Archives des Biologie cellulaire, développement et évolution

A small group of neural stem cells isolated from mice and cultured in vitro observed under a confocal microscope. (LaminB1 in green, Sox2 in red) © Perception and Memory Unit – Institut Pasteur

The process of aging is often related to the onset of cognitive decline, depression and memory loss. Scientists from the Institut Pasteur, CNRS and Inserm have discovered that administration of the GDF11 protein, which is known to regenerate murine neural stem cells, improves cognitive abilities and reduces the depressive state in aged mice. They also demonstrated the mechanism of action of this protein in different mouse models. The scientists then investigated these results further in relation to depression, and showed that in humans, the levels of GDF11 are inversely related to depressive episodes. The results of this study were published in the journal Nature Aging on February 2, 2023.

The process of aging is often related to the onset of neurological symptoms such as cognitive decline, memory loss or mood disorders such as depression. Previous studies have shown that the growth factor GDF11, a protein found in blood, has a beneficial effect on olfactory perception and on the generation of new cells in the brains of aged mice. The mechanism of action of GDF11 in the brain remained unknown.

Researchers from the Institut Pasteur, CNRS and Inserm have discovered that long-term administration of the GDF11 protein to aged mice improves their memory and significantly reduces behavioral disturbances related to depression, allowing them to return to a behavior similar to that seen in younger mice.

The scientists conducted further studies in different aged mouse models or mouse models with depression-like behavioral disorders and in vitro neuronal cultures, which enabled them to identify the molecular mechanism of action of GDF11. They discovered that administration of GDF11 activates the natural process of intracellular cleaning, called “autophagy”, in the brain and the elimination of senescent cells. The GDF11 protein thus indirectly increases cell turnover in the hippocampus and restores neuronal activity.

To better understand the link between depressive disorders and the GDF11 protein in humans, scientists from the Institut Pasteur, CNRS and Inserm, in collaboration with scientists from McMaster University, quantified the protein in the blood serum of an international cohort of young patients with major depressive disorder. They observed that GDF11 levels are significantly lower in these patients. Moreover, by measuring the levels of this protein at different stages, the scientists observed a fluctuation in the level depending on the depressive state.

“This work provides clinical evidence linking low blood levels of GDF11 to mood disorders in patients with depression,” said Lida Katsimpardi, a researcher in the Institut Pasteur’s Perception and Memory Unit, affiliated with Inserm at the Institut Necker-Enfants Malades, and co-last author of the study. “In the future, this molecule could be used as a biomarker to diagnose depressive episodes. It could also serve as a therapeutic molecule for the treatment of cognitive and affective disorders,” she concludes.

Section showing the interaction of the microbiota and the intestinal epithelium in the colon. In blue, the mucus secreted by the intestinal epithelium in protection against the microbiota. In pink, the epithelial cell nuclei. © Noëmie Daniel/Inserm

Emulsifiers are food additives that are used to improve texture and extend shelf life. They are found in many processed products (ice cream, packaged cakes, sauces, etc.) despite having demonstrated harmful effects on intestinal balance. In a new study, scientists from Inserm, CNRS and Université Paris Cité at Institut Cochin in Paris sought to counteract these effects by using Akkermansia muciniphila, a bacterium naturally present in the intestine, to repopulate and thus strengthen the intestinal epithelium. The addition of this bacterium to the gut microbiota is thought to prevent the damage caused by the consumption of emulsifiers. These data, published in Gut, confirm the growing potential of Akkermansia muciniphila as a probiotic.

Emulsifiers are consumed by millions of people every day and are among the most widely used additives in the food industry. Something that is not surprising given that they improve the texture of foods and extend their shelf life. For example, emulsifiers such as lecithin and polysorbates ensure the smooth texture of mass-produced ice cream and prevent it from melting too quickly once served.

Previous studies by the team of Benoît Chassaing, Inserm researcher at Institut Cochin (Inserm/CNRS/Université Paris Cité), have shown the consumption of certain emulsifiers to lead to alterations of the gut microbiota [1] and how it interacts with the digestive system. Such alterations lead to chronic gut inflammation and metabolic dysregulation. More specifically, this research has shown the consumption of food emulsifiers to induce the ability of certain elements of the microbiota to come into close contact with the epithelium, which is the first line of defense of the digestive tract and usually sterile.

In this new study, the researchers wanted to counteract the harmful effects caused by the consumption of emulsifiers by reinforcing the intestinal epithelium. To do this, they focused more specifically on the bacterium Akkermansia muciniphila, which, being naturally present in the intestine has already been shown to have an impact on the interactions of the microbiota with the rest of the body.

It is also known that the quantity of this bacterium is reduced when emulsifiers are consumed.

In the study, groups of mice were fed emulsifying agents as part of their diet, which for some of them was supplemented with a daily dose of Akkermansia muciniphila. The scientists saw that while the consumption of food emulsifiers was sufficient to induce the chronic inflammation associated with metabolic alterations and high blood glucose, the mice receiving Akkermansia muciniphila were totally protected against such effects. The administration of Akkermansia muciniphila was also sufficient in preventing all molecular alterations normally induced by the consumption of emulsifying agents, including the encroachment of bacteria into the wall of the epithelium.

“This research supports the notion that using Akkermansia muciniphila as a probiotic could be an approach to maintaining metabolic and intestinal health in the face of modern stressors such as emulsifiers that promote chronic gut inflammation, and the resulting harmful consequences. Furthermore, this suggests that colonization of the intestine with Akkermansia muciniphila could be predictive of individual propensity to develop intestinal and metabolic disorders following the consumption of emulsifiers: the greater the presence of the bacterium, the more likely the individual is protected from the harmful effects of food additives on the microbiota,” explains Chassaing, the last author of the study.

[1] All of the microorganisms – non-pathogenic (commensal) bacteria, viruses, parasites, and fungi – that live in the intestine.

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Category: Biologie cellulaire, développement et évolution

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