the higher the blood pressure, the higher the CAVI.

The scientists then tried to determine a threshold for arterial stiffness that would be associated with an increased cardiovascular risk and could be commonly recognised and adopted by clinicians, in order to implement more intensive patient monitoring. They found that a CAVI of over 9.25 was associated with a high cardiovascular risk from the age of 60.

Finally, they observed that treatment for cholesterol or diabetes affected the rate of progression of arterial stiffness. Although these observations are still being studied, they do suggest that certain treatments could help slow the progression of arterial stiffness.

‘Our findings suggest that CAVI could be a quick, easy and non-invasive tool for predicting cardiovascular risk. In the future, it could be included on the list of tests recommended in clinics to predict a person’s cardiovascular risk and provide preventive monitoring,’ explains Magnus Bäck, first author of the study.

‘As well as being easy to deploy, we could use CAVI to determine the actual age of the cardiovascular system,’ explains Athanase Benetos, the study’s final author.

[1] WHO data: https://www.who.int/fr/health-topics/cardiovascular-diseases#tab=tab_1

[2] An index of 10 is already a sign of great rigidity.

[3] TRIPLE-A-Stiffness is an international longitudinal cohort study having recruited more than 2,000 participants over 40 years of age from 18 European countries. Of these, 1,250 subjects (55% of whom women) were followed for a median duration of 3.82 (2.81 – 4.69) years.

A scanning electron micrograph shows the Nipah virus (yellow) budding from the surface of a cell.© National Institute of Allergy and Infectious Diseases, NIH

The WHO recently classified the Nipah virus (NiV) as one of the eight main emerging pathogens likely to cause major epidemics in the future. In a context where no treatment or vaccine is yet available, a team comprising researchers from Inserm (Unit 955-VRI) and from the Université Paris-Est Créteil (UPEC) is presenting the preclinical results of an innovative vaccine against this virus. Most candidate vaccines target the viral surface proteins required for entry into human cells. To develop its new vaccine, the team at the VRI (Vaccine Research Institute of the ANRS MIE/Inserm) focused on the central role played by antigen-presenting cells (APCs) in the development of protective responses. The candidate vaccine, called CD40.NiV, carries specific parts of the surface proteins of the NiV-B virus, the Bangladesh strain. Following infection with the Nipah virus in animals, CD40.NiV demonstrated immunogenicity, neutralisation and complete protection, representing an important step towards the clinical development of a vaccine against the infection. The results of this work have just been published in the March 2024 issue of Cell Reports Medicine.

The Nipah virus (NiV) is a zoonotic virus, meaning it is transmitted from animals to humans. However, it can also be transmitted via contaminated food or directly between individuals. The clinical presentation can range from asymptomatic infection to acute respiratory infection to fatal encephalitis. First identified in Malaysia in 1999, the virus has since spread regularly through outbreaks in Bangladesh and India. Mortality linked to these outbreaks is estimated to be between 75% and 90%.

The virus has recently been included on the WHO list of priority emerging pathogens. There is currently no approved treatment or vaccine. Numerous candidate vaccines are under study or development. Most target the G and F proteins on the surface of the virus, which are necessary for it to enter human cells and spread throughout the body.

The teams at Inserm and UPEC have developed an original approach involving antigen-presenting cells (APCs), in particular dendritic cells, which play an important role in the immune response. To construct the CD40.NiV vaccine, specific parts (or epitopes) of the G, F and N proteins of the Bangladesh strain of Nipah virus (NiV-B) were attached to an antibody recognising the CD40 receptors on the surface of dendritic cells. The epitopes are thus presented directly to the cells of the immune system.

Immunogenicity (the ability to induce an immune response) of the vaccine was assessed in mice and non-human primates after two administrations of CD40.NiV vaccine (the so-called “prime-boost” strategy). As early as 10 days after the first vaccination with CD40.NiV (prime), NiV-specific IgG and IgA antibodies, as well as neutralising antibodies (specific antibodies that prevent infection by blocking viral entry into target cells) were produced. The neutralising antibody response is maintained for at least 100 days after the peak of the immune response. In addition, the team showed that the antibodies induced against NiV also neutralise various strains of NiV (Malaysia, Cambodia) and the Hendra virus (this is known as cross-neutralising immunity), an infectious agent transmitted by bats and causing a highly fatal infection in horses and humans.

To ensure that the vaccine was effective, the animals were infected with the NiV virus 60 days after the second injection of CD40.NiV (boost). Protection was complete.

This preclinical study demonstrated that the CD40.NiV vaccine candidate confers protection against the development of Nipah virus, with 100% survival of immunised animals until the end of the study, 28 days after infection. The absence of significant clinical signs or virus replication suggests that the candidate vaccine provides ‘sterilising immunity’, meaning that it can prevent the disease and its transmission.

Overall, results obtained with CD40.NiV are highly promising for fighting NiV infection and represent an important milestone towards the clinical development of a vaccine against this virus.

An essential component of the haemoglobin in red blood cells, iron is crucial to many biological processes – including the transport and storage of oxygen in the body. © Inserm/Claude Féo

Anaemia is a major public health problem worldwide, affecting around one third of the population. Its causes are multiple, but the most common are a lack of red blood cell production, a lack of iron in the blood, and genetic diseases such as thalassaemia. A better understanding of iron metabolism is essential to improve the care of the many patients affected. In a new study, Inserm researchers at the Digestive Health Research Institute (Inserm/INRAE/Université Toulouse III – Paul-Sabatier/Toulouse National Veterinary School) identified the major role of a protein called FGL1 in iron metabolism. Their discovery paves the way for new clinical possibilities in the treatment of anaemia. These findings have been published in the journal Blood.

Anaemia is a disease in which the number of red blood cells – or the haemoglobin levels of the red blood cells – is lower than normal. A major factor in the morbidity and mortality of one third of the world’s population, anaemia is a major public health problem.

Anaemia can be caused by a deficit of iron in the blood resulting from dietary deficiencies, infections, chronic diseases, heavy menstruation, problems during pregnancy or by genetic diseases that affect the production of red blood cells (thalassaemia).

An essential component of the haemoglobin in red blood cells, iron is crucial to many biological processes – including the transport and storage of oxygen in the body. In other words, insufficient iron in the body means insufficient haemoglobin and red blood cells for transporting oxygen to the organs and tissues, which ultimately leads to organ failure.

However, too much iron is also toxic to the body, meaning that its intake needs to be carefully regulated to avoid excessively high or low levels which are responsible for severe clinical complications.

Understanding iron metabolism

For several years, knowledge about anaemia and iron metabolism has been steadily increasing. It is now well known that iron levels in the body are regulated by a hormone called hepcidin.

We also now know that if the body needs more iron, as is the case with anaemia, a hormone called erythroferrone (ERFE) suppresses the expression of hepcidin in the liver. This process supplies the bone marrow with iron to synthesise new red blood cells and increase haemoglobin levels.

The identification of ERFE in 2014 by Inserm researcher Léon Kautz and his colleagues represented an important step in this field of research. However, these data obtained ten years ago were already suggesting that ERFE was not the only hormone controlling this process. The scientists hypothesised that a second protein, previously unknown, performed a similar function.

A new factor identified

This is what they have now confirmed by conducting new experiments in mouse models of anaemia, in two specific cases: one during an increased synthesis of red blood cells aimed at correcting induced anaemia in mice and the other in mice with thalassaemia.

The scientists started by studying the molecular mechanisms activated in the animals’ liver to identify the genes whose expression was increased during the anaemia. They observed that the expression of the gene coding for protein FGL1 was increased in the liver when the oxygen concentration decreased.

The researchers then produced different forms of protein FGL1 to test its mode of action in vivo in mice and in vitro in human liver cells. They were able to show that its mode of action is similar to that of the hormone ERFE, because FGL1 also represses hepcidin expression.

‘In addition to the fundamental aspects of this research in understanding anaemia, we believe that identifying the role of FGL1 will lead to the development of new therapeutic strategies to treat anaemia of various causes and for which the current treatments are ineffective,’ emphasises Léon Kautz, Inserm staff scientist.

For the moment, the team will start by conducting additional research to verify that FGL1 levels are indeed increased in the blood of patients with different types of anaemia. But the scientists plan to go further, with Inserm Transfert having already filed two patent applications for this study.

On the one hand, the first patent aims to better treat anaemia resulting from chronic diseases such as cancer. The objective is to identify analogous molecules or molecules that activate FGL1 synthesis, which would reduce hepcidin expression in these patients and increase their haemoglobin levels.

On the other hand, thalassaemia is characterised by very low levels of hepcidin, leading to excess iron that is harmful to the organs, causing high mortality. The team hypothesised that FGL1 is also involved in this process. The second patent therefore aims to achieve proof of concept that FGL1 inhibition could improve iron overloads in patients suffering from thalassaemia.