The cardiology service team at the Hôpital Bichat and the Mixed INSERM Unit 698 (AP-HP, Université Paris Diderot), in collaboration with international teams of researchers, studied a cohort of patients suffering from coronary disease. The study showed that those patients with a history of stroke or transient ischæmic attack (TIA) are not only at higher risk of cardio-vascular episodes but also of haemorrhagic events, stressing the therapeutic challenge involved in treating such patients. The research is published online in Circulation*.

© Serimedis/Inserm

Heart and cerebro-vascular disorders represent the two leading causes of death throughout the world. They are sometimes combined in a single patient and their combination represents both a considerable risk to the patient and a therapeutic challenge

Today’s anti-thromobotic, blood-thinning medication provides effective treatment for coronary heart disease. Several randomised tests to assess new anti-thrombotic treatments in coronary patients have identified the fact that a history of stroke or TIA constitutes a marker for increased risk of intracranial bleeding that could prove fatal for the patient. The study was conducted by the Cardiology Service Team of the Bichat Hospital and INSERM Unit 698, working with several international teams, and consisted in monitoring and analysing 26,389 coronary patients from REACH, the international register of athero-thrombic patients, over a four-year period, in order to very accurately assess the ischaemic and haemorrhagic risk associated with a history of stroke or TIA in coronary patients.

The results of this study highlight the frequency of the phenomenon. It showed that 4,460 patients, 17% of the cohort of coronary patients, had a history of stroke or TIA. This stroke or TIA antecedent was associated, moreover, with an approximate 50% increase (in relation to coronary patients without a history of stroke) of dying from a heart attack or stroke, with increased risk of ischæmic and hæmorrhagic stroke.

This study also aims at investigating the therapeutic challenge of treating such patients. In fact, higher doses of anti-platelet or anti-coagulant are associated with a particularly high increased risk of hæmorrhage.

“The conclusions of the study are important since they emphasise the difficulty in treating this type of patient, a type that is frequent but whose prognosis is particularly serious. It also shows how important it is to provide the right anti-thrombotic treatment. Additional clinical trials are currently being conducted to test new treatment strategies for these patients”, explained Professor Steg of the Cardiology Department at the Hôpital Bichat.

Researchers from INRA and Inserm have discovered that intestinal bacteria (“microbiota”) cause metabolic complications in the liver related to obesity. This is the first time such a link has been established using intestinal bacteria transplanted in mice. The results, published online in the journal Gut on 29 November 2012, pave the way towards preventive and therapeutic treatments based on controlling intestinal microbiota to cure type-2 diabetes and obesity-related liver conditions.

© Fotolia

Certain types of liver disease are linked to a condition called metabolic syndrome and develop in obese individuals in particular. The severity of these illnesses varies, from steatosis, in which lipids accumulate abnormally in the liver (a condition present in 80% of obese patients), to cirrhosis (present in 20 to 30% of all cases).

No two metabolisms react in exactly the same way to the same high-fat diet.  Based on that premise, the INRA team, working with a team from Inserm, decided to study the role played by the billions of bacteria present in the digestive tract – known as intestinal microbiota – in the appearance or worsening of obesity-related liver diseases. To establish the precise effects of the bacteria, researchers transplanted microbiota into mice initially devoid of them. One group received intestinal microbiota from a mouse suffering from insulin resistance and steatosis, while another group received bacteria from a healthy mouse. Fed an excessively fat-rich diet for 16 weeks, all the mice became obese. Those which had been transplanted with microbiota from the insulin resistant and steatosis-afflicted mice, however, developed hyperglycaemia and hyperinsulinaemia, while the second group did not. Analysis of the liver tissue also revealed a more severe degree of steatosis in the first group, as confirmed by a higher concentration of lipids in the livers of these mice (see photos, below). Sequencing of the composition of the microbiota revealed the presence of different bacteria species in the two groups.

These results show that the composition of intestinal microbiota (determined by a wide variety of factors, including diet, genetic predisposition, and environment) plays a role in the development of metabolic syndrome-related illnesses. While the exact mechanisms of these bacteria remain unknown, the study suggests that controlling or transplanting intestinal microbiota could be a new way to prevent and/or treat type-2 diabetes and obesity-related liver disease.

Sections of liver in mice transplanted with microbiota from other mice presenting metabolic disorders (left) and with microbiota from healthy mice (right).

Only the mice transplanted with “bad” microbiota (left) developed severe steatosis when exposed to an excessively fat-rich diet (as evidenced by the clearly visible white fat droplets).

© Stephan Bouet, Histiology Workshop, GABI, INRA

(1) Metabolic syndrome is a medical condition known to precede the development of several serious illnesses, including type-2 diabetes, heart disease and stroke.

(2) Insulin resistance is typically present in cases of obesity. During periods of insulin resistance, the pancreas of an obese person secretes insulin which no longer has an effect on its receptors, a phenomenon known as desensitisation. Despite the presence of insulin, glucose enters cells less effectively and accumulates in the bloodstream, increasing blood sugar levels (hyperglycaemia). This in turn provokes a hypersecretion of insulin (hyperinsulinaemia).

Nathalie Vergnolle, director of research at Inserm, and her team at the Centre for Physiopathology at Toulouse Purpan (CPTP Inserm / Université Toulouse III – Paul Sabatier /CNRS), with Philippe Langella director of research at INRA and his team at the Institut Micalis[1], in collaboration with the Institut Pasteur, have recently succeeded in producing “beneficial bacteria” capable of protecting the body against intestinal inflammation. This protection is provided by a human protein, Elafin, which is artificially introduced into dairy produce bacteria (Lactococcus lactis and Lactobacillus casei). In time, this discovery could be useful for individuals suffering from chronic inflammatory diseases such as Crohn’s disease or ulcerative colitis.

The results of this research were published in the Science Translational Medicine review on 31 October 2012.

It is well known that breast feeding increases the secretion of the prolactin hormone and inhibits ovulation in women. This prevents the onset of a new pregnancy too soon, and so breast feeding was used in the past as a method of contraception. In addition to this physiological condition, there are many other pathological conditions in which the production of prolactin is increased. One of the most frequent is the existence of tumours that induce an over-secretion of this hormone. These women present with chronic infertility due to anovulation. Thanks to the work of the Inserm researchers from unit 693 “Steroid receptors: endocrinian and metabolic physiopathology”, the intimate mechanism of the hyperprolactinaemia alterations affecting reproduction in mice has been discovered.

This work has been published in the journal JCI.

Hyperprolactinaemia is a major cause of anovulation and is responsible for menstruation disorders and infertility.  However, not much was know in detail of the mechanisms that cause this pathology.

All that was known was that an increase in prolactin in women disturbed one of the most important hormones affecting reproduction and fertility: GnRH[1].

Up until now, we had been unable to understand this inhibition of prolactin in the GnRH neurons, because most of these neurons did not express the prolactin receptor.

So the researchers put forward another hypothesis: what if it was due to the indirect action of other molecules?

The team led by Jacques Young and Nadine Binart from Inserm unit 693 “Steroid receptors: endocrinian and metabolic physiopathology” at the Bicêtre hospital, discovered that prolactin had an indirect effect on GnRH. Using mice as models, they demonstrated that prolactin effectively inhibits the secretion of neurons situated upstream the GnRH neurons and that are essential to their functioning. They secrete a neurohormone known as kisspeptin.

Kisspeptin: the key to infertility?

In mice, hyperprolactinaemia directly inhibits the secretion of kisspeptin and by preventing the secretion of GnRH, effectively blocks ovarian cyclicity. By administering kisspeptin, we can restore the release of GnRH and restart ovarian cyclic functioning and ovulation despite hyperprolactinaemia.

Sorry, this press release is only available in French.

Frequently recommended in weight-loss diets, dietary proteins have proven effectiveness thanks to their appetite-suppressing effects. A team led by Gilles Mithieux, Director of Inserm’s Unit 855 “Nutrition and the Brain” in Lyon, has managed to explain the biological mechanisms behind these properties. The researchers describe in detail the chain reactions triggered by digesting proteins, sending a ‘satiety’ message to the brain long after a meal. Their results, published on 5 July in the Cell review, will make it possible envisage improved care for obese or overweight patients.

The team of researchers from Inserm, CNRS⁽²⁾ and the Université Clause Bernard Lyon 1 has managed to shed light on the sensation of fullness experienced several hours after a protein-rich meal. This sensation is explained by messages exchanged between the digestive system and the brain, initiated by the dietary proteins that are mainly found in meat, fish, eggs or even some cereal-based products.

In previous studies, researchers proved that consuming dietary proteins triggers glucose synthesis in the intestine, after periods of food assimilation (a function known as gluconeogenesis). The glucose that is released in the blood circulation (portal vein) is detected by the nervous system, which sends an “appetite-suppressing” signal to the brain. Best-known in the liver and kidneys from which it supplies other organs with sugar, gluconeogenesis in the intestine sends an “appetite-suppressing” message after meals, characteristic of the sensation of “fullness”.

In this new study, the researchers managed to accurately describe how digesting proteins triggers a double-loop of chain reactions involving the ventral (via the vagus nerve) and dorsal (via the spinal cord) peripheral nervous systems.

The in-depth study of biological mechanisms identified the specific receptors (μ-opioid receptors [1]) found in the portal vein nervous system, at the outlet of the intestine. These receptors are inhibited by oligo-peptides, produced during protein digestion.

In an initial phase, the oglio-peptides act upon the μ-opioid receptors, which send a message through the vagus nerve and the spinal chord to areas of the brain specially-designed to receive these messages.

During a second phase, the brain sends a return-message that triggers gluconeogenesis via the intestine. The intestine then sends the “appetite-suppressing” message to areas of the brain that control food intake, such as the hypothalamus

1 Consumption of dietary proteins

2 Protein residues (oligo-peptides) travel to the intestine in the portal vein

3 Recognition of oligo-peptides by μ-opioid receptors

4 Receipt of peripheral signals

5 Gluconeogenesis induction

6 “Appetite-suppressing” message sent to brain

Identifying these receptors and their role in intestinal gluconeogenesis paves the way to explore new avenues for the treatment of obesity. The challenge is now to determine how to act on the μ-opioid receptors to control the fullness sensation over long periods. According to Gilles Mithieux, the leading author in the study: “If used too intensely, these receptors may become insensitive. A means of inhibiting them ‘moderately’ must be found, thus retaining their long-term beneficial effects on controlling food intake”.