Agriculture is in the midst of a crisis among farmers. The old model based on chemistry is cracking all over the place. But powerful solutions for renewing our practices - both agricultural and medical, by the way - come from the modulation of organisms by their commensals, microbes. A deluge of publications has been raining down on these "microbiotes" for the past few months. With the prospect of manipulating these microflora of plants, skin, mouth, vagina but especially intestines. Zoom on experiments and markets of the future ...
L’man cannot survive without his germs. With nearly two kilos of bacteria in the belly - that's 100,000 billion microorganisms - everyone can not only assimilate what they eat but also receive signals that modulate the immunity, inflammation and resilience of cells.
A specialist in this intestinal flora or "microbiota", Joël Doré has been working for 30 years at the French National Institute for Agricultural Research (INRA, Jouy-en Josas) and has played a pioneering role in discovering the protective role for our health of the microorganisms we harbour. For him, all our therapeutic strategies are being reoriented because "With the microbiota, we have a formidable prevention tool: a balanced microbiota is the signature of good health: it allows you to resist stress; the loss of its diversity opens the way to disease.
Frequency modulation for effective prevention
The flora plays a determining role in our immunity: 70% of immune cells are located around the intestine. It also conditions the good assimilation of food, participates in the manufacture of vitamins B and K, facilitates the digestion of proteins and milk, and degrades part of the cholesterol. Four families of bacteria are dominant and inescapable and their disappearance seems to sign the installation of diseases.
You lose. Faeccali bacterium and you suffer from inflammatory bowel pain: all people with Crohn's disease have lost this strain capable of providing anti-inflammatory molecules. French teams have just demonstrated the production of analgesic substances by the strain. Faeccali prausnitzii (Scientific Reports, 18 January 2016). A team of researchers led by Harry Sokol of the Department of Gastroenterology and Nutrition at Hôpital Saint-Antoine-APHP used a high-throughput sequencing method to show that the fungal microbiota was unbalanced in patients with chronic inflammatory bowel disease with correlations between disease type and lesion topography. The fungal part (composed of fungi and yeasts) of the microbiota has been little studied at this stage despite the existence of numerous clues implicating it in the occurrence of this type of disease. This work was published online in the journal Gut on February 4, 2016.
The second vital bacterial family is Akkermansia. People who are obese or overweight often miss it. It is a companion that protects against type 2 diabetes. The third is Eubacterium which plays a similar role. Finally, the fourth intestinal inhabitant essential to our good health belongs to the type Blautia. It protects against functional disorders such as flatulence.
Intervening in the intestinal ecosystem to cure even mental... illnesses...
In general, it is observed that people with impoverished flora have a higher risk of developing metabolic diseases (diabetes, cardiovascular diseases, obesity, liver disorders, blood anomalies ...) and gain weight more easily. These risks concern a quarter of the population.
So today we can intervene on diseases by treating the intestinal ecosystem. This is the case in the case of severe diarrhoea at Clostridium difficult, which can be cured by transplanting intestinal contents from siblings, for example. Both the National Agency for the Safety of Medicines and Health Products (NAMHP) and the US Food and Drug Administration (FDA) have observed the very convincing results of the first trials of these therapies as early as 2012 and now regard them as conventional treatments.
Cardiovascular risk could also be avoided by intervening on intestinal hosts, according to work on mice carried out by Stanley Hazen's team based at the Cleveland Clinic in Ohio (published in Cell on 17 December 2015). The American researcher has shown that commensal bacteria intervene to destroy TMAO (trimethylamine oxide) derived from the trimethylamine, gas formed during digestion by bacteria of food choline (from meat and eggs). This absorption reduces atherosclerotic plaque that can clog arteries.
Even more surprisingly, the intestinal microbiota seems to have a moderating effect on the stress response. Experiments carried out in 2004 by Japanese scientist Nobuyuki Sudo, from the University of Kyūshū, with rodents that had been made germ-free (so-called axenic) show that animals become hypersensitive to stress, anxious and depressed. The explanation seems to be related to the blood concentration of corticosterone, a stress-related hormone, which is doubled in animals lacking microbiota. Can a stress relieving effect be obtained by seeding the intestine? Two studies carried out in 2011 and 2012 by Javier Bravo, from the University of Cork, and his colleagues, and by Afifa Ait-Belgnaoui, from INRA, suggest so.
Researchers are exploring the bacterial trail as a trigger for autism in children. This is the case with Prof. Luc Montagnier, Nobel Prize in Medicine in 2008, who uses antibiotics to fight the bacteria and regress the disease. In Geneva, the team of child psychiatrist Stephan Eliez is about to launch a study testing the transplantation of microbiota in about thirty very young autistic children. In France, the Pasteur Institute in Paris is developing the " Microbiote and cerveau " programme, coordinated by Pierre-Marie Lledo, director of the institute's neurosciences department and director of research at the CNRS. " Les neurosciences must become a core network, in connection with immunology, microbiology... The aim is to work like physicists, by seeking to a general law applicable to different disciplines".
The researcher is studying receptors for fragments of intestinal bacteria found in certain regions of mouse brains. " En activating these receptors, we have seen many disorders appear, especially sleep disorders. These rodents were no longer dreaming and had problems with memory and humeur ", says Pierre-Marie Lledo. The track seems all the more exciting as these receivers have their equivalent humain : the NOD2. However, the gene coding for this receptor can be mutated in a chronic inflammatory digestive disease, Crohn's disease, which has recently been associated with bipolar disorders.
This vital partnership is the fruit of an adventure that the great immunology specialist, Patrice Debré, professor at Pierre-et-Marie-Curie-Paris-VI, describes very well in his book "L'homme microbiotique" published at the end of 2015 (Odile Jacob editions). "I wished to give another vision of microbes, of those who, strangers and our own, inhabit us and without whom we could not live. Our future depends on this indispensable partnership". It describes the extraordinary adventure of the immune system, which learns through the microorganisms it tolerates, to resist those that are dangerous to it.
Birth is a key moment: the passage through the vaginal tract plays a major role in seeding the newborn and initiating its digestive capacities. Similarly, breast milk, which contains bacterial debris, informs the baby about tolerable bacteria. It is a learning process of positive cohabitation.
Marie-Gloria Dominguez-Bello, a microbiome specialist at New York University has revealed the immune consequences of caesarean sections (1/2 of births in China and Brazil, 30% in the United States) which prevent the baby from being inoculated. Studies indicate that children born by caesarean section are more vulnerable to allergies and infections than children born by the vaginal route. These findings lead to the researcher to be concerned about the generalization of Western practices in terms of birth or feeding. "We don't have much time to conserve and restore the diversity of the ancestral microbes that protect us, especially since the massive use of antibiotics is disastrous". she confides. She has published convincing results showing that you can enrich the intestinal flora of a newborn baby by having him/her suck on a gauze soaked in the mother's vaginal mucus. These leads will be undertaken in France by Prof. Jacky Nisard at the Pitié Salpétrière in cooperation with Joël Doré.
It is easy to imagine that the intestinal microbiota is necessary for post-natal growth and will play on the size of adult individuals, particularly in the case of undernourishment. The key element in this relationship is the growth factor Insulin-like Growth Factor-1 (IGF-1) whose production and activity is partly controlled by the microbiota. This result was obtained by researchers from Lyon (CNRS/ENS Lyon/Université Claude Bernard - Inserm/Inra//Insa Lyon) and published on 19 February 2016 in Science, in collaboration with researchers from the Academy of Sciences of the Czech Republic. As a result, certain strains of intestinal bacteria, belonging to the species Lactobacillus plantarumThe development of a national strategy to combat the harmful effects of chronic child undernutrition could be a useful avenue to combat the harmful effects of chronic child undernutrition.
Innovation strategies and bioethics
We are therefore moving towards preventive medicine based on the evaluation of the quality of microbiomes and their handling. The means are being put in place: in the United States the NIH has launched the Human Microbiome, while in Europe the MetaHIT programme, coordinated by Stanislav Dusko Ehrlich (INRA Jouy-en-Josas) has created a working platform bringing together clinicians, genomists, microbiologists, computer scientists and bio-analysts. The results: the deciphering of the intestinal metagenome (our "second genome"), the discovery of enterotypes (a classification of microbial types) and the discovery of the increased risk for a large part of the population to develop chronic diseases.
A major investment has also been made in the MetaGenoPolis project, led by Joël Doré in collaboration with the University Hospital Institute of Cardiometabolism and Nutrition (ICAN). Financed to the tune of 19 million euros, it will make available a national biobank of more than one million human intestinal samples, metagenomics platforms to characterize the molecules and mechanisms of dialogue between intestinal bacteria and human cells and to define the "normal" intestinal microbiota and to propose a follow-up over time of the effect of interventions (drugs or food). An ethical and societal component (notably related to diagnosis and prognosis) is provided by the Catholic University of Lyon. "Because the microbiota has become predictive of cancer severity, underlines Joël Doré. As the disease worsens, it appears that negative feedback loops develop that drastically reduce the diversity of the microbiota.
Show me your microbiota and I'll tell you how you're doing.
On the business side, a dozen companies have been set up in the microbiota niche over the last three years. In the United States, OpenBIOME buys intestinal contents from voluntary donors, carries out safety checks and stores them to supply them to hospitals. In France, MaatPharma is involved in autologous transplantation (the donor is the patient himself) during chemotherapy. But the added value of such cheap products can only be achieved after the creation of targeted therapeutic cocktails made of bacterial mixtures or molecules produced by the precious microbes .
The analytical side will be essential in order to provide tools (DNA chips...) capable of characterizing the strains present in the faeces. The company Enterome, created in 2012 by Stanislav Dusko Ehrlich and Pierre Bélichar, has raised 19 million euros to progress in this market. Its ambition is to establish a qualitative and quantitative genetic fingerprint of an individual's microbiota, starting from 1g of faeces, by sequencing the genes of intestinal bacteria at very high throughput.
Of course, many companies have been involved in this sector for a long time to provide probiotics (bacteria, viruses or yeasts...) that can "feed" the intestinal flora and help it to function properly. In animal husbandry, these probiotics are used on a massive scale with major effects on animal health and growth.
Initiatives are being taken to keep these living assets in the public domain. In San Francisco, for example, Alexandra Carmichael, Director of Products, Community and Growth at U-Biome which aims to give everyone the means to maintain and check their microbiota. It has raised 360,000 euros through crowd-sourcing to support its citizen and participatory science project. A kind of FabLab so that the data remains the property of all.
There's still one angry question. What measures are in sight that will prevent the damage caused by medicines, particularly antibiotics? According to Joël Doré, the pharmaceutical industry has no obligation to inform prescribers and consumers about the effects of active molecules on the microbiota. However, we understand that the public health stakes are colossal. Protecting populations from "therapeutic clubs" that would definitively weaken them, as the American specialist Marie-Gloria Dominguez-Bello repeats over and over again. This challenge can be seen as a fight for the conservation of the ancestral microbiotic biodiversity... In the end, it would seem useful to demand that any future medicine should preserve these "health guardians" that are our microbial acolytes.
"Microbiota: the bacteria that govern us", a film by Mario Fossati and Ventura Samarra: