divulgatum está dedicado a la difusión de conocimiento científico en español e inglés, mediante artículos que tratan en detalle toda clase de temas fascinantes pero poco conocidos.
divulgatum is devoted to the dissemination of scientific knowledge in Spanish and English, through articles that go into the details of all sorts of fascinating, if not
widely known, subjects.

Sunday, April 17, 2016

The walking ecosystem

The vast community of microbes living inside us is starting to reveal its many roles in human biology.

This artificially coloured electron micrograph shows part of the great variety of bacteria that inhabit the human gut, as well as a vegetal fibre. (Credit: Martin Oeggerli/National Geographic.)

WHEN WE LOOK around us, it is easy to think that the world is dominated by the creatures we see: humans, mammals, birds, plants, insects. We often forget that all these superior life forms closely depend on other kinds of organisms, those that are too small to be seen. Microscopic bacteria, protozoa, archaea, fungi and viruses compose the vast majority of the biological material on the planet; everything, from the immense oceans to our bodies, teems with them. This myriad of microbes plays a crucial part in almost everything that happens on Earth, including both the elegant ecological cycles responsible for renovating the organic material that makes life possible, and the mechanisms that ensure the internal balance of our own bodies.

This beneficial relationship between microbes and their hosts stretches back probably as far as the history of animals themselves. When, just over five hundred million years ago, the world witnessed the explosion of animal life, microbes had already been populating the Earth for three billion years; in fact, some of them created the oxygen-rich atmosphere that made the development of multicellular life possible. Amongst all the milestone advances which marked animal evolution, one of the most essential was the digestive system, which allowed the new life forms to move in search of food. This alimentary canal not only empowered animals to move and digest at the same time, but granted them the ability to carry with them those microorganisms that were needed for digestion, thus setting up an alliance between microbes and animals that is still strong today. Through this symbiosis, the animal is in charge of acquiring food, whereas the microbes, in exchange for their share, collaborate in the digestive process, fermenting the material that their host is unable to assimilate on its own. Over time, the animal body developed a huge reliance on the functions provided by these microorganisms, which explains the fact that the majority of the microbes in our body are housed in the intestine.

In the mid-seventeenth century, Antoni van Leeuwenhoek, the father of microbiology, observed a microorganism for the first time, thanks to a microscope built by himself. Van Leeuwenhoek christened the newly discovered creatures as animalcules (from Latin animalculum, ‘little animal’). Due to the relationship of some germs with devastating diseases, the idea that all microbes are enemies of the human being soon became widespread. Even today, the media and health campaigns consolidate a negative image of microbes as exclusively harmful organisms, a threat to be combated by means of antibiotics, antivirals and vaccines.

Only recently have we begun to glimpse the inaccuracy of this assumption. Over the course of the last few decades, the inconceivable variety of microorganisms occupying every nook and cranny of our outer and inner environment has been explored, if only to some small extent. This has shown the human body to be home to a vast microbial community, brought together under the term microbiota. This community’s composition — that is, the species that comprise it in different proportions — not only depends closely upon the region of the body in question, but also differs considerably from one person to the next, and can even change rapidly in the same person.

Microorganisms have been found even in regions of our anatomy that were deemed sterile until very recently, such as the placenta. This seems to be one of the routes for the transfer of the first microbes that colonise the body of the yet-unborn baby. After acquisition of different microbial species through the placenta and the neck of the uterus during birth, the first embrace of a baby and their mother, besides a most tender act of love, is the way in which the baby ‘embraces’ their new skin microbiota. For its part, breast milk, which was also believed to be germ-free, contains a mix of microbes that settle in the brand-new intestine, setting up the largest, and probably the most important, community of the body: the gut microbiota.

This initial microbiota that colonises almost every niche offered by the newborn’s body is destined to change dramatically throughout the first years of development, before forming the typical community of an adult human, dominated by certain bacterial groups. Nonetheless, the intestinal microbiota is more than just bacteria, including unicellular fungi, archaea and, of course, a plethora of viruses. In this ‘microecosystem’, viruses act as predators of bacteria and other microorganisms, establishing a predator-prey dynamic that differs very little from the ones that characterise other ecosystems. By means of this dynamic, viruses shape and stabilise the bacterial flora’s composition during the first years of life, which in turn affects this viral population’s own structure.

Said transformations of the infant microbiota are crucial in the formation of an adult microbiota that will play a fundamental role in its owner’s health. Numerous independent studies in different countries are revealing the function, unimaginable until very recently, of certain gut bacteria in the development of diseases related to the immune system, such as Crohn’s disease, which is characterised by chronic bowel inflammation. Such observations arouse the suspicion that, besides protecting us against external microorganisms, the immune system has the mission of ‘breeding’ or ‘culturing’ those bacteria that help to keep us healthy; even more surprising, such bacteria seem in turn to influence certain aspects of the immune system, forging an interdependence between guests and host.

The most notable amongst these bacteria belong to a series of groups known as the clostridial clusters; as the name suggests, they are distant relatives of the infectious bacterium Clostridium difficile, which is a frequent cause of death by severe colitis. However, the benign clostridial bacteria have the opposite effect, contributing to the health of the intestinal barrier that prevents the microorganisms housed in the bowel from invading the rest of the body, and modulating the immune system’s inflammatory potential — a feature that renders them a potential remedy for inflammatory disorders such as Crohn’s disease.

Evolution of the gut bacterial community throughout the first 24 months of life. The abundance of each bacterial family is represented by the proportion of the corresponding colour in each bar (month).
(Source: Lim E.S.
et al. Nature Medicine 21, 1228–1234 (2015); doi: 10.1038/nm.3950.)

This knowledge finds us at a time when the incidence of inflammatory, allergic and autoimmune diseases has more than doubled, whilst infectious diseases, which are a major cause of inflammation, have become considerably less common. Many scientists believe that the increase in the incidence of diseases related to the immune system could be due not to the presence of harmful microorganisms, but to the absence of particular benign species that were originally part of our intestinal flora. The reason for this and other changes in the composition of the modern human microbiota is evident: although it is easy to ignore, our present lifestyle differs radically, and in almost every aspect, from the way of life that our species has followed during most of its history. In particular, a diet high in fats and sugars, far removed from the fibre-based diet of our ancestors, and the overuse of broad-spectrum antibiotics, which cause dramatic changes in the digestive system’s bacterial populations, have led to a large-scale shift in the composition of the human gut microbiota. This seems to be the root of the hypersensitivity of modern man’s immune system, which gives rise to allergic and inflammatory responses targeted against the own body. In line with this theory, bacteria in the clostridial groups are specialised precisely in fermenting the vegetal fibre that humans are incapable of digesting, producing in turn substances that appear to be important for the digestive system’s health. Both our intestine and our immune system show signs of being adapted for keeping these anti-inflammatory bacteria ‘happy’, providing them with sugars that complement their fibre-based diet. Japanese research has reinforced this idea by demonstrating that the removal of clostridial bacteria from mice triggers a condition similar to the food allergies experienced by many people, and that this condition can be prevented by the reintroduction of said species in the intestine.

In the same vein, studies of the gut microbiota of hunter-gatherer societies that still maintain their distant ancestors’ way of life, like the Hadiza of the African Rift Valley, have revealed that members of these societies possess an incredibly diverse microbiota, including a multitude of species that are not found in Westernised societies. As in any ecosystem, a high diversity implies a great flexibility and resilience against the ‘microecological’ repercussions of infections, parasites and fluctuations in the amount of food available. As one might expect, the diet of these societies contains much more fibre than that of the modern man. Almost certainly, the intestinal flora of our hunter-gatherer ancestors was at least as diverse as that of such societies. It is thus possible that the restoration, at least in part, of the intestinal flora’s ecological balance, re-establishing the population of anti-inflammatory bacteria that are capable of preventing the immune system’s hyperactivity, lies in something as simple as a higher fibre ingestion.

Apart from diet, both malnutrition and antibiotics use can have irreversible effects on health, especially when these conditions occur in childhood, as proven by studies in the United States, Bangladesh and other countries. Antibiotics overuse during infancy has been associated with a greater risk of disorders such as obesity, type 1 diabetes, Crohn’s disease, allergies and asthma. Some studies have also linked the consumption of artificial additives known as emulsifiers, which are found in many processed foods and considered to be ‘safe’, to the development of intestinal diseases and obesity.

In the presence of severe diseases, such as chronic bowel inflammation or Clostridium difficile infections, a change in diet is clearly not enough. For these cases, there are already therapies aimed at modifying part of, or a whole, gut community. Outstanding amongst these is the faecal transplantation, which consists of extracting a microbial population from the faeces of a healthy individual, and introducing it into the intestine of a sick one, after a lavage that removes the existing microbiota. By means of this, a ‘healthy’ population of microorganisms is effectively transplanted, replacing an unhealthy one. This treatment has turned out to be especially effective against recurrent infections that do not respond to antibiotic-based therapies. Faecal transplantation is an example of the increasing perception of the microbiota as just another organ of the body, with the difference that this ‘organ’ can be more easily treated and manipulated than any other.

Apart from regulating the immune system’s behaviour, gut bacteria remarkably influence the animal body in other ways. Different experiments in rodents have demonstrated that the transfer of certain bacterial species allows the transmission between animals of physical attributes, including leanness and obesity — which can be transferred from humans to mice — and even mental ones, such as anxiety.

In the light of these findings, it appears that the expression ‘We are what we eat’ is acquiring a new dimension: our diet affects not only us, but also all the living microorganisms that are part of the walking ecosystem that is our body. A lifestyle ignorant of our microscopic partners’ needs can lead to the disappearance of many of these species, diminishing the ecosystem’s diversity and, with this, its ability to defend us against invading organisms, digest our food and soothe our immune system. Above all, the recent discoveries stemming from the effort to comprehend the human microbiota remind us how much we have yet to discover about ourselves.

Special thanks are due to Isobelle Bolton for her invaluable help with translation.

Supplement: Innovations in the microbiome. Nature (2015).
Chassaing, B. et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature (2015).
Lemon, K.P. et al. Microbiota-targeted therapies: an ecological perspective. Science Translational Medicine (2012).
Smith, P.A. Brain, meet gut. Nature (2015).
Subramanian, S. et al. Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature (2014).
Aagaard, K. et al. The placenta harbors a unique microbiome. Science Translational Medicine (2014).
Lim, E.S. et al. Early life dynamics of the human gut virome and bacterial microbiome in infants. Nature Medicine (2015).