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


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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Regional organization in Ile-de-France and ECMO results in the management of extremely serious respiratory damage caused by Covid-19



The teams of the cardiac and thoracic surgery departments (Prof. Pascal Leprince, Dr Guillaume Lebreton), and intensive medicine-intensive care (Prof. Alain Combes) of the Pitié-Salpêtrière hospital AP-HP, Sorbonne University and the Inserm, reported the results of the ECMO in the care of patients with extremely serious respiratory damage caused by Covid-19, and the regional organization set up by the Ile-de- France to deal with the pandemic. This work is the subject of a publication on April 19, 2021, in the Lancet Respiratory .

In extremely serious respiratory disorders (ARDS) escaping conventional resuscitation techniques, ECMO (extracorporeal membrane oxygenation) can be used to ensure oxygenation of the blood while awaiting healing of the lungs.

At the start of the Covid-19 pandemic, it was not certain that ECMO could be used for the care of patients with extremely serious respiratory damage caused by Covid-19. Very quickly, in Ile-de-France, a group of experts met to reflect on the place that ECMO could have in this indication, but also on the organization to be put in place to be able to cope with this indication. crisis. Regional regulation has been put in place by ARS Ile-de-France, in conjunction with all stakeholders, to centralize indications and pool resources. A regional doctrine has been developed and published in this direction.

In this multicenter cohort study, the authors present an analysis of all adult patients with laboratory-confirmed Covid-19 infection and severe ARDS requiring ECMO, who were admitted to 17 care units intensive in Ile-de-France between March 8 and June 3, 2020.

During the first wave, six ECMO mobile teams were formed and 17 resuscitations with ECMO experience were identified. 302 patients were thus able to be assisted by ECMO throughout the region, whether or not they were taken care of in intensive care units equipped with ECMO thanks to the mobile teams (mobile circulatory assistance units). These UMACs ensured the establishment of the ECMO then the transfer (55% of patients) of the patient to a specialized intensive care unit.

The analysis of the results at 90 days shows a survival of 46% for these most serious patients with a predictable survival without ECMO almost zero. The age of the patients, the duration of mechanical ventilation before ECMO, renal impairment and the volume of ECMO of the centers appeared to be prognostic factors. The results of cannulation of the patient by a mobile team and then transfer to ECMO in a specialized intensive care unit were not significantly different from those of patients cannulated in a center with ECMO, which validates the concept of a mobile unit. circulatory assistance (UMAC).

Regional regulation, pooling of resources and centralization of indications made it possible to effectively cope with the first wave of Covid-19 by assisting patients requiring ECMO in the Ile-de-France region, regardless of their hospital of origin. After this experience, this organizational model was extended for the following waves.

Many scientific studies have shown the health impacts of air pollution.

Pollution atmosphérique en Île-de-France

While PM10 emissions have decreased in Paris in recent years, it still has the highest PM10 levels of any European Union city. © Louis Paulin – Unsplash

Many scientific studies have shown the health impacts of air pollution. In the Île-de-France region, informational and warning air quality alerts (AQA) have been in place since 2007 to improve protection of the population from daily exposure to high levels of air pollutants. Using quasi-experimental statistical methods, researchers from Inserm and Sorbonne Université at the Pierre Louis Institute of Epidemiology and Public Health (IPLESP, Nemesis team) joined forces with the University of California San Diego to evaluate the public health efficacy of these measures taken in the Paris region, namely their preventive effects on mortality in the general population and more specifically in people over 75 years of age. Their findings have been published in Environment International.

Air pollution can have various short and long-term health effects. On the one hand, the continued exposure to pollution over a period of several years increases the risk of chronic diseases (such as lung cancer). On the other, acute exposure to high daily levels of air pollutants can worsen the symptoms of respiratory diseases or trigger a myocardial infarction.

A policy of alerts combined with emergency measures, such as the restriction of car traffic (for example, the reduction of speed limits), has been implemented in Paris and several other major world cities to protect their populations on days when exposure to air pollutants is particularly high. This policy involves identifying episodes or “peaks” of air pollution when the informational and recommendation threshold or the warning threshold defined by national regulations is exceeded or risks being exceeded for the following four pollutants: particulate matter (PM) smaller than 10 micrometers (PM10), ozone (O3), nitrogen dioxide (NO2) and sulfur dioxide (SO2).

For the first time since 2007, the year in which the PM10 pollution peak alert procedures were deployed in the Île-de-France region, a team of researchers from Inserm and Sorbonne Université at the Pierre Louis Institute of Epidemiology and Public Health (IPLESP) has measured their effects on mortality in the general population and more specifically in adults over the age of 75. The researchers were particularly interested in PM10 air pollutants and the impacts on the health of the region’s inhabitants of the emergency measures taken during pollution peaks.

“While PM10 emissions have decreased in the region in recent years, Paris still has the highest levels of any European Union city and 60,000 of its residents are regularly exposed to PM10 levels in excess of EU regulatory thresholds,” emphasizes Anna Alari, Inserm researcher and study author.

A quasi-experimental methodology using data from the 2000-2015 period

The research results are based on the study of data collected between the years 2000 and 2015, supplied by AirParif (the Île-de-France air quality observatory) and the Inserm Epidemiology Center on the Medical Causes of Death (CépiDC). The researchers identified two key dates for this period. The first being 2007, the year the first informational threshold value of pollution peaks involving interventions was implemented, when the presence of PM10 in the air exceeded 80 µg/m3, and the second being 2011, when this threshold was revised downwards to 50 µg/m3.

The analysis thus focused on the comparison of data collected over three distinct phases:

  • the pre-intervention period, when measures to combat pollution peaks had not yet been taken (from January 1, 2000 to December 31, 2007);
  • the first intervention period using the initial threshold values (from January 1, 2008 to November 29, 2011);
  • and the latest intervention period using the revised threshold values (from November 30, 2011 to December 31, 2015).

Effects on cardiovascular mortality

The study results did not show any effect on mortality of the informational and warning procedures as implemented in their first form in 2007 with relatively high informational thresholds. In contrast, the researchers did identify a benefit on cardiovascular mortality following application of the stricter thresholds in late 2011, with a 7% to 25% reduction in daily mortality in the general population (avoiding an estimated 386 deaths thanks to these measures over the 2011 to 2015 period) and a 9% to 28% reduction in daily mortality for older adults (avoiding an estimated 348 deaths). The study did not show any effect on respiratory mortality.

The use of so-called “quasi-experimental” methods made it possible to infer causal relationships (not correlations) between the deployment of the interventions and the observed effects on the population’s health.

All in all, the results suggest that this type of threshold-based policy, which only concerns acute exposure episodes, has no effect on mortality when regulatory thresholds are excessively high, as in 2007. When the thresholds are tightened, as in 2011, protective effects on mortality can be seen.

“The implementation of public policies focused on structural changes (pedestrianization of certain urban areas, strengthening of public transport networks to limit car use) or aiming to reduce emissions from industries are measures that could prove particularly beneficial, with a potentially stronger impact than short-term actions, such as the restriction of car traffic,” concludes Alari.

In France, an interministerial decree defines the informational and warning procedure in the event of a pollution episode and organizes emergency measures aimed at informing the population and reducing and/or limiting the emission of pollutants into the atmosphere in order to limit the impacts on health. A stricter update of this decree was made in April 2016 (updated on August 26, 2016), with tightening of the measures concerning emissions-based traffic restrictions, and in 2019, with the automatic application of those emissions-based traffic restrictions as well as the rollout of free residential parking during pollution episodes[1].

[1] The updated measures taken in the event of pollution peaks in Île-de-France can be found on the city of Paris website (information available only in French)

Arterial hypertension resistant to drug treatments: an international study demonstrates the blood pressure benefit of endovascular renal denervation by focused ultrasound

Hypertension artérielle

In France, arterial hypertension affects around 30% of the population and can lead to serious cardiovascular, cerebrovascular and renal complications, sometimes fatal. © Photo by Mufid Majnun on Unsplash

Teams from the Georges-Pompidou European Hospital AP-HP, the University of Paris, Inserm and the Presbyterian Hospital in New York carried out work coordinated by Prof. Michel Azizi, Head of Department (Center of Excellence in Arterial Hypertension at the Georges-Pompidou European Hospital AP-HP) and coordinator of CIC1418 APHP-Inserm-University of Paris, to demonstrate the blood pressure benefit of endovascular renal denervation by focused ultrasound. 

After the first positive results in mild to moderate hypertension (hypertension) published in The Lancet in 2018, promising new results were obtained in patients with severe hypertension and resistant to drug treatments in the international study RADIANCE TRIO. They were the subject of a new publication, on May 16, 2021, in the journal The Lancet .

In this study designed and conducted by Prof. Michel Azizi in collaboration with an American start-up (ReCor Medical), renal denervation via the endovascular route consisted in interrupting the electrical activity of the nerves of the sympathetic nervous system for renal use by delivering focused ultrasound through a catheter.

For this study, 136 patients, 80% of whom were men with an average age of 52 years, with hypertension resistant to a combination of three antihypertensive drugs administered in a single tablet, were randomly divided into two groups: the one treated by renal denervation by ultrasound and the other by “sham” intervention consisting of diagnostic arteriography. Neither the patients nor the follow-up medical team knew the group to which the patients had been assigned by the draw.

The results showed that renal denervation reduced blood pressure in patients with hypertension resistant to triple antihypertensive therapy conducted according to current recommendations.

Indeed, after two months of follow-up without modification of the antihypertensive treatment except for safety reasons, the results of the study show that:

– daytime ambulatory systolic pressure was reduced by 8 mmHg in the denervation group while it was reduced by only 3 mmHg in the “sham” group, i.e. a clinically relevant difference of 4.5 mmHg in favor of renal denervation.

– 67% of patients treated with renal denervation had a reduction of ≥ 5 mmHg compared to 42% in the “sham” group.

– 38% of patients not controlled by antihypertensive treatment at randomization had their blood pressure normalized two months after renal denervation while maintaining the same drug treatment.

– There was only one reversible complication (pseudoaneurysm) at the puncture on the femoral artery. 

“Patients with resistant hypertension, that is to say who have failed treatment despite taking antihypertensive drugs correctly, are those most at risk of having a complication of hypertension. Long-term maintenance of the reduction in blood pressure after renal denervation procedure would have beneficial consequences in terms of reducing cardiovascular and cerebrovascular events in these patients. The follow-up at 6, 12 and 36 months is in progress and will give indications on the maintenance at a distance of the decrease in blood pressure .These new positive results, along with those obtained in mild to moderate hypertension, demonstrate that renal denervation lowers arterial pressure across the entire hypertension spectrum. However, there is inter-individual variability in the response we are working on, ”explains Prof. Michel Azizi.

The RADIANCE-II research program is currently continuing.

In France, arterial hypertension affects around 30% of the population and can lead to serious cardiovascular, cerebrovascular and renal complications, sometimes fatal. Despite the availability of many different drug classes, hypertension remains poorly controlled in more than 45% of hypertensive patients in France [1] and worldwide.


[1] ESTEBAN epidemiology study conducted by Public Health France

(* mmHg: millimeter of mercury)

Long COVID: 60% of Hospitalized Patients Still Have at Least One Symptom Six Months Later

Coronavirus SARS-CoV-2

SARS-CoV-2 coronavirus attached to human respiratory epithelial cell cilia.  © Manuel Rosa- Calatrava, Inserm; Olivier Terrier, CNRS; Andrés Pizzorno, Signia Therapeutics; Elisabeth Errazuriz-Cerda UCBL1 CIQLE. VirPath (International Research Center for Infectious Diseases U1111 Inserm – JRU 5308 CNRS – ENS Lyon – UCBL1). Colorized by Noa Rosa C.


How long can COVID-19 symptoms persist after hospitalization for SARS-CoV-2 infection? Scientists continue to have many questions about this emerging virus and the long-term impacts of the disease it causes. The teams studying the problem of so-called “long COVID” include the investigators of the French COVID cohort, sponsored by Inserm. In a new study published in the journal CMI, these researchers from Inserm, the Paris hospitals group AP-HP and Université de Paris show that a significant proportion of patients who were hospitalized and followed up as part of French COVID continue to have symptoms three and six months after infection.

Is it possible to have COVID-19 symptoms several months after being infected with SARS-CoV-2? The question of “long COVID” continues to interest the scientific and medical community and is at the center of a number of research projects, notably those conducted by the French COVID investigators.

Launched at the end of January 2020, French COVID is a French cohort study sponsored by Inserm. It is based on the follow-up of a large group of patients having developed a clinical form of the disease that required hospitalization, either in a medical department or in intensive care. As at March 17, 2021, a total of 4,310 patients had been enrolled in this cohort, the largest French cohort to date of patients hospitalized with SARS-CoV-2 infection.

For each participant, clinical, virological, immunological, genetic, serological and transcriptomic data are collected in order to better characterize the disease. The objective is to build up knowledge on COVID-19, especially its most severe forms, in order to improve management in cases where hospitalization is required. The aim is also to better understand the short and long-term outcomes of patients by looking at the potential persistence of symptoms in the months following diagnosis.

Impact of long COVID

In their new study, the team describes the frequency and nature of symptoms persisting in 1,137 patients from the French COVID cohort, assessed at follow-up visits three and six months after they were hospitalized for COVID-19.

This research suggests that 60% of patients are still affected by at least one symptom six months after infection and one quarter by three or more symptoms.

What is more, 2% of the patients had to be re-hospitalized. Major fatigue, respiratory discomfort, and muscle and joint pain were among the most frequently reported persistent clinical manifestations during these follow-up visits.

A correlation between the initial severity of the disease and the persistence of symptoms over the long term also appears to be emerging. Indeed, the persistence of three or more symptoms six months after infection is more common in those whose COVID-19 disease required a stay in ICU compared with those hospitalized in a medical department, and in the most symptomatic patients on the day of hospital admission. The researchers also observe differences according to sex: while men are at greater risk of severe forms, women appear to be at greater risk of persistent symptoms over time.

Finally, the study underlines that these forms of “long COVID” sometimes also have wider economic and social consequences. For example, among patients reporting symptoms at six months who were working when they became infected, one-third did not return to work.

In order to better understand the consequences of the virus on the body and the long-term impact of the disease, and above all to provide better patient care, continuing this follow-up beyond six months on an even larger population could be of great interest.

“The mechanisms that cause symptoms to persist after the body has rid itself of the virus remain unclear. We will continue to follow up the patients included in French COVID up to 18 months after infection, by also proposing tests to evaluate the neurocognitive functions,” emphasizes the cohort’s coordinator, Jade Ghosn, who is an associate professor-hospital practitioner at Université de Paris and a professor in the Department of Infectious and Tropical Diseases at Bichat Claude-Bernard Hospital AP-HP.

COVID-19: discovery of the mechanisms of short- and long-term anosmia

Epithélium olfactif_SARS-CoV-2

Scanning electron microscopy image showing changes in the olfactory epithelium following SARS-CoV-2 infection. The ciliated cells towards the edges of the photograph are normal. In the center, loss of cilia 2 days post-infection is discernible. Viral particles are budding off the surface of infected cells that have lost their cilia. © Perception and Memory Unit – Institut Pasteur

Loss of smell, or anosmia, is one of the earliest and most commonly reported symptoms of COVID-19. But the mechanisms involved had yet to be clarified. Scientists from the Institut Pasteur, the CNRS, Inserm, Université de Paris and the Paris Public Hospital Network (AP-HP) determined the mechanisms involved in the loss of smell in patients infected with SARS-CoV-2 at different stages of the disease. They discovered that SARS-CoV-2 infects sensory neurons and causes persistent epithelial and olfactory nervous system inflammation. Furthermore, in some patients with persistent clinical signs, anosmia is associated with prolonged epithelial and olfactory nervous system inflammation and lasting presence of the virus in the olfactory epithelium. These findings were published in the journal Science Translational Medicine on May 3, 2021.

Although COVID-19 caused by the SARS-CoV-2 virus is principally a respiratory disease, many patients present with non-respiratory symptoms. These include a sudden loss of smell in individuals infected with SARS-CoV-2, which has been reported throughout the world since the beginning of the pandemic. Until recently, there has been uncertainty as to whether the virus plays a direct role in anosmia. According to one hypothesis generally accepted until now, it was assumed that a transient edema of the olfactory clefts inhibited airflow transporting odor molecules to the olfactory neurons (the familiar sensation of a blocked nose experienced during a common cold).

In a recent study, scientists from the Institut Pasteur, the CNRS, Inserm, Université de Paris, and the Paris Public Hospital Network (AP-HP) shed light on the mechanisms involved in COVID-19-related anosmia. The study was conducted with COVID-19 patients and supplemented with tests on an animal model. This study unexpectedly demonstrates that nasopharyngeal swabs may test negative by standard RT-qPCR even if the virus is still present at the back of the nasal cavities, in the olfactory epithelium. In light of this discovery, SARS-CoV-2 diagnosis by nasal brushing may be envisaged in addition to nasopharyngeal swabbing for the PCR test in patients experiencing loss of smell.

This work also sheds light on the mechanism of COVID-19-related smell loss by revealing a series of chronological steps:

1) Cilia carried by sensory neurons are lost post-viral infection. These cilia enable the sensory neurons to receive odor molecules;
2) Virus present in sensory neurons;
3) Disruption of the olfactory epithelium (sensory organ) integrity linked to apoptosis (i.e. cell death). The epithelium is organized into regular lamellae, which are destructured by coronavirus infection;
4) Virus dissemination to the olfactory bulb, which is the first cerebral relay station in the olfactory system;
5) Inflammation and viral RNA present in several regions of the brain.

Anosmie Covid anglais

Diagram representing the various steps occurring in the sensory system and contributing to COVID-19-related anosmia.

This study demonstrates that loss of smell is also caused by deterioration of the sensory organ at the back of the nasal cavities. “We observed that SARS-CoV-2 infects not only the sensory neurons, but also the olfactory nerve and the olfactory nerve centers in the brain,” comments Pierre-Marie Lledo, CNRS scientist, head of the Perception and Memory Unit (Institut Pasteur/CNRS), and co-author of the study.

“Another key finding from this study emerged from an observation of animal models, which revealed that once the virus enters the olfactory bulb, it spreads to other nerve structures, where it induces a major inflammatory response,” explains Hervé Bourhy, head of the Lyssavirus Epidemiology and Neuropathology Unit at the Institut Pasteur and co-author of the study. Infection of the olfactory neurons may therefore provide a gateway to the brain and explain why some patients develop various psychological clinical signs (anxiety disorders, depression) or those of a neurological nature (cognitive decline, susceptibility to developing a neurodegenerative disease), for which further studies are necessary.

Marc Lecuit, head of the Biology of Infection Unit (Institut Pasteur, Inserm, Université de Paris, AP-HP) and co-author of the study concludes: “According to our results, loss of smell in COVID-19 may persists for several months in some patients and this persistence of clinical signs may be attributed to the persistence of the virus and inflammation in the olfactory mucosa.” These observations should be used to adapt the diagnosis and management of long-term COVID-19 signs.

In summary, this study has led to the following 4 key findings:

  • The virus can be detected by nasal brushing in instances where it is not detected by swabs;
  • SARS-CoV-2 may persist in the olfactory epithelium for several months;
  • SARS-CoV-2 infects sensory neurons and prompts immune cell recruitment in the sensory organ;
  • SARS-CoV-2 may cause persistent inflammation of the olfactory epithelium and the olfactory nervous system.

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