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.

Image showing the endothelial healing process in mice 3 days following carotid artery injury. © Coralie Fontaine.

A commonly used treatment in some forms of breast cancer, tamoxifen acts on the cancer cells by blocking the estrogen receptor (ER)a and thereby inhibiting their proliferation. However, the action of this drug appears to be more complex than that, with the addition of protective effects on the arteries that could reduce the risk of developing cardiovascular disease. Researchers from Inserm and Université Toulouse III – Paul Sabatier at the Institute of Cardiovascular and Metabolic Diseases have studied the effects of tamoxifen on the arteries in animal models in order to better understand its mechanism of action and refine its clinical use. Their findings have been published in the journal Circulation Research.

Following breast cancer, women are at increased risk of developing cardiovascular disease. Several studies have confirmed this association, highlighting risk factors common to both disease types as well as the toxicity of certain cancer treatments, such as chemotherapies, to the cardiovascular system. However, experimental and clinical data suggest that tamoxifen – a hormone therapy that reduces the risk of recurrence of certain forms of breast cancer[1] – also has protective effects against cardiovascular disease.

In the cancer cells, tamoxifen acts as an anti-estrogen: without eradicating the production of this hormone, it takes its place in its receptors (the ERa receptors), thereby blocking the proliferation of these cells.

Different mechanisms of action

In their study, the researchers have shown that tamoxifen accelerates arterial healing by promoting the renewal of the endothelial cell layer that protects the arteries, thereby revealing a novel beneficial effect of this drug in terms of cardiovascular risk.

In order to explain this novel beneficial action of tamoxifen, the team shows that contrary to its inhibiting effect on the cancer cells, the drug mimics the action of the estrogens in the arteries, bringing about their healing.

Whereas estradiol (the main estrogen) induces this effect by directly activating the estrogen receptors in the arterial endothelial cells, the researchers show that tamoxifen produces this same effect on the arteries by also activating the estrogen receptors, but in another cell type (the underlying smooth muscle cells).

This research therefore shines a new light on the action of tamoxifen, showing that this molecule can mimic the action of estrogens by targeting the different functions of their receptors in different cell types.

These findings could have various clinical implications, particularly because they enable a deeper understanding of the spectrum of action of this drug that is prescribed to thousands of patients in oncology.

“The vision we have of tamoxifen at present is that of a hormone therapy that blocks the receptors present on the cancer cells, but this only partially explains its action. Our study emphasizes that this drug mimics estrogens by targeting pathways that are not always the ones we expect. We have revealed a protective effect on the arteries through an indirect action on the endothelial cells, but this action could also affect the immune system cells, which play a key role in the immune surveillance of tumors”, emphasize Jean-François Arnal, professor at Université Toulouse III – Paul Sabatier, and Coralie Fontaine, Inserm researcher, who have coordinated this research.

[1]So-called “hormone-dependent” cancers, for which the cancer cells express the estrogen receptor

Diet plays a major role in the composition of our gut microbiota. From what we consume, the gut bacteria produce organic compounds known as metabolites, which can affect our health. © Adobe Stock

An imbalanced diet has been linked to a disruption of the gut microbiota, which promotes metabolic diseases such as diabetes. Researchers from Inserm, Sorbonne Université, Paris hospitals group AP-HP and the French National Research Institute for Agriculture, Food and Environment (INRAE) in collaboration with a Swedish team have shown, in a large European cohort, that changes in the composition of the gut microbiota lead to increased blood levels of the molecule imidazole propionate. A molecule known to render the body’s cells resistant to insulin, thereby increasing the risk of developing type 2 diabetes. Their findings have been published in Nature Communications.

Diet plays a major role in the composition of our gut microbiota. From what we consume, the gut bacteria produce organic compounds known as metabolites, which can affect our health if they are present in too large or too small a quantity in our body.

Previous studies have shown that changes in the makeup of the gut microbiota and the production of certain metabolites can directly influence the development of type 2 diabetes.

Other recent research suggests that an alteration of the gut microbiota disrupts the metabolism of histidine, an amino acid found in many foods, leading to increased levels of the metabolite imidazole propionate. This molecule blocks the action of insulin, preventing it from lowering blood glucose levels.

The present study published in Nature Communications confirms these initial findings in a large European cohort of 1990 participants from France, Germany and Denmark, called METACARDIS. Coordinated by Inserm, the objective of this cohort is to study the impact of changes in the gut microbiota on the onset and progression of cardiometabolic diseases and associated pathologies. “METACARDIS is a unique and valuable database in that it allows us to access very detailed characteristics of each person enrolled in the cohort with large amounts of phenotypic, metabolic, and bacterial genetic data,” emphasizes the project’s coordinator, physician Karine Clément, teacher-researcher in nutrition at Sorbonne Université.

She and her colleagues show that in the cohort, subjects with prediabetes[1] or type 2 diabetes do indeed have higher levels of imidazole propionate in their blood. The gut microbiota of these subjects is also characterized by a significant depletion of bacteria.

The researchers suggest that these alterations in the bacterial composition of the microbiota are linked to an imbalanced diet. They cause a disruption in the metabolism of histidine, which in turn leads to an increase in imidazole propionate and problems regulating blood glucose. The risk of developing type 2 diabetes then becomes higher.

“Our study suggests that people with poor diets have increased levels of imidazole propionate and that there is a clear link between the depleted composition of the microbiota, diet and type 2 diabetes. Its aim is to convey a message of prevention, emphasizing that a more varied diet can enrich the microbiota. This study also has therapeutic implications since we could envisage the future development of drugs to modify the synthesis of certain metabolites such as imidazole propionate,” explains Clément.

A number of questions continue to be raised and are expected to be elucidated in future research based on METACARDIS. In particular, the researchers want to understand how the elevation of one or more metabolites can predict, in people with diabetes, the risk of developing other complications, such as those affecting the cardiovascular system. They also want to study how increased imidazole propionate levels in people with prediabetes could increase their risk of developing type 2 diabetes earlier on in their clinical course.

This large-scale research project, based on close collaboration between several European scientific teams, has received support from the European Community (7th Framework Programme FP7-Metacardis), as well as from the Leducq Foundation.

[1] Prediabetes is a blood glucose disorder at a less advanced stage than diabetes itself. It is characterized by fasting blood glucose levels of between 1.10 g/L and 1.25 g/L (normal fasting blood glucose is below 1.10 g/L). The risk of going on to develop type 2 diabetes is increased.

Animal and vegetable sources of omega-3 such as salmon, avocado, flax seeds, eggs, butter, nuts, almonds, pumpkin seeds, parsley leaves and colzal oil. © Fotolia

Omega-3 fatty acids* are essential, necessarily supplied by the diet and indispensable to brain development. Scientists from INRAE and University of Bordeaux, working in collaboration with INSERM, Laval and Toronto Universities in Canada and other partners (Harvard, Fondation Basque, etc.) have focused in particular on the impact of the maternal diet during gestation and lactation on the brain development of their offspring. They have thus shown for the first time in mice how an insufficient intake of omega-3 in the mother can alter the development of neuronal networks in the offspring, causing memory deficits. They have also deciphered the molecular mechanisms underpinning these effects. This unprecedented work, which is the result of several years of research, is published on 30 November 2020 in Nature Communications.

Essential fatty acids (omega 3 and 6) are massively incorporated in the brain of offspring via the maternal diet during gestation and lactation. Patchy scientific findings indicated that an insufficient consumption of these fatty acids by the mother during the perinatal period constitutes a risk factor for cognitive deficits in children (language, memory, learning, etc.). But what is the causal mechanism?

INRAE scientists from the Nouvelle-Aquitaine Research Centre and University of Bordeaux, and their colleagues, focused on a particular cell type in the brain: the microglial cells (or microglia) that participate in the shaping of the neuronal networks sustaining memory abilities. These brain macrophages lie at the interface between the environment and neurons.

During brain development, the microglia “sculpt” neuronal networks by “engulfing” useless synapses – the connectors between neurons – and only retaining those that are essential for satisfactory brain functioning.

The scientists focused their studies on a mouse model to determine whether maternal omega 3 status – and hence that of offspring – could exert an effect on microglia activity.

Omega 3 deficiency impacts the activity of a particular cell type in the mouse brain

The results showed for the first time that an insufficient intake of omega 3 via the maternal diet affects the activity of microglia in the developing brain; these cells adopt abnormal functioning and become hyperphagic; i.e. they lose the ability to recognise the synapses that needed to be deleted, hence “engulfing” too many of them. The neuronal network is thus poorly formed, causing deficits in the offspring memory capacities. The scientists were also able to decipher the molecular mechanisms responsible for this abnormal microglial activity.

To study this link between omega 3 intake and brain development, the scientists also developed several innovative technologies to evaluate the modification of microglial behaviour towards synapses, to analyse their lipid content, and to test different molecules in order to identify those responsible for this dysfunction and determine how it could be restored.

This work offers new perspectives for research, and studies will continue in humans in order to better understand the links between omega 3 and brain development.

* _{Omega 3 fatty acids are a family of essential fatty acids. This contains the fatty acids that are essential to developing satisfactory functioning of the body, but they can only be supplied by diet. They are found in numerous vegetable oils (walnut, rapeseed, linseed, etc.) and in the flesh of fatty fish.}