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Microbiota, the intestinal revolution. © INRA

Microbiota, the intestinal revolution

How does the microbiota evolve over the course of a lifetime?

At birth, the human digestive tract is sterile. But in a matter of a few hours, it is colonised by billions of bacteria. What factors come into play in this colonisation? How does our microbiota then evolve, in terms of diversity, composition, and growth, over the course of a lifetime? Birth, breastfeeding, antibiotic treatments, growing old… INRA researchers are leaving no stone unturned to better understand the evolution of the human microbiota and ultimately, improve health.

Updated on 04/28/2017
Published on 02/16/2017

First colonies of bacteria: essential for newborns

. © Fotolia
© Fotolia

At birth, a baby makes the formidable journey from a protected environment to one swarming with bacteria. The first contact between epithelial cells that line the digestive tract and the massive onslaught of bacteria is decisive. In a matter of just a few days, billions of bacteria colonise a newborn’s digestive tract. But if this “explosion” of bacterial populations is to be beneficial, the first colonies must make things nice and cosy for the ones to follow. INRA researchers have shown that rats devoid of a microbiota react to an injection of a strain of Escherichia coli (bacteria naturally present in human and animal intestines) by reorganising their intestinal epithelium*. Epithelial cells then multiply rapidly, thickening the walls of the digestive tract. But that’s not all. This multiplication of cells also stimulates the production of mucus by intestinal cells, which nourishes bacteria and fosters their development. In short, the pioneering strain of E. coli develops an environment that allows it to settle in comfortably. Although it got a bad rap among the general public for contaminating food, E. coli actually plays a key role in newborns, establishing a non-pathogenic, privileged relationship with its host. Scientist go so far as to say that this sort of bacteria may “hijack” intestinal functions temporarily to promote the bacterial colonisation that is indispensable to newborns. Is it only a matter of time before E. coliis used to remedy the damaged digestive tract of adults?

 

Adult size: the microbiota controls, in part, growth

The intestinal microbiota plays a role in determining people’s ultimate size. That is what teams of INRA researchers working in collaboration with the Institute of Functional Genomics of Lyon (ENS Lyon, CNRS, Université Claude Bernard Lyon 1) have found. By experimenting on mice with normal microbiota (conventional mice) and others with no microbiota (axenic mice), the scientists unveiled the key role bacteria play in growth. Indeed, bacteria affect IGF-1, an important growth factor. With a normal diet or underfed, axenic mice gained less weight and remained smaller than those with a microbiota, and their IGF-1 levels were lower. In other words, intestinal bacteria “control” in part growth mechanisms. But the researchers also found that some species of bacteria, such as Lactobacillus plantarum, foster post-natal growth in animals. Their findings are opening up new doors in the fight against the deleterious effects of chronic under-nutrition in infants.

In mice, gut microbiota is all-important for optimal postnatal growth and therefore plays a role in the ultimate size of adult mice. To the left, a young mouse bred with its gut microbiota; to the right, a young adult mouse with no gut microbiota. Note the difference in size between the two. The bacterial colonisation of the mice is illustrated by the presence or absence of bacterial colonies in an agar plate.. © CNRS, Vincent Moncorgé
In mice, gut microbiota is all-important for optimal postnatal growth and therefore plays a role in the ultimate size of adult mice. To the left, a young mouse bred with its gut microbiota; to the right, a young adult mouse with no gut microbiota. Note the difference in size between the two. The bacterial colonisation of the mice is illustrated by the presence or absence of bacterial colonies in an agar plate. © CNRS, Vincent Moncorgé

Antibiotics and microbiota: a bad mix

Antibiogram by diffusion in agar (petri dish method). Inhibition diameters are measured (transparent halos) and compared to critical values set by the antibiogram committee of the French Society for Microbiology. Depending on the results, bacterial strains are classified into three different categories: susceptible, resistant and intermediary.. © INRA, Florence Carreras
Antibiogram by diffusion in agar (petri dish method). Inhibition diameters are measured (transparent halos) and compared to critical values set by the antibiogram committee of the French Society for Microbiology. Depending on the results, bacterial strains are classified into three different categories: susceptible, resistant and intermediary. © INRA, Florence Carreras

After colonising the digestive tract with lightning speed, our 100,000 billion bacteria diversify over the course of the first three years of life before reaching levels that remain remarkably stable for years. To be sure, a poor diet can temporarily upset the microbiota, but our precious bacteria have a more fearsome enemy: antibiotics. A single course of treatment with antibiotics significantly disturbs the dominating microbiota, but the microbiota is very resilient and gets back to its normal self within weeks after treatment is discontinued. However, chronic antibiotic treatment in animals leads to apparently irreversible losses. American scientists have found that the microbiota of North Americans are significantly less diversified than that of South Americans and Africans. One possible explanation is that a native of the US or Canada has undergone an average 18 antibiotic treatments by age 18! Antibiotics are therefore known to have a lasting, even definitive, effect on our microbiota, and things are thought only to get worse with each generation.

The project EvoTAR, for “Evolution and Transfer of Antibiotic Resistance”, bringing together INRA, AP-HP (the Paris public hospital authority), Inserm and European partners, seeks to gain a better understanding of how bacterial resistance to antibiotics comes about. In a worrying context where pharmaceutical companies no longer develop new antibiotics, or very few, and where existing antibiotics are less and less effective, EvoTAR is focussing on families of microbial genes involved in bacterial resistance to antibiotics. By using metagenomics, scientists are exploring new ways to conduct systematic research on antibiotic resistance genes present in bacteria in very diverse contexts (human, animal, environmental, food), to determine their capacity to transfer to pathogenic bacteria. The pharmaceutical industry could then use the findings to develop new ways to design new antibiotics.

What happens to food nanoparticles in the intestine

Scanning electron microscope image of interactions between titanium dioxide food nanoparticles (food additive E171, in dispersed form), and E. coli bacteria.. © INRA, Christel Cartier & Muriel Mercier-Bonin
Scanning electron microscope image of interactions between titanium dioxide food nanoparticles (food additive E171, in dispersed form), and E. coli bacteria. © INRA, Christel Cartier & Muriel Mercier-Bonin

Nanoparticles, such as silver and titanium dioxide, are widely used in many common consumer products but also in food. They are used as additives or in food packaging to add colour or texture, or for their antimicrobial properties. Nanoparticles are defined as solid particles measuring less than 100 nanometres, i.e. 100 billionths of a metre. The consequences of chronic exposure to nanoparticles have today raised important public health issues. In light of this, INRA researchers have turned their attention to what becomes of food nanoparticles in our microbiota. How do our intestinal bacteria interact with silver or titanium dioxide nanoparticles? Working in tandem with physicians from Synchrotron SOLEIL, INRA researchers observed thein vitrobehaviour of the bacteria Escherichia coli in the presence of an antimicrobial coating containing nano-silver. They found that bacterial growth was disturbed, and proteins and lipids affected by the silver stress. Similar experiments were carried out, again withE. coliand also with the food bacteria Lactococcus lactis after exposure to nanoparticles of titanium dioxide (food additive E171). Researchers are now trying to understand what happens in vivo.

Lapereaux. © INRA, NICOLAS Bertrand

Antibiotics and livestock production: bacteria fight back!

Researchers are now looking for ways to cure animals of disease while minimising the risk of resistant bacteria. In animals as in humans, antibiotics are ingested with food and drink, and only partially absorbed by the intestines before making their way into the blood. The remainder is “set free” in nature after having had contact with the bacteria of the digestive tract during digestion. Because genetic material is exchanged naturally between bacteria, the emergence of bacterial strains that are resistant to antibiotics is unavoidable. Some of these newly-resistant bacteria end up in water and soil, thereby contaminating food and coming full circle since they end up, once again, in the digestive tract of humans. This vicious cycle will persist as long as new, virtuous antibiotics that are innocuous to intestinal microbiota, alternatives to antibiotics, or strategies to combat resistance are not found. INRA is fully invested in this branch of research, notably through its project MICRORESET (Microbial Reset), which consists of taking stock of anti-bio-resistance genes in the microbiota of rabbits and pigs. The idea is to allow for the colonisation of the intestines of newborns (piglets and young rabbits) by a microbiota that is devoid of resistance genes, through coprophagia* (since these animals normally eat the faeces of their mother). By replacing the mothers’ faeces, which have been exposed to antibiotics, with the faeces of animals that have not been exposed, researchers attempted to stop the transmission of antibiotic-resistant bacteria from one generation to the next. And initial findings prove that the technique works! Another project underway at INRA: “Changing the way antibiotics are used in livestock production” (TRAJ). It consists of focussing on socio-economic and socio-technical dynamics involved in the use of antibiotics in order to change how they are used in livestock production.