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.

Visualization of immune cell (lymphocyte) proliferation in the mesenteric lymph nodes, under the influence of a microbiota modulated by a high-fat diet. © Soraya Taleb/PARCC

Although a high-fat, low-fiber diet is recognized as promoting cardiovascular diseases such as atherosclerosis, the mechanisms involved have not yet been fully identified. Researchers from Inserm and Université Paris Cité have studied the role of the gut microbiota in the development of atherosclerosis. Their work in mice reveals that the low fiber content of the high-fat diet leads to an imbalance in the gut microbiota, which itself causes systemic inflammation, worsening the development of atherosclerotic plaques in the arteries. These findings, published in Cell Reports, provide further evidence of the importance of fiber in the diet, both for good bowel function and for preventing the onset of cardiovascular diseases.

Cardiovascular diseases constitute one of the leading causes of death worldwide. Among them, atherosclerosis is characterized by the formation of an atherosclerotic plaque (atheroma), composed mainly of lipids, on the walls of the arteries. Over time, these plaques can cause damage to the arterial wall, obstruct the vessel, or rupture – often with serious consequences. Among the major risk factors for atherosclerosis is obesity, particularly when caused by a diet that is too high in fat and low in fiber. As such, it is not just diet but also its impact on the gut microbiota that are now avenues of interest for research into cardiovascular diseases.

A team led by Soraya Taleb, Inserm research director at the Paris-Center for Cardiovascular Research (Inserm/Université Paris Cité), looked at the influence of a high-fat, low-fiber diet on the gut microbiota of mice and how this could contribute to the development of atherosclerosis.

The researchers used a mouse model of diet-induced atherosclerosis to compare the effects of several diets on the metabolism, microbiota and development of atherosclerosis.

Unsurprisingly, in the mice fed a high-fat, low-fiber diet, their findings show an increase in metabolic risk factors linked to cardiovascular diseases (significant weight gain, hyperglycemia, insulin resistance, increased weight of the liver and its triglyceride content, etc.).

However, these are not the only effects observed of this diet, which also appears to be associated with an overall imbalance in the microbiota – in its composition and immune response –, reflected in the altered production of metabolic derivatives by its component bacteria. In particular, short-chain fatty acids, derived from the fermentation of fiber and recognized for their positive impact on health, are produced in smaller quantities.

However, this imbalance itself appears to be associated not only with metabolic risk factors but also with a worsening of the manifestations of atherosclerosis at vascular level, with an increase in atheromatous plaque size in the aorta as well as a systemic inflammatory phenomenon which results in an increase in the number of immune cells in these plaques. However, supplementation with fiber made it possible to counteract these effects.

“These findings show, in mice fed a high-fat diet, that a pathological gut microbiota accelerates the development of atherosclerosis,” comments Taleb. Our observations also show that, more than its high fat content, it is the small amount of fiber in this diet that causes the microbiotal imbalance and as such the worsening of the atherosclerosis. This further supports the idea of the essential role of fiber in structuring a healthy microbiota and in preventing systemic inflammatory diseases such as cardiovascular diseases”, she continues.

But how can we explain the surprising link that appears between the composition of the microbiota and the accumulation of immune cells in atheromatous plaques? In mice grafted with a gut microbiota initially modulated by a high-fat diet, the research team observed an increased proliferation of immune cells in the mesenteric lymph nodes[1], the site of their activation in the gastrointestinal tract.

Techniques used to track migration of the immune cells confirmed that it was indeed cells from the mesenteric lymph nodes that, after passing from the gut into the bloodstream, accumulated in atheromatous plaques, thereby contributing to the development of atherosclerosis.

“The fact that we have seen that immune cells are capable of migrating from the gut to the periphery and thereby generate systemic inflammation that worsens the atheromatous plaques adds a new dimension to our understanding of the link between diet, gut, microbiota and atherosclerosis,” explains Taleb. Additional work is needed in order to identify which of the bacteria in the microbiota are involved in this mechanism, in order to envisage targeted therapeutic approaches and study these mechanisms in humans”, concludes the researcher.

 

[1] The mesenteric lymph nodes are located in the mesentery, a fold of the peritoneum (the membrane lining the abdominal cavity and covering the abdominal organs) that suspends the small intestine from the posterior abdominal wall.

The gelada (Theropithecus gelada) is one of the primate species without an appendix referenced in this research. ©Vallée des singes

Although the cecal appendix is no longer considered a vestige of evolution with no particular role, its exact function remains to be discovered and several hypotheses are currently being explored. A research team from Inserm, CNRS, the French National Museum of Natural History (MNHN), Université de Rennes, Sorbonne Université and the Eugène Marquis Center looked at how the presence of an appendix affects the onset and severity of infectious diarrhea in primates, an animal order that is particularly affected by these diseases. Its research shows that the primate species with an appendix are less affected by infectious diarrhea and that it is less severe than in those without an appendix. They are also better protected against these infections during the first part of their lives, a period that is more vulnerable to severe diarrhea and crucial for reproduction. These findings, published in Scientific Reports provide new evidence supporting the advantageous role of the appendix in evolution.

The cecal appendix (more commonly referred to as the “appendix”) is a small blind-ended tube located in the lower part of the cecum, the first part of the large intestine. It is found in some mammals and particularly in some primate species, including humans. While it has long been considered an unnecessary vestige of evolution, research over the past decade has challenged this paradigm with scientists now tending to view it as a potential evolutionary advantage, although its function remains poorly understood.

One hypothesis concerning the role of the appendix is based on its composition of microorganisms. Different from that of the rest of the gut microbiota, it could constitute a reservoir of healthy flora safeguarded from the fecal flow, likely to recolonize the gut after a gut infection and enable faster remission. And it just so happens that primates are an animal order particularly affected by infectious diarrhea. In humans, mortality related to these infections was identified in 2015 as being the second leading cause of mortality in children between 1 month and 5 years of age. More specifically, in patients who have had their appendix removed (appendectomy), there has been an increased risk of the occurrence and/or severity of certain forms of infectious diarrhea, although no direct link has been demonstrated at this time.

A research team led by Éric Ogier-Denis, Inserm research director at the Oncogenesis Stress Signaling unit Inserm/Université de Rennes/Eugène Marquis Center), and Michel Laurin, CNRS research director at the Center for Research on Paleontology – Paris (CNRS/MNHN/Sorbonne Université), had shown in previous research that the mammalian species with an appendix had longer longevity than those without one[1]. As a continuation of this research, the team looked at how the presence of a cecal appendix could affect the frequency and severity of diarrhea in primates and thus be a determining factor in the life span of each species.

To do this, the researchers examined the veterinary records of 1 251 primates of 45 different species – 13 with an appendix, 32 without – living in semi-liberty in “La Vallée des Singes” zoological park in Romagne, France. They listed the frequency and severity of the diarrhea episodes that occurred between 1998 and 2018 in these animals.

The gorilla (Gorilla gorilla gorilla) is one of the species of primates with an appendix referenced in this research. ©Vallée des singes

Half of the primates had experienced at least one episode of diarrhea during the 20-year follow-up period, with 13% of the episodes qualifying as “severe”.

In the primates with an appendix, the frequency of diarrhea episodes was very much lower (by around 85%) than in those without one. The cases of severe diarrhea were also much less frequent, particularly during the first quarter of life when the risk is highest (but then gradually decreases throughout life).

In addition, in the species with an appendix, the median age of onset of diarrhea, whether severe or not, was significantly higher.

“These findings support the hypothesis of a protective role of the cecal appendix against infectious diarrhea in primates, comments Jérémie Bardin, co-first author of the study. The observation of a particularly high protective effect in the first part of life, the period most vulnerable to severe diarrhea, but also the most optimal in terms of reproductive capacity, argues in favor of a selective advantage role in evolution”, adds Ogier-Denis.

The research should therefore be continued in order to gain deeper insights into the cecal appendix and a better understanding of the role of its specific flora. One of the next steps could be to compare the composition of the appendix microbiota between primate species in order to highlight possible similarities.

Finally, the last interesting observation in this study was that none of the primates with an appendix had been diagnosed with acute appendicitis over the 20-year period.

“Although this is more common in humans than in other primate species, if the protection associated with the presence of the appendix in humans is of the same level as that observed in primates, it would very much counterbalance the risk related to fatal appendicitis“, concludes Maxime Collard, co-first author of the study.

[1]See our August 3, 2021 press release: https://presse.inserm.fr/en/the-appendix-is-not-an-unnecessary-organ-but-is-in-fact-correlated-with-a-longer-lifespan/60347/