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Оглавление2:A Newly Discovered Organ: The Human Microbiome
Invisible Life
The idea of humans being inhabited by countless microbes invisible to the naked eye is as old as the first microscope. Born in 1632 in the city of Delft, in what is now the Netherlands, Antoni van Leeuwenhoek was a tradesman with a special interest in lens making. His desire to see the intricacies of the cloths he marketed drove him to shape glass rods into spheres using a flame. These almost perfect spheres allowed him to magnify not just threads, but anything else he wanted to view in great detail. Although he wasn’t formally trained as a scientist, he was one at heart and he soon began to put the oddest things under his rudimentary microscopes: water from a creek, blood, meat, coffee beans, sperm, etc. He methodically wrote everything down and sent his findings to the Royal Society of London, which began publishing his curiosities-filled letters.
One day in 1683, he decided to scrape the white residue between his teeth and place it under his lens, writing in his notes:
An unbelievably great company of living animalcules, a-swimming more nimbly than any I had ever seen up to this time. The biggest sort (whereof there were a great plenty) bent their body into curves in going forwards . . . Moreover, the other animalcules were in such enormous numbers, that all the water . . . seemed to be alive . . . All the people living in our United Netherlands are not as many as the living animals that I carry in my mouth this very day.
Naturally, Leeuwenhoek’s observations of a never-before described world filled with microscopic “animalcules” were met with great skepticism and ridicule. It wasn’t until other British scientists saw it with their own eyes that they began to acknowledge that Leeuwenhoek was not hallucinating. Leeuwenhoek had written many letters to the Society, but discovering microscopic life is what sealed his long-lasting fame. As a result of his many discoveries, Leeuwenhoek is considered the “Father of Microbiology.”
Still, these findings remained nothing more than curiosities of the natural world, with no real connection to human biology until scientists discovered that those “animalcules” caused diseases. This revelation took place almost two hundred years later, when Robert Koch, Ferdinand Cohn, and Louis Pasteur each separately confirmed that diseases such as rabies and anthrax were caused by microbes. Pasteur’s work also showed that microbes caused the spoilage of milk, and he thus designed the process known as pasteurization, in which microbes are killed with the use of high heat. Milk contamination led Pasteur to the idea that microbes could be prevented from entering the human body, and together with Joseph Lister, they developed the first antiseptic methods. These began to be widely adopted, with one of them still in use today: Listerine.
Avoiding Contagion at Any Cost
The work of Pasteur, Cohn, Koch, and others led to the widespread knowledge that diseases could be avoided by preventing contact with microbes, and by killing them, and so the quest to eradicate them began in earnest. Health departments opened in London, Paris, New York, and other big cities. Garbage, which had previously been left to pile high on sidewalks, was now collected and disposed of; drinking water was treated; rats and mice were hunted; sewer systems were built; and people with contagious diseases were often placed in isolation. It was through all this that the word “bacteria” gained its bad reputation and inherent connotation of disease, contagion, and plague. Germs were (and still are) entities to be feared, avoided, and fought.
Fast-forward another two hundred years and an equally astounding discovery is now in progress: in our quest to clean up our world, we have been killing more microbes than necessary and, ironically, this can make us sick. Why? Because our bodies know how to properly develop only in the presence of lots of microbes. This groundbreaking concept significantly expands on what science already knows about the nonharmful bacteria that inhabit our body: that they aid in the digestion of certain foods, and that they fabricate certain essential vitamins. However, only very recently have we begun to comprehend how profoundly necessary microbes are for our normal development and well-being.
Microbes: Partners in Evolution
The last twenty years of studying microbes has allowed us to understand that microbes aren’t optional forms of life that live within us; they truly constitute part of who we are biologically. To get a better grasp on this, we must first understand that our partnership with microbes is as old as the first species of hominids (our ancestors), and that the evolutionary changes that hominids experienced were accompanied by changes in our microbiota, too. Throughout human history there have been only a few landmark evolutionary bursts (rapid evolutionary changes) that have marked the course of hominids. Interestingly, two of them can be clearly linked to changes in our intestinal physiology and thus with our microbiome.
As hunters and gatherers (a lifestyle that lasted about 2.5 million years), our ancestors had no permanent homes, living in temporary shelters with few possessions so they could easily move from one place to another. Depending on the geographic region they inhabited, early humans ate different mixtures of meats, roots, tubers, and fruits—whatever was in season. Then an extremely important event occurred that led to one of these evolutionary bursts: our ability to control fire and cook food. We completely take it for granted now, but cooking food made it safer to eat, as heat kills the disease-causing bacteria that thrive in decomposing meat. It also changes the chemistry of the food itself, making it much easier to digest and a lot richer in energy. This sudden increase in energy levels changed everything for humans. No longer did our ancestors have to spend hours chewing raw food in order to extract enough calories to sustain everyday life. Think of what our closest relatives in nature, apes, are almost always doing when see them in the zoo or on TV. If humans hadn’t developed a way to cook food we, too, would have to spend six hours chewing five kilos of raw food every day to get enough energy to survive, just like our primate cousins do.
The fossil records of humans from this period consist of bones and teeth, making it impossible to determine what type of microbiota lived in the intestines of ancient hunters and gatherers. However, anthropologists have been able to show that the change in lifestyle and diet that resulted from the advent of cooking had anatomical consequences involving the intestines. As energy intake increased, the intestines of our human ancestors shortened and, amazingly, their brains grew, too, increasing in size by about 20 percent. Given what we know today about the link between gut microbes and brain development, it is very likely that intestinal microbiota had a part in this “sudden” brain growth. Brain enlargement improved our capacity to hunt, communicate, and socialize. In other words, cooking made us smarter—it made us human.
Another evolutionary landmark occurred about eleven thousand years ago. Certain groups of humans realized, probably by chance, that fallen grains from the wild wheat stalks they collected would give rise to more wheat if planted. When humans learned to domesticate plants for food, they tossed away their nomadic ways for a settled lifestyle. Having crops nearby meant that previously small tribes of a few dozen humans could grow to a few hundred, which in turn gave rise to basic traits of civilization, such as trade, written language, and math. If it weren’t for farming, we would all still be picking berry after berry from bushes and walking miles every day. The emergence of agriculture coincides with the appearance of the first cities; inadvertently, agriculture built our modern social structures. This lifestyle change was so successful that farmers replaced foragers, and these days only a handful of people maintain a hunter-gatherer way of life.
As expected, the lifestyle associated with farming came with major dietary changes. Humans no longer ate small bites throughout the day with the occasional feast after a hunt since farmers had a steady and somewhat predictable supply of foods. So how did this affect our microbiota? By domesticating grains and consequently obtaining most of their daily calories from their new crops, the diet of farmers became less diverse. Based on what is currently known about the microbiota’s response to diet, their microbiota likely became less diverse, too. In fact, comparing the intestinal microbiota of the Hazda people of Tanzania, one of the few contemporary tribes that relies on foraging, to a modern farmer is like comparing a rain forest to a desert, in terms of biodiversity. Less diversity in our microbiota is associated with a number of human diseases, many of which we cover in later chapters.
Although farming has been around for only eleven thousand years (just 0.004 percent of human history!), physiological changes have also been linked to the agricultural diet, and some of these changes involve our resident microbes. The new diet brought with it cavities and other periodontal diseases, mediated by bacteria rarely found in foragers. Our teeth, jaws, and faces have grown smaller, too, probably because chewing was reduced on such a diet. Some evolutionary biologists believe that we lived a healthier lifestyle as foragers, and that humans traded in that healthier lifestyle for food security and more babies (not a bad deal, actually!). Certain nutritionists have extrapolated from this a recommendation that, in order to promote health, all modern humans should eat the way hunters and gatherers did, but this has been debunked by top evolutionary biologists based on the fact that humans have adapted genetically to the challenges that farming generated (see the Caveman Diet, page 30).
What these two major events in human history teach us is that changes in lifestyle are accompanied by changes in our microbiota, and that these microbial changes might affect our health for better (e.g., cooking food and decreasing infections) or worse (e.g., agriculture and less microbial diversity). Whether we like it or not, we are married to microbes for life, in sickness and in health, for richer or for poorer.
Bugs “R” Us
Our microbes are part of what make us human, but our current way of living and eating, especially in the Western world, has exerted further changes in our microbiota and in our biology. In the past hundred years, and especially the last thirty years, humans have learned to process foods to make them tastier, more digestible, and more shelf-stable than ever before. On top of this, our push to clean up our world in order to fight infectious diseases, including the use of antibiotics, has further shifted the composition and diversity of our microbial communities. Double-punching our microbiota like this has induced huge changes in our intestinal environments and, as we will learn in the following chapters, on many other aspects of our bodies’ normal functions.
In order to appreciate how the microbiota influences our health, it is important that we discuss certain basic biological concepts about our microbiota and the organ most of them call home, the human intestine. The human microbiota consists of bacteria, viruses, fungi, protozoa, and other forms of microscopic life. They inhabit our skin, oral and nasal cavities, eyes, lungs, urinary tract, and gastrointestinal tract—pretty much any surface that has exposure to the outside world. Another term that is frequently used is microbiome, which refers not only to the identity of all the microbes living within us, but also to what they do. A total of 1014 microbes are estimated to live in the human body and, as mentioned, the intestinal tract is the biggest reservoir of microbes, harboring approximately 1013 bacteria. It is this community that influences us, their host, the most. In fact, unless otherwise noted throughout this book, when we use the term microbiota, we are referring to the intestinal microbiota. Although bacteria are approximately twenty-five times smaller than human cells, they account for a significant amount of our weight. If we were to get rid of our microbiota we would lose around three pounds, or about the weight of our liver or brain! A single bowel movement is 60 percent bacteria numbering more than all the people on this globe, a deeply disturbing fact for germophobes.
For microbes, the gastrointestinal system is a fabulous place to live. It’s moist, full of nutrients, and sticky (allowing microbes to adhere to it), and in many sections it completely lacks oxygen. Although it seems counterintuitive that any life-form would favor a place without oxygen, an enormous number of bacterial species either prefer or require such a place, as this world evolved for billions of years without oxygen. Microbes living without air are called anaerobes and our gut is packed with them.
About 500–1,500 species of bacteria live in the human gut; the types and numbers vary according to the different sections of the gastrointestinal system. Starting from the top down, the mouth harbors a diverse and complex microbiota—the tongue, cheeks, palate, and teeth are all covered in a dense layer of bacteria known as a biofilm. For example, the dental plaque that dentists remove from our mouths is one of these biofilms. The stomach, on the other hand, is not the best place for microbes, as it is as acidic as battery acid. Still, a few bacterial species have adapted to live under such conditions. Farther down are the small and large intestines, where the number of microbes continues to increase until we reach the very end of the large intestine. Oxygen follows the opposite pattern, as it gradually decreases towards the lower portions of the gut, allowing strict anaerobes (those that die when exposed to the slightest bit of oxygen) to flourish in the large intestine. The differences in living conditions within the small and large intestines determine the number and the types of bacteria that reside in each portion of the gut. For example, the slightly acidic and oxygenated environment in the upper small intestine allows for bacteria that are tolerant to these conditions, such as the bacteria we often eat in our yogurt, known as Lactobacilli. Unlike the upper small intestine, the large intestine, also known as the colon, moves or churns its contents very slowly and produces a lot of mucus, allowing for many more bacteria to grow, especially those that use mucus for food.
Another characteristic of the human microbiota is its variability between individuals. Although about one-third of bacterial species are shared between all humans, the rest of them are more specific, making our microbiome unique like a fingerprint. Similarities in microbiota are highly dependent on diet and lifestyle, and to a lesser extent, on our genes. For example, identical twins (who share all of their genes) can have very different microbiotas if one is a vegetarian and the other eats meat. Family members, including husbands and wives who are not genetically related, tend to have similar microbiotas due to a shared living environment and diet. Humans also have striking similarities with the microbiotas of several species of apes, but only those that are omnivores like us. Mountain gorillas, for example, have a microbiota much more closely related to pandas, because they both spend their days leisurely eating bamboo.
Once established in our intestine, microbial communities are very stable. Only drastic changes, such as adopting a vegan lifestyle or moving to a completely different part of the world, will significantly alter your microbiota. Going on antibiotics for a week to treat an infection will also affect your microbiota, but only temporarily in most cases. It will generally bounce back to something resembling its pre-antibiotic state after you finish the treatment and go about your old way of eating. However—and this is a big however—the microbiota takes about 3–5 years from the time we’re born to become a fully established community, and during this period it’s very unstable, especially during the first few months of life. Any drastic changes to it have a very high chance of altering the microbiota permanently. In fact, it is the early colonizers of the intestinal microbiota that have a major influence on the type of microbiome we have later in life. Thus, a short-lived event like a C-section may have long-lasting consequences, since a baby born this way starts with a very different microbiota than a baby born vaginally. The potential health outcomes and impact of this type of event during early life has major implications for later health and disease, as discussed in later chapters.
Immune Cell School
Given the strong associations between early-life alterations to the microbiota and immune diseases later in life, we might ask: What exactly are microbes doing to us when we’re babies that is so important? As mentioned in the previous chapter, microbes help us use food that we can’t digest properly, and they also fight off bacteria capable of causing us harm. We’ve known about these roles for decades, but they are just the tip of the iceberg. As soon as we’re born and begin getting colonized with bacteria, bacteria kick-start a series of fundamental biological processes in our body. One of them is the maturation of the immune system, the network of cells and organs that defend us from diseases.
Before scientists started unraveling the role of the microbiota in immunity, every doctor and scientist was taught that we’re born with an immature immune system that gets trained in a small organ called the thymus. Here, immune cells known as T cells—the strategists of our immune system—are taught who is a friend and who is a foe. This training boot camp lasts for a few years only, until the thymus disappears, and all our immune cells have acquired this knowledge. Immunologists deciphered a complex series of mechanisms showing exactly how this occurs, but they couldn’t explain one big question: How does the thymus teach immune cells which kinds of bacteria are beneficial and which ones aren’t? After all, since we’re covered head to toe (also inside and out) with microbes, mostly good ones, how do immune cells know the difference? The thymus does not interact with bacteria, so where could it get this information? It turns out this very important aspect of the training doesn’t occur in the thymus—it happens in our gut.
Before we’re born, the lining of our gut is full of immature immune cells, and as soon as we come into the world and bacteria start moving into their new home, these immune cells “wake up” almost magically. They start multiplying, they change the type of activities they do, and they even move to other parts of the body to train other cells with the information they just received. Experiments with germ-free mice, which are mice that are born into and kept in a completely microbe-free environment, show that without microbes the immune system remains immature, sloppy, and unable to fight off diseases properly.
Scientists haven’t figured out exactly how microbes do this at the molecular level, but it is known that most bacteria will teach these immune cells to tolerate them, whereas some bacteria—the pathogens that cause disease—have the opposite effect. This makes sense; if our immune cells started fighting off all bacteria indiscriminately, there would be an out-of-proportion inflammatory battle between the small quantity of immune cells and the vast numbers of bacteria right after we’re born. In reality it’s quite the opposite; despite the enormous amount of bacteria living in the intestine, it’s a relatively controlled and harmonious place. The way this is achieved is by the microbiota modulating the immune system, allowing most microbes to be tolerated.
Many inflammatory diseases, such as asthma, allergies, and IBD, are characterized by an overreactive immune response. Knowing what we do now about the importance of microbiota in immune system development, it’s not surprising that these diseases are being diagnosed in more and more children. They are, to a great extent, a consequence of the modern lifestyle changes that are altering the types of microbes that affect the immune system. There’s a reason immune cells wait for microbes to come and train them right after we’re born: because this is the way it has happened for millions of years and is the way it will always be. We need to find ways to modify our modern behavior so that immune cell school can function properly.
Feeding Our Microbes So They Can Feed Us
Another fundamental function of microbes is to aid in the regulation of our metabolism. Humans, just like any other living animal, obtain energy from food that is digested and absorbed in the intestines. Besides helping us digest certain foods that the intestines can’t handle on their own, bacteria produce energy for us, and the amount they produce is noteworthy. Germ-free mice weigh significantly less than conventionally raised mice, but once bacteria begin to colonize them they have a 60 percent weight gain, despite not eating more food than regular mice. One of the mechanisms by which they accomplish this is a process known as fermentation. Think of the intestine as a bioreactor where bacteria ferment fiber, carbohydrates, and proteins that were not digested and absorbed in the small intestine. The end-products of this process are called short-chain fatty acids (SCFA), and three of them are very important to different aspects of human energy metabolism: acetate, butyrate, and propionate. Intestinal cells rapidly absorb SCFA and use them as an energy source to stay fueled. SCFA are also transported very rapidly to the liver, where they are transformed into critical compounds involved in energy expenditure and energy storage. SCFA help determine how and when we use the energy obtained from food, and, importantly, when to store it as fat. Thus, it’s not surprising that alterations in the production of SCFA have been associated with obesity, both in mice and in humans.
SCFA are not exclusively produced by the microbiota. These compounds are too critical for our metabolism to rely entirely on bacteria for their production. Still, studies performed on patients genetically unable to produce propionate have shown that approximately 25 percent of the propionate in our body is derived from bacterial activity in the gut. The implications of this are significant, considering that treatment with many types of antibiotics severely alters intestinal SCFA production. If antibiotics are given during early childhood, especially in the first few months of life, the risk of experiencing long-lasting metabolic and immune alterations due to abrupt changes to the microbiota increases dramatically.
Scientists haven’t yet figured out all the functions that our metabolism delegates to the microbiota. Immune training and metabolizing energy are two essential things that our microbes do for us, but it’s clear that there are more. Brand-new research shows that the microbiota plays an important role in neurological development (discussed in chapter 15), and even in the health of our blood vessels. These types of discoveries have led scientists to call our microbiome a “new organ,” perhaps the last human organ to be discovered by modern medicine. Although most of this knowledge has just recently emerged and many pieces of the puzzle remain unsolved, it is evident that protecting the initial developmental stages of our microbiota has a significant impact in human health.
In the next four chapters we discuss the life stages that are most influential in the development of the human microbiome, all of which occur during infancy and early childhood. We will explore how some of the actions parents take during pregnancy and birth, as well as through diet, can have profound implications in the communities of microbes that are part of our children’s bodies. With scientific information parents have learned to make better choices when raising their kids, such as limiting sugar intake and even the amount of time spent in front of the TV. With our newfound awareness of how important the microbiome is, let’s explore what we might do as parents to improve our children’s health by caring for their microbes.
THE CAVEMAN DIET
The newest diet fad suggests that eating the way our Paleolithic ancestors did will make us be healthier and live longer. However, evolutionary biologists don’t agree with this because it’s not based on current scientific knowledge. Some assumptions of the “paleo diet” include:
•Our ancestors ate mostly meat, and no legumes or grains. Actually, our ancestors ate incredibly different diets depending on where they lived. One could expect this statement to be close to the truth in Arctic environments, but in more temperate weather this was not the case. Biochemical analysis of dental fossil records from this period show that foragers did eat grains and legumes. Also, the meat we consume today—from domesticated livestock—is completely different than the wild game our ancestors ate.
•Our ancestors did not eat dairy. While this is generally correct, modern humans from many regions of the world where dairy is consumed have genetically modified their metabolism to digest and absorb dairy products. In other words, we have evolved, in a somewhat short period of time, to digest foods that our ancestors didn’t eat. Our genes have changed since we roamed the savannahs.
It is impossible for modern humans to eat the way our ancestors did because our foods today are completely different than before. Carrots, broccoli, and cauliflower did not exist back then, and neither did the leaves used to make salads. All of these are products of agriculture. What certainly is true is that the typical modern human diet has extremely low diversity and is heavily processed, compared to food consumed a hundred years ago.
In addition, only very recently have people stopped eating just what is in season and whole foods. These are the dietary changes that really have an impact on our health, in great part because of the effects on our microbiota. Yes, eating fewer refined carbohydrates and more vegetables will help you lose weight and feel better, but this does not reflect our Paleolithic past in the way “paleo” enthusiasts believe it does.
