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Category: Circulation, metabolism, nutrition

Research shows fatty liver disease endangers brain health

Posted on by newround

Liver cells invaded by lipid droplets (in white) from an animal on a diet rich in sugars and fats. © University Institute of Pathology of the University of Lausanne.


People with liver disease caused by eating too much sugar and fat could be at increased risk of developing serious neurological conditions like depression or dementia. In a study examining the link between non-alcoholic fatty liver disease (NAFLD) and brain dysfunction, scientists at the Roger Williams Institute of Hepatology, affiliated to King’s College London and the University of Lausanne, found an accumulation of fat in the liver causes a decrease in oxygen to the brain and inflammation to brain tissue – both of which have been proven to lead to the onset of severe brain diseases.

NAFLD affects approximately 25% of the population and more than 80% of morbidly obese people. Several studies have reported the negative effects of an unhealthy diet and obesity can have on brain function however this is believed to be the first study that clearly links NAFLD with brain deterioration and identifies a potential therapeutic target.

The research, conducted in collaboration with Inserm (the French National Institute of Health and Medical Research) and the University of Poitiers in France , involved feeding two different diets to mice. Half of the mice consumed a diet with no more than 10% fat in their calorie intake, while the other half’s calorie intake contained 55% fat; intended to resemble a diet of processed foods and sugary drinks.

After 16 weeks researchers conducted a series of tests to compare the effects of these diets on the body and more specifically, on the liver and the brain.

They found that all mice consuming the higher levels of fat were considered obese, and developed NAFLD, insulin resistance and brain dysfunction.

The study which was funded by the University of Lausanne and Foundation for Liver Research, published today in The Journal of Hepatology, also showed that the brain of mice with NAFLD suffered from lower oxygen levels. This is because the disease affects the number and thickness of the brain blood vessels, which deliver less oxygen to the tissue, but also due to specific cells consuming more oxygen while the brain is becoming inflamed. These mice were also more anxious and showed signs of depression.

By comparison, the mice consuming the healthy diet did not develop NAFLD or insulin resistance, they behaved normally, and their brain was completely healthy.

“It is very concerning to see the effect that fat accumulation in the liver can have on the brain, especially because it often starts off mild and can exist silently for many years without people knowing they have it,” said lead author Dr Anna Hadjihambi, sub-team lead in the Liver-Brain Axis group at the Roger Williams Institute of Hepatology and honorary lecturer at King’s College London.

To try and combat the dangerous effect that NAFLD has on the brain, the scientists bred mice with lower levels of a whole-body protein known as Monocarboxylate Transporter 1 (MCT1) – a protein specialised in the transport of energy substrates used by various cells for their normal function.

When these mice were fed the same unhealthy fat- and sugar-rich diet as those in the initial experiment, they had no fat accumulation in the liver and exhibited no sign of brain dysfunction – they were protected from both ailments.

“Identifying MCT1 as a key element in the development of both NAFLD and its associated brain dysfunction opens interesting perspectives,” said Professor Luc Pellerin, director of the Inserm U1313 research unit at the University of Poitiers in France and senior researcher in the study. “It highlights potential mechanisms at play within the liver-brain axis and points to a possible therapeutic target.”

Dr Hadjihambi added: “This research emphasises that cutting down the amount of sugar and fat in our diets is not only important for tackling obesity, but also for protecting the liver to maintain brain health and minimise the risk of developing conditions like depression and dementia during ageing, when our brain becomes even more fragile.“

The full paper is available to view online in The Journal of Hepatology.

Decoding a direct dialog between the gut microbiota and the brain

Posted on by Lea Roy

Diagram showing the direct dialog between the gut microbiota and the brain

© Institut Pasteur / Pascal Marseaud

 

Gut microbiota by-products circulate in the bloodstream, regulating host physiological processes including immunity, metabolism and brain functions. Scientists from the Institut Pasteur (a partner research organization of Université Paris Cité), Inserm and the CNRS have discovered that hypothalamic neurons in an animal model directly detect variations in bacterial activity and adapt appetite and body temperature accordingly. These findings demonstrate that a direct dialog occurs between the gut microbiota and the brain, a discovery that could lead to new therapeutic approaches for tackling metabolic disorders such as diabetes and obesity. The findings are due to be published in Science on 2022 04 15.

The gut is the body’s largest reservoir of bacteria. A growing body of evidence reveals the degree of interdependence between hosts and their gut microbiota, and emphasizes the importance of the gut-brain axis.

At the Institut Pasteur, neurobiologists from the Perception and Memory Unit (Institut Pasteur/CNRS)[1], immunobiologists from the Microenvironment and Immunity Unit (Institut Pasteur/Inserm), and microbiologists from the Biology and Genetics of the Bacterial Cell Wall Unit (Institut Pasteur/CNRS/Inserm)[2] have shared their expertise to investigate how bacteria in the gut directly control the activity of particular neurons in the brain.

The scientists focused on the NOD2 (nucleotide oligomerization domain) receptor which is found inside of mostly immune cells. This receptor detects the presence of muropeptides, which are the building blocks of the bacterial cell wall. Moreover, it has previously been established that variants of the gene coding for the NOD2 receptor are associated with digestive disorders, including Crohn’s disease, as well as neurological diseases and mood disorders. However, these data were insufficient to demonstrate a direct relationship between neuronal activity in the brain and bacterial activity in the gut. This was revealed by the consortium of scientists in the new study.

Using brain imaging techniques, the scientists initially observed that the NOD2 receptor in mice is expressed by neurons in different regions of the brain, and in particular, in a region known as the hypothalamus. They subsequently discovered that these neurons’ electrical activity is suppressed when they come into contact with bacterial muropeptides from the gut. “Muropeptides in the gut, blood and brain are considered to be markers of bacterial proliferation,” explains Ivo G. Boneca, Head of the Biology and Genetics of the Bacterial Cell Wall Unit at the Institut Pasteur (CNRS/Inserm). Conversely, if the NOD2 receptor is absent, these neurons are no longer suppressed by muropeptides. Consequently, the brain loses control of food intake and body temperature. The mice gain weight and are more susceptible to developing type 2 diabetes, particularly in older females.

In this study, the scientists have demonstrated the astonishing fact that neurons perceive bacterial muropeptides directly, while this task was thought to be primarily assigned to immune cells. “It is extraordinary to discover that bacterial fragments act directly on a brain center as strategic as the hypothalamus, which is known to manage vital functions such as body temperature, reproduction, hunger and thirst,” comments Pierre-Marie Lledo, CNRS scientist and Head of the Institut Pasteur’s Perception and Memory Unit.

The neurons thus appear to detect bacterial activity (proliferation and death) as a direct gauge of the impact of food intake on the intestinal ecosystem. “Excessive intake of a specific food may stimulate the disproportionate growth of certain bacteria or pathogens, thus jeopardizing intestinal balance,” says Gérard Eberl, Head of the Microenvironment and Immunity Unit at the Institut Pasteur (Inserm).

The impact of muropeptides on hypothalamic neurons and metabolism raises questions on their potential role in other brain functions, and may help us understand the link between certain brain diseases and genetic variants of NOD2. This discovery paves the way for new interdisciplinary projects at the frontier between neurosciences, immunology and microbiology, and ultimately, for new therapeutic approaches to brain diseases and metabolic disorders such as diabetes and obesity.

 

[1] This research unit is also known as the “Genes, Synapses and Cognition Laboratory” (Institut Pasteur/CNRS).
Paris Brain Institute (CNRS/Inserm/Sorbonne Université/AP-HP) also contributed to these findings.

[2] The CNRS unit’s name is the “Integrative and Molecular Microbiology Unit” and the Inserm unit’s name is the “Host-Microbe Interactions and Pathophysiology Unit” (Institut Pasteur/CNRS/Inserm).

Artificial Sweeteners: Possible Link to Increased Cancer Risk

Posted on by Graziella Cara

édulcorant artificiel

Aspartame, a well-known artificial sweetener, is for example present in thousands of food products worldwide. © Mathilde Touvier/Inserm

Artificial sweeteners are used to reduce the amounts of added sugar in foods and beverages, thereby maintaining sweetness without the extra calories. These products, such as diet sodas, yoghurts and sweetener tablets for drinks, are consumed by millions of people daily. However, the safety of these additives is the subject of debate. In order to evaluate the risk of cancer linked to them, researchers from Inserm, INRAE, Université Sorbonne Paris Nord and Cnam, as part of the Nutritional Epidemiology Research Team (EREN), analyzed data relating to the health of 102,865 French adults participating in the NutriNet-Santé cohort study and their consumption of artificial sweeteners. The results of these statistical analyses suggest a link between the consumption of artificial sweeteners and an increased risk of cancer. They have been published in PLOS Medicine.

Given the adverse health effects of consuming too much sugar (weight gain, cardiometabolic disorders, dental caries, etc.), the World Health Organization (WHO) recommends limiting free sugars1 to less than 10% of one’s daily energy intake2. Therefore, in order to ensure that foods maintain that sweet taste so sought after by consumers worldwide, the food industry is making increasing use of artificial sweeteners. These are additives that reduce the amount of added sugar (and calories) without reducing sweetness. What is more, in order to enhance flavor, manufacturers use them in certain products that traditionally contain no added sugar (such as flavored potato chips).

Aspartame, a well-known artificial sweetener, is for example present in thousands of food products worldwide. While its energy value is similar to that of sugar (4 kcal/g), its sweetening power is 200 times higher, meaning that a much smaller amount is needed to achieve a comparable taste. Other artificial sweeteners, such as acesulfame-K and sucralose, contain no calories at all and are respectively 200 and 600 times sweeter than sucrose.

Although several experimental studies have pointed to the carcinogenicity of certain food additives, there are no robust epidemiological data supporting a causal link between the everyday consumption of artificial sweeteners and the development of various diseases. In a new study, researchers sought to examine the links between the consumption of artificial sweeteners (total and most often consumed) and the risk of cancer (global and according to the most common types of cancer) in a vast population study. They used the data provided by 102,865 adults participating in the NutriNet-Santé study (see box below), an online cohort initiated in 2009 by the Nutritional Epidemiology Research Team (EREN) (Inserm/Université Paris Nord/CNAM/INRAE), which also coordinated this work.

The volunteers reported their medical history, sociodemographic data and physical activity, as well as information on their lifestyle and health. They also gave details of their food consumption by sending the scientists full records of what they consumed over several 24-hour periods, including the names and brands of the products. This made it possible to accurately evaluate the participants’ exposure to additives, and more particularly to artificial sweeteners.

After collecting information on cancer diagnoses over the NutriNet-Santé study period so far (2009-2021), the researchers conducted statistical analyses in order to study the links between the use of artificial sweeteners and the risk of cancer. They also took into account various potentially confounding factors, such as age, sex, education, physical activity, smoking, body mass index, height, weight gain over the study period so far, family history of cancer, as well as intakes of energy, alcohol, sodium, saturated fatty acids, fiber, sugar, whole grain foods and dairy products.

The scientists found that compared with those who did not consume artificial sweeteners, those who consumed the largest amounts of them, especially aspartame and acesulfame-K, were at increased risk of developing cancer, irrespective of the type.

Higher risks were observed for breast cancer and obesity-related cancers.

“In accordance with several in vivo and in vitro experimental studies, this large-scale, prospective study suggests that artificial sweeteners, used in many foods and beverages in France and throughout the world, may represent an increased risk factor for cancer,” explains Charlotte Debras, PhD student and lead author of the study. Further research in other large-scale cohorts will be needed in order to replicate and confirm these findings.

“These findings do not support the use of artificial sweeteners as safe alternatives to sugar, and they provide new information in response to the controversy regarding their potential adverse health effects. They also provide important data for their ongoing re-evaluation by the European Food Safety Authority (EFSA) and other public health agencies worldwide,” concludes Dr. Mathilde Touvier, Inserm Research Director and study coordinator.

NutriNet-Santé is a public health study coordinated by the Nutritional Epidemiology Research Team (EREN, Inserm / INRAE / Cnam / Université Sorbonne Paris Nord) which, thanks to the commitment and loyalty of over 170,000 participants (known as “Nutrinautes”), advances research into the links between nutrition (diet, physical activity, nutritional status) and health. Launched in 2009, the study has already given rise to over 200 international scientific publications. In France, new participants are currently being encouraged to join in order to continue to advance research on the relationship between nutrition and health.

By devoting a few minutes per month to answering various online questionnaires relating to diet, physical activity and health, participants contribute to furthering knowledge of the links between diet and health. With this civic gesture, we can each easily participate in research and, in just a few clicks, play a major role in improving the health of all and the wellbeing of future generations. These questionnaires can be found on the secure platform www.etude-nutrinet-sante.fr.

 

1 Sugars added to foods and beverages and sugars naturally present in honey, syrups, and fruit juices.

2 World Health Organization, 2015

Persistence of severe hepatic fibrosis despite substantial weight loss with bariatric surgery

Posted on by Graziella Cara

stéatose hépatique.

Detail of a steatosis, accumulation of a fat, triglyceride, in the liver cell. © Inserm/Hadchouel, Michelle

A research team from AP-HP, Inserm and Sorbonne University carried out work, within the IHU ICAN, on the effects of bariatric surgery on the severity of liver damage in patients with NASH (Non-Alcoholic Steatohepatitis or Metabolic Steatohepatitis) and severe fibrosis (bridge fibrosis or compensated cirrhosis). This study shows that in 50% of patients who underwent bariatric surgery, despite significant weight loss (20% to 30% of initial BMI) and improvement in metabolic risk factors (mainly type 2 diabetes), severe fibrosis persists in the medium term (5 years after surgery). The results of this work were published on January 25, 2022 in the journal Hepatology .

Obesity in France concerns 17% of the adult population and it increasingly affects children and adolescents. It has many consequences on the state of health of people who are affected, including the development of “fatty liver” (liver steatosis). Hepatic steatosis is defined by the accumulation of fat in liver cells favored by the presence of metabolic risk factors (particularly diabetes and obesity).

In France, liver steatosis affects 18% of the population and 25% of the general population worldwide. Eventually, this pathology, also called NASH, can lead to the appearance of more serious diseases such as cirrhosis or liver cancer. To date, there is no effective drug treatment for NASH, which makes research around other avenues of care for patients all the more important.

Previous work has shown dramatic improvement in NASH liver damage after bariatric surgery in parallel with weight loss. Nevertheless, efficacy data in patients with advanced forms of NASH remain limited.

The study, coordinated by Dr Raluca Pais (AP-HP, IHU ICAN), Dr Judith Aron-Wisnewsky (AP-HP, Inserm, Sorbonne University, IHU ICAN), Pr Vlad Ratziu (AP-HP, INSERM, Sorbonne University, IHU ICAN) and Pr Karine Clément (AP-HP, Inserm, Sorbonne University, NutriOmic Unit), analyzed the effects of bariatric surgery on the evolution of severe histological lesions of NASH. The patients, from the “BARICAN bariatric surgery” cohort coordinated by the nutrition department led by Pr Jean-Michel Oppert at the Pitié-Salpêtrière AP-HP hospital, had an initial liver biopsy at the time of surgery. bariatric and a follow-up biopsy.  

This study confirms the excellent results of bariatric surgery: overall, 29% of patients had normal histology at follow-up biopsy; 74% had NASH resolution without fibrosis progression; 70% had fibrosis regression.

However, in patients with severe fibrosis before surgery, severe fibrosis persisted in 47% of cases in the medium term after surgery, despite the resolution of NASH in 69% of cases.

Patients who do not respond to bariatric surgery have a lesser improvement in metabolic risk factors (less weight loss, remission of diabetes) even if clinically significant. The factors associated with the persistence of fibrosis after bariatric surgery, in addition to the follow-up interval, were age and type of surgery (less regression of fibrosis after the sleeve regardless of weight loss). The factors associated with the absence of liver lesions after bariatric surgery were greater weight loss, improved insulin resistance and less initial severity of necroinflammatory lesions.

In conclusion, Dr. Raluca Pais specifies that “ this study shows that, despite established efficacy for the regression of NASH, bariatric surgery is less effective for the regression of severe fibrosis. Fibrosis regression requires more time and probably additional mechanisms. Weight loss alone may not be enough to reverse severe fibrosis. »

Improvement in the Health of Two Infants with Severe Disharmonious Overgrowth Syndromes

Posted on by Graziella Cara

Co-labeling of mouse skin expressing a PIK3CA gene mutation. © Marina Firpion/Guillaume Canaud – Inserm unit 1151

 

Disharmonious overgrowth syndromes are rare genetic diseases associated with a PIK3CA gene mutation. Since 2016, a team of researchers from Inserm, Paris Public Hospitals Group (AP-HP), Université de Paris, the Disharmonious Overgrowth and Vascular Abnormalities Unit of Institut Necker-Enfants Malades and the clinical departments of Hospices Civils of Lyon has demonstrated the therapeutic efficacy of alpelisib, a molecule used to fight certain cancers, in treating a group of children and adults with severe forms of these diseases. In a new publication, the team reports clinical, biological, and imaging improvements in two infants with severe forms of disharmonious overgrowth syndromes treated with alpelisib. These are the first data obtained on the use of this molecule in severe neonatal forms of the disease. The results of this one-year follow-up have been published in Journal of Experimental Medicine (JEM).

Disharmonious overgrowth syndromes are rare genetic diseases characterized by an increase in both the size and number of cells in the body. They manifest by an asymmetry that can affect any body part or tissue (fat, vessels, muscles, bones, etc.), including the brain. In 95% of cases, the disease is linked to a mutation, occurring during embryonic development, of the PIK3CA gene that regulates cell growth and proliferation.

When PIK3CA is overactivated, the parts of the body affected by the mutation grow excessively, leading to physical deformities that are more or less debilitating depending on the number of tissues affected. While some symptoms can be alleviated by surgery and other supportive care, there is currently no approved drug treatment for the disease.

In previous research, the drug alpelisib, a PIK3CA inhibitor recently approved for the treatment of certain forms of breast cancer1, had shown promising results – first in animal models of overgrowth syndrome, and then in a small number of adults and children. The drug is currently undergoing a series of larger-scale clinical trials, but until now there had been no data on its efficacy in infants.

In this new study, a team of researchers from Inserm, Paris Public Hospitals Group (AP-HP) and Université de Paris, coordinated by Professor Guillaume Canaud, reports encouraging results with alpelisib administered for one year to two infants – one girl and one boy aged 8 months and 9 months, respectively, at the start of treatment – presenting with a variety of severe symptoms caused by PIK3CA gene mutations. These symptoms included extreme blood vessel malformations, anemia, excessive asymmetric growth of the limbs and fingers and, in the boy, excessive growth of one of the brain hemispheres (hemimegaloencephaly) associated with epileptic seizures2. Before the start of treatment, the girl’s condition was life-threatening and the boy had a serious neurological prognosis, which did not respond to conventional epilepsy drugs.

Good tolerability

In both infants, daily oral doses of 25 mg alpelisib led to rapid and significant clinical improvement in the symptoms. Twelve months of treatment stopped the boy’s epileptic spasms and reduced the girl’s number of vascular malformations. The considerable decrease in the volume of her right leg has enabled her to remain upright and walk, with assistance. The anemia resolved in both children following initiation of the treatment.

The infants’ length and weight that initially were outside the norm for their age corrected themselves following the introduction of alpelisib. It is important to note that they had no side effects related to the treatment. Further analyses revealed that with a dose of 25 mg per day, their blood levels of alpelisib were much lower than those safely tolerated by adults3.

“The results of the alpelisib treatment in these two infants are encouraging because they show an improvement across all parameters, whether clinical, biological, or radiological. The high level of efficacy observed may be because alpelisib was started early. The patients had no history of surgery, which is relevant because we know that the remodeling caused by it can affect how well alpelisib is absorbed by the tissues. Furthermore, it is very likely that the plasticity of the tissues at this age enables the treatment to work better, explains Professor Canaud, coordinator of the study. These results should however be interpreted with caution and be confirmed over time and with further monitoring,” he says.

This use of alpelisib in overgrowth syndromes continues to be the subject of clinical trials in a population of consisting not just of adults but also of children from 6 years of age. These encouraging results make it possible to envisage extending the drug’s approval to include the clinical treatment of severe neonatal forms.

The treatment of these infants with alpelisib is provided as part of a compassionate use program, in which the French medicines agency (ANSM) issues exceptional approval to treat patients suffering from diseases with a severe prognosis and with no appropriate treatment available, in a given therapeutic indication.

 

1 The PIK3CA gene is frequently mutated in a certain number of cancers. This mutation is believed to occur in approximately 40% of breast cancers.

2 The boy had West syndrome, also known as infantile spasms, a rare form of epilepsy in infants.

3 When treating cancer, the daily dose of alpelisib administered to an adult (between 300 and 350 mg) is approximately 15 times higher.

Cohort study identifies genetic cause for rare form of diet-induced Cushing syndrome

Posted on by Graziella Cara

Coupe de rein humain grossie 400 fois par un microscope à immunofluorescence polychromatique

Human kidney section magnified 400 times by a polychromatic immunofluorescence microscope. © Inserm/Oriol, Rafael

 

The team made up of researchers from the endocrinology and reproductive diseases department of Bicêtre AP-HP hospital, Inserm and Paris-Saclay University, carried out work, coordinated by Professor Peter Kamenický, to study the genetic cause of bilateral macronodular adrenal hyperplasia with diet-induced Cushing’s syndrome. This rare disease affects the two adrenal glands located above the kidneys and causes an overproduction of cortisol, a steroid hormone whose excess has harmful consequences for the body . Researchers were able to determine the molecular explanation for the occurrence of this disease 30 years after its initial description. This work was published on October 13, 2021 in the journal The Lancet Diabetes & Endocrinology .

This rare form of adrenal Cushing syndrome, studied by these researchers, is due to the abnormal expression of the GIP receptor (Glucose-dependent insulinotropic peptide) in both adrenal glands of patients. GIP is a hormone produced by the small intestine in response to the ingestion of food. In patients with this particular form of Cushing’s syndrome, cortisol levels increase abnormally after each food intake. Patients with this disease develop the typical clinical signs of Cushing’s syndrome such as weight gain associated with muscle atrophy, high blood pressure, diabetes mellitus, osteoporosis, and depression. The pathology is associated with an increase in mortality, especially cardiovascular causes.

In this international study involving researchers from six countries, and based in particular on close Franco-Quebec collaboration, the team reports that GIP-dependent macronodular hyperplasia of the adrenals, in both familial and sporadic forms, is a genetic disease caused by germline mutations of Lysine Demethylase 1A (KDM1A) with secondary loss of the second KDM1A locus, comprising the second copy of the gene, in adrenal tissue. KDM1A acts mainly as a transcriptional repressor (ie a regulator which prevents a gene from being expressed), the loss of its function results in deregulation of the expression of various genes in the adrenal tissue, including the GIP receptor but also of other receptors coupled to G proteins.

This discovery will make it possible to offer genetic counseling and earlier detection of this rare disease to patients and their relatives. Rare diseases are generally underdiagnosed. This is all the more important as the pathogenic variations of KDM1A also predispose to myeloma and other types of cancer.

In addition, this new role of KDM1A as an epigenetic regulator of the expression of the GIP receptor and other receptors coupled to G proteins could have pharmacological implications.

COVID-19: Artificial Intelligence Identifies Gene Signature Specific to Patients Suffering from Critical Forms

Posted on by Graziella Cara

SARS-CoV-2

Covid-19: Intracellular observation of reconstituted human respiratory epithelium MucilAir™ infected with SARS-CoV-2. © Manuel Rosa-Calatrava, Inserm ; Olivier Terrier, CNRS ; Andrés Pizzorno, Signia Therapeutics ; Elisabeth Errazuriz-Cerda  UCBL1 CIQLE. VirPath (Centre International de Recherche en Infectiologie U1111 Inserm – UMR 5308 CNRS – ENS Lyon – UCBL1). Colorisé par Noa Rosa C.

 

What are the molecular and genetic characteristics that distinguish patients with critical forms of COVID-19 – and particularly acute respiratory distress syndrome (ARDS)? To answer this question, researchers from Inserm and Université de Strasbourg at Unit U1109 Molecular Immunology and Rheumatology, in collaboration with clinician-researchers at the Strasbourg University Hospitals, have investigated the biological and genomic data of a targeted cohort of young patients. Patients hospitalized in intensive care with ARDS were compared with COVID-19 patients hospitalized in a non-critical care ward.

As part of a Franco-US collaboration with researchers from the company Genuity Science in Boston and the University of Southern California in Los Angeles and using the most advanced artificial intelligence techniques to interpret these data, the scientists have succeeded in identifying a gene signature that differentiates these critical patients from their non-critical counterparts. Some of the genes included in this signature could ultimately become therapeutic targets for severe forms of COVID-19 or ARDS. The findings from this research have been published in Science Translational Medicine.

COVID-19 varies broadly from one patient to another. While some are asymptomatic, others develop flu-like symptoms. Then there are others who progress towards severe forms of the disease, in some cases developing acute respiratory distress syndrome (ARDS) that requires mechanical ventilation in an intensive care unit. Although this group of patients accounts for only a small proportion of those infected with the virus, its mortality rate is high – reaching around 25%.

While age and comorbidities such as diabetes and cardiovascular diseases are the main risk factors for developing these severe, potentially fatal, forms of COVID-19, scientists do not yet know why some younger and previously healthy patients also develop these forms. In molecular and genetic terms, what is it that distinguishes these patients with severe respiratory symptoms from the others?

There has been research into the subject since the start of the pandemic and some avenues have been identified, but so far each study addressed the question from a single methodological angle, generally focusing only on one aspect – genetic and metabolic factors, immune response parameters, etc.

Young patients with no comorbidities

The scientists from Inserm and Université de Strasbourg, in conjunction with the Strasbourg University Hospitals, were in this case interested in a patient cohort with restrictive and strict inclusion criteria. The patients had been hospitalized during the first wave of the pandemic, were under 50 years of age and had no major comorbidities. A total of 72 patients were recruited into two groups, one consisting of intensive care patients with ARDS and the other of less severe COVID-19 patients hospitalized in a non-critical ward. A “control” group of 22 healthy individuals was also studied.

“We chose to focus on a restricted but very well-defined patient cohort, excluding confounding factors such as age and certain diseases so that we could really study the molecular and genetic mechanisms directly associated with the severe forms, which are exclusively linked to viral infection and not to other pre-existing risk factors,” emphasizes Seiamak Bahram [1], last author of the study.

The scientists collected various samples in order to perform a multi-omics analysis –that is say retrieve and analyze the various genomic, proteomic, transcriptomic (investigation of all messenger RNA) data and other virological, immunological, and serological data from these patients. This allowed them to confirm that ARDS is associated with a major inflammatory state and an immune system surge (the so-called “cytokine storm”).

Using artificial intelligence

However, given the considerable mass of data generated as part of this multi-omics analysis, it was impossible to take the interpretation further without the help of artificial intelligence (AI). Thus, in collaboration with the AI Research Institute of Genuity Science [2] , a biotech in Boston (USA), the team was able to identify a network of 600 genes involved in the progression towards the critical forms of COVID-19, thanks to the cross-application of several AI algorithms (including one having run on the quantum computer made available by the University of Southern California in Los Angeles).

As part of this transatlantic collaboration, these large quantities of data were modelled and analyzed with the help of AI, making it possible to more accurately identify five genes that are overexpressed in these patients.

One of them, ADAM9, is a particularly interesting “driver gene,” with previous studies having shown that it interacts with SARS-CoV-2 proteins. The findings obtained here are consistent with that, suggesting that ADAM9 overexpression would “drive” some patients towards severe forms of COVID-19 and ARDS.

The researchers then conducted in vitro experiments which showed that blocking ADAM9 in cell lines is associated with a reduction in the quantities of SARS-CoV-2 in these cells, as well as reduced replication of the virus, thereby confirming not just its importance in critical disease but also its potential as a therapeutic target.

Of course, further studies will have to be carried out to confirm this last point, but the scientists believe that these findings have opened up an interesting therapeutic avenue, especially given the current clinical trials in oncology that are testing monoclonal antibodies which inhibit ADAM9. Therapeutic repurposing strategies could therefore be considered in the longer term.

 

[1] Professor Seiamak Bahram, a university professor and hospital practitioner, is the director of Inserm Unit 1109, head of the Strasbourg Precision Medicine Interdisciplinary Thematic Institute, and head of the Biological Immunology Department at Strasbourg University Hospitals.

[2] It has since become the company HiberCell

Découverte de nouveaux marqueurs génétiques à l’origine d’une maladie des artères essentiellement féminine

Posted on by Graziella Cara

The appendix is not an unnecessary organ but is in fact correlated with a longer lifespan

Posted on by Graziella Cara

koala

The appendix is an anatomical structure that can be found in a wide range of very different species, from the orangutan to the koala, beaver, and of course humans. © David Clode/Unsplash

 

Long considered an unnecessary organ, the appendix is now the focus of several studies that aim to better understand its role. Present in many mammals, including humans, it appears to have developed at least 16 times over the course of the evolutionary history of mammals, suggesting that its function must confer a positive selective advantage on those that have it. A new study carried out by researchers from Inserm and the French Museum of Natural History suggests that the presence of the appendix is in fact correlated with greater longevity. Their findings have been published in the Journal of Anatomy.

The appendix is a small anatomical structure of a few centimeters in size, located in the abdomen and attached to the colon, the function of which has long been poorly understood. According to the theories of Charles Darwin, the appendix was a vestigial structure, useless and devoid of function. It might even be seen as potentially dangerous to health due to the risk of inflammation of the organ. If such inflammation, known as “appendicitis,” is left untreated, it can develop into peritonitis and result in death.

Over the last few years, researchers have sought to learn more about the role of the appendix. Studies have, for example, shown that an appendectomy performed in cases of confirmed appendicitis before the age of 20 has a protective effect against the onset of a particular form of chronic inflammation of the colon and rectum: ulcerative colitis.

Researchers have also shown that the appendix is not only present in humans. It first appeared in mammals at least 80 million years ago, and over the course of evolution has developed independently multiple times in several mammalian lineages, with no obvious correlation with diet, social life, or the environment. Today it can be found in a wide range of animals: from orangutans and koalas to manatees, beavers, and platypuses. Its function has however remained a mystery, with no study reaching a definitive conclusion.

A link with mammalian longevity

The team led by Inserm researcher Eric Ogier-Denis and his colleague Michel Laurin from the French Museum of Natural History approached the question by analyzing data from 258 species of mammals, 39 with and 219 without an appendix. The scientists focused in particular on the theoretical maximum longevity (the theoretical lifespan of mammals, established based on their weight) and actual maximum longevity of the various species considered.

They have shown for the first time that the presence of the appendix is correlated with an increase in the maximum longevity observed for a species. Compared to mammals of the same weight without an appendix, mammals with an appendix have a longer lifespan.

“The idea of focusing on longevity developed from our work on the relationship between appendicitis/appendectomy, ulcerative colitis and the involvement of the immune system. A more active and better educated immune system should theoretically provide greater resistance to the environment and a longer lifespan. We therefore tested this hypothesis by partnering with two internationally renowned evolutionary experts from the French Museum of Natural History. This is the first time the existence of a correlation between the presence of the appendix and a trait in the life history of mammals has been demonstrated,” explains Eric Ogier-Denis.

The team has also shown that the appendix has developed at least 16 times and has only been lost once (by the lemur Hapalemur griseus, endemic to Madagascar) during the evolutionary history of mammals, which supports the idea that

through its function this organ provides a significant positive selective advantage with regard to the laws of natural selection.

A bacterial sanctuary

The researchers believe that the most likely hypothesis to explain the link between the presence of the appendix and longevity is that the shape of the organ enables the development of a selective “bacterial sanctuary” that reduces mortality from infectious diarrhea by promoting rapid recolonization of bacterial species that are essential to the host. The presence of the appendix would therefore be associated with a decrease in mortality and thus greater longevity in mammals that have this organ.

“This does not mean that an appendectomy performed on a human to treat appendicitis has an effect on longevity. Appendicitis at a young age is clearly beneficial by strengthening the education of the immune system and enabling it to fight any subsequent infection more effectively. The treatment for appendicitis remains appendectomy and this work does not provide any evidence to suggest this treatment approach should be changed. Only an appendectomy performed in a patient without appendicitis might have harmful consequences in the context of inflammatory and infectious bowel disease,” explains Eric Ogier Denis.

This work therefore opens up clear new avenues of research for elucidating the controversial issue of the function of the appendix. Over the coming months, the researchers will build on it with field studies looking at different species of mammals to confirm the link between the appendix and longevity.

Hippurate, a metabolite derived from gut bacteria, is associated with microbiotal diversity

Posted on by Léa Surugue

Microbiote

Insulin is produced by the beta cells of the pancreatic islets of Langerhans. Cells which, in type 1 diabetes, are destroyed by the immune system. In this study, the administration of hippurate improved blood glucose control and stimulated insulin secretion in animal models. © Inserm/U845/UMRS975/EndoCells SARL

 

Good gut microbiota function has an impact on our general physical and psychological health. Understanding how the architecture of the microbiota and the function of the bacteria that inhabit it affect the body has become a key research focus in recent years.

Within this context, researchers from Inserm and Université de Paris, in collaboration with teams from INRAE, Imperial College London and the University of Copenhagen in Denmark, have shown that hippurate, a metabolite derived from gut bacteria, is associated with microbiotal diversity. Hippurate is thought to play an important role in our cardiovascular and metabolic health, particularly by helping to regulate blood sugar. This research has been published in Gut.

For several years, the gut microbiota has been considered to play a key role in our health. Many scientific studies have highlighted the existence of a link between the diversity of the bacterial strains present and certain health parameters, particularly cardiovascular and metabolic.

The team led by Inserm researcher Dominique Gauguier focused on hippurate, a metabolite produced by the gut bacteria and that is found in urine.

The scientists combined two methods, DNA sequencing (analysis of the genetic profile) of the gut microbiota bacteria and urinary metabolomic profiling (analysis of small metabolites present in urine) in 271 individuals from a Danish cohort (the MetaHIT study).

From the data obtained, the scientists show that high levels of hippurate in urine are associated with greater gut flora diversity and increased microbiotal gene richness, two parameters that protect against cardiometabolic risk (the risk of developing cardiovascular disease and/or diabetes).

The researchers also had information about the participants’ dietary habits and body mass index (BMI). They found that in obese individuals with a diet high in saturated fat and a risk of developing cardiovascular and metabolic problems, high levels of hippurate had beneficial effects on weight and metabolic health.

schéma Gauguier eng

Figure representing the main study findings.

These findings were supplemented by a validation study in obese mice fed a fatty diet. In these animal models, the administration of hippurate improved blood glucose control and stimulated insulin secretion. “This research confirms the importance in human health of gut flora architecture and function by demonstrating the beneficial role of a metabolite produced by gut bacteria. Something we had already shown with the metabolite cresol,” emphasizes Gauguier.

The relevance of these findings is both diagnostic, as hippurate can be considered a biomarker of microbiotal diversity, and therapeutic.

One could, for example, envisage modifying the microbiota using probiotic systems to produce larger quantities of the gut bacteria that synthesize the precursors of hippurate. This would then increase hippurate levels with their attendant protective effects on cardiometabolic risk.

For the scientists, the next step is to continue their research by studying the cellular mechanisms that explain how hippurate promotes insulin secretion and blood glucose regulation.

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