we will consider this amazing process.Microbes go from zero to trillions in a short time.There is a well-choreographed succession from the founders to the later inhabitants over the first three years of life. Ultimately,a unique population of residential microbes develops at each location on the inner and outer surfaces of your body.The crook of your elbow and the spaces between your toes are home to different species.The bacteria,fungi,and viruses on your arms are different from those in your mouth and in your colon. Your skin is a huge ecosystem a bit larger than a half sheet of plywood, encompassing about twenty square feet of planes,folds,channels,and crannies. Most of these spaces are tiny,even microscopic.Your smooth skin,when viewed up close,may more closely resemble the surface of the moon,pocked by craters with hills and valleys.Which microbes take up residence on what piece of real estate depends on whether the area is oily like the face,moist like the armpit,or dry like the forearm.sweat glands and hair follicles have their own microbes.some of your bacteria eat dead skin,some make moisturizers from the oils secreted by your skin,and others keep harmful bacteria and fungi from invading your body. As for your nose,researchers recently found the signature of many pathogens (disease-causing microbes)living peacefully in the nasal passage of healthy people.One,Staphylococcus res,is notorious.It can cause boils,sinusitis food poisoning and bloodstream infections.But it can also have a completely benign presence in your nose,just minding its own business.At any one time,at least a third of us,and maybe more,are carrying it. Your intestinal tract is where most microbes in your body make their living beginning from the top,in your mouth.If you look in the mirror,you can immediately see that there are discrete areas in your mouth,for example,your teeth. your tongue,your cheeks,and your palate.And each site has multiple surfaces. There is the top of your tongue and its bottom.Each tooth has multiple surfaces,and there is a juncture where the tooth descends into the gums.It is fair to say that for every surface there is a different population of bacteria normally living in your mouth we know a lot about this from the human microbiome proiect (HMP)a five-year program launched by the National Institutes of Health in 2007.Among the HMP goals was a large project to sequence the genetic material of microbes taken from nearly 250 healthy young adults.One of the take-home messages is that although the overall census of the bacteria present showed a lot of similarities among group members,everyone was unique.Our microbial differences far surpass the differences in our human genes.Our microbes are very personal,a reality we will come back to again and again.Still,there are general principles of organization.We can consider them in the gastrointestinal tract. In the HMP,the mouth was extensively sampled.Certain families of organisms were found to be common in many sites,such as the Veillonellas,Streptococci,and Porphyromonads,but their distribution varied widely.And other organisms were 27
we will consider this amazing process. Microbes go from zero to trillions in a short time. There is a well-choreographed succession from the founders to the later inhabitants over the first three years of life. Ultimately, a unique population of residential microbes develops at each location on the inner and outer surfaces of your body. The crook of your elbow and the spaces between your toes are home to different species. The bacteria, fungi, and viruses on your arms are different from those in your mouth and in your colon. Your skin is a huge ecosystem a bit larger than a half sheet of plywood, encompassing about twenty square feet of planes, folds, channels, and crannies. Most of these spaces are tiny, even microscopic. Your smooth skin, when viewed up close, may more closely resemble the surface of the moon, pocked by craters with hills and valleys. Which microbes take up residence on what piece of real estate depends on whether the area is oily like the face, moist like the armpit, or dry like the forearm. Sweat glands and hair follicles have their own microbes. Some of your bacteria eat dead skin, some make moisturizers from the oils secreted by your skin, and others keep harmful bacteria and fungi from invading your body. As for your nose, researchers recently found the signature of many pathogens (disease-causing microbes) living peacefully in the nasal passage of healthy people. One, Staphylococcus aureus, is notorious. It can cause boils, sinusitis, food poisoning, and bloodstream infections. But it can also have a completely benign presence in your nose, just minding its own business. At any one time, at least a third of us, and maybe more, are carrying it. Your intestinal tract is where most microbes in your body make their living, beginning from the top, in your mouth. If you look in the mirror, you can immediately see that there are discrete areas in your mouth, for example, your teeth, your tongue, your cheeks, and your palate. And each site has multiple surfaces. There is the top of your tongue and its bottom. Each tooth has multiple surfaces, and there is a juncture where the tooth descends into the gums. It is fair to say that for every surface there is a different population of bacteria normally living in your mouth. We know a lot about this from the Human Microbiome Project (HMP), a five-year program launched by the National Institutes of Health in 2007. Among the HMP goals was a large project to sequence the genetic material of microbes taken from nearly 250 healthy young adults. One of the take-home messages is that although the overall census of the bacteria present showed a lot of similarities among group members, everyone was unique. Our microbial differences far surpass the differences in our human genes. Our microbes are very personal, a reality we will come back to again and again. Still, there are general principles of organization. We can consider them in the gastrointestinal tract. In the HMP, the mouth was extensively sampled. Certain families of organisms were found to be common in many sites, such as the Veillonellas, Streptococci, and Porphyromonads, but their distribution varied widely. And other organisms were 27
present only in a limited area. The richest zone in the mouth is the gingival crevice,the interface between tooth and gum.It is teeming with bacteria,many of which are anaerobic (they don't like oxygen).They may be killed by it.It seems counterintuitive that we harbor a big population of oxygen-sensitive bacteria in our mouths,where oxygen-containing air is constantly passing but it is true.This immediately tells us that there are special niches,some very small,where anaerobic bacteria may flourish. Ever wonder why your breath smells different in the morning when you wake up?It's because most of time when you sleep,you breathe through your nose.The air exchange in your mouth goes down,and the populations of anaerobic bacteria go up.They produce the chemicals,ofen volatile,that cause"morning mouth." When you brush your teeth,you are removing tiny debris and whole populations of bacteria.Total counts go down,and the census distributions change.This cycle continues throughout the course of the day. It is not just in your mouth that microbes cause odor.It is everywhere there are microbes,which in fact is everywhere.In some places,armpits and groin,for instance,microbial concentrations are very high,and the populations are dominated by microbes that produce particularly smelly products.Although whole industries have arisen to control these odors,they are not accidental.From insects on up,our microbial odors identify who we are.They indicate who are our friends,our kin. our enemies,our lovers,or potential mates,and they tell us when might be a good time to mate.Mothers know the smell of their babies and vice versa.Smell is important,and it is mostly microbial in origin.It even determines who is attractive to mosauitoes.Once we fully understand how this works.we might harness that information to become more invisible or repulsive to those pests.But I have digressed. After food leaves your mouth-where your teeth,saliva,enzymes,and friendly bacteria begin to break it up-it passes into your esophagus,a long tube that separates your mouth and pharynx from your stomach.No one thought bacteria resided in the esophagus until 2004,when we found a rich microbial community of dozens of species living there. Food then passes into your stomach,where digestion begins with the help of acid and digestive enzymes.Despite strong acidity,bacteria also live there, including H.pylori (mentioned earlier),which when present usually dominates Other species may be found in lower abundance.Your stomach makes hormones as if it were a gland like the thyroid.Its wall contains immune cells that help fight infection,just like your spleen or lymph nodes and colon.H.pylori plays a role in the production of acid and hormones and the state of immunity Next stop,your small intestine,a long tube that contains the major elements- detergents,enzymes,transporters-for breaking down and absorbing food into you body.This is where you digest most of your meals.Bacteria are present there,too, 28
present only in a limited area. The richest zone in the mouth is the gingival crevice, the interface between tooth and gum. It is teeming with bacteria, many of which are anaerobic (they don’t like oxygen). They may be killed by it. It seems counterintuitive that we harbor a big population of oxygen-sensitive bacteria in our mouths, where oxygen-containing air is constantly passing, but it is true. This immediately tells us that there are special niches, some very small, where anaerobic bacteria may flourish. Ever wonder why your breath smells different in the morning when you wake up? It’s because most of time when you sleep, you breathe through your nose. The air exchange in your mouth goes down, and the populations of anaerobic bacteria go up. They produce the chemicals, often volatile, that cause “morning mouth.” When you brush your teeth, you are removing tiny debris and whole populations of bacteria. Total counts go down, and the census distributions change. This cycle continues throughout the course of the day. It is not just in your mouth that microbes cause odor. It is everywhere there are microbes, which in fact is everywhere. In some places, armpits and groin, for instance, microbial concentrations are very high, and the populations are dominated by microbes that produce particularly smelly products. Although whole industries have arisen to control these odors, they are not accidental. From insects on up, our microbial odors identify who we are. They indicate who are our friends, our kin, our enemies, our lovers, or potential mates, and they tell us when might be a good time to mate. Mothers know the smell of their babies and vice versa. Smell is important, and it is mostly microbial in origin. It even determines who is attractive to mosquitoes. Once we fully understand how this works, we might harness that information to become more invisible or repulsive to those pests. But I have digressed. After food leaves your mouth—where your teeth, saliva, enzymes, and friendly bacteria begin to break it up—it passes into your esophagus, a long tube that separates your mouth and pharynx from your stomach. No one thought bacteria resided in the esophagus until 2004, when we found a rich microbial community of dozens of species living there. Food then passes into your stomach, where digestion begins with the help of acid and digestive enzymes. Despite strong acidity, bacteria also live there, including H. pylori (mentioned earlier), which when present usually dominates. Other species may be found in lower abundance. Your stomach makes hormones as if it were a gland like the thyroid. Its wall contains immune cells that help fight infection, just like your spleen or lymph nodes and colon. H. pylori plays a role in the production of acid and hormones and the state of immunity. Next stop, your small intestine, a long tube that contains the major elements— detergents, enzymes, transporters—for breaking down and absorbing food into your body. This is where you digest most of your meals. Bacteria are present there, too, 28
although in relatively small numbers,perhaps because high levels of microbial activity could interfere with the critical functions of nutrient digestion and absorption. Eventually what remains of the food reaches your colon,where it finds wall-to- wall bacteria.Far and away,most of the microbes in your body live there.The numbers are astounding.One milliliter (about a thousandth of a quart)of colonic contents (and you have several thousand milliliters)contains many more bacteria than there are people on Earth.Your colon contains a universe of bacteria,densely packed,chemically active,accompanying you in your everyday journeys through life.You might think of this as part of the essential bargain of life:we provide them with room and board,and they help keep us alive.But that simplification is not entirely true.Many thousands of people have lost their colon and all of its bacteria because of illness or injury,yet they can live healthy lives for decades.So while this ocean of bacteria that you carry in your colon is very useful,it is not essential (As mentioned,the same cannot be said for your complete microbiome;its total loss likely would be catastrophic. The microbes in your colon break down fibers and digest starch.In one sense everything that has passed through to the end of your small intestine is on its way out,indigestible by you.But those hungry bacteria in your colon can metabolize quite a lot.They can digest the fibers in an apple that has passed through your small intestine and turn them into food-primarily to feed themselves-but some of their products,especially molecules called short-chain fatty acids,are released and actually feed you,starting with the cells in the wall of your colon.They nourish you,their innkeeper. Up to 15 percent of the calories present in your food are extracted by the guest bacteria in your colon and used to feed you.Like all our resident microbes,they are more than casual or random guests;we coevolved to help each other.Among all mammals,even ones that separated from one another tens of millions of years ago. there are remarkable similarities in the types of colonic bacteria and in their functions The gut environment is warm,wet,and oozy,with numerous different neighborhoods occupied by specialized microbes.Some that make particular vitamins might live in particular niches,whereas ones that turn starches into simple sugars may live in much larger neighborhoods.There is competition.As in cities prized parking spaces and spots in private schools are desirable.Many bacteria hungry for the same nutrients are equipped with identical enzymes and,like lions and cheetahs stalking the same prey,compete vigorously for similar foods.It seems to me that many want to lay their heads on the same soft layers of mucus and use the same limited number of hiding spaces protected from the harsh rain of stomach acid or bile.Meanwhile,many cells lining your gastrointestinal tract are sloughed off every day,so today's hiding place may be tomorrow's sinking ship.By the end, 29
although in relatively small numbers, perhaps because high levels of microbial activity could interfere with the critical functions of nutrient digestion and absorption. Eventually what remains of the food reaches your colon, where it finds wall-towall bacteria. Far and away, most of the microbes in your body live there. The numbers are astounding. One milliliter (about a thousandth of a quart) of colonic contents (and you have several thousand milliliters) contains many more bacteria than there are people on Earth. Your colon contains a universe of bacteria, densely packed, chemically active, accompanying you in your everyday journeys through life. You might think of this as part of the essential bargain of life: we provide them with room and board, and they help keep us alive. But that simplification is not entirely true. Many thousands of people have lost their colon and all of its bacteria because of illness or injury, yet they can live healthy lives for decades. So while this ocean of bacteria that you carry in your colon is very useful, it is not essential. (As mentioned, the same cannot be said for your complete microbiome; its total loss likely would be catastrophic.) The microbes in your colon break down fibers and digest starch. In one sense, everything that has passed through to the end of your small intestine is on its way out, indigestible by you. But those hungry bacteria in your colon can metabolize quite a lot. They can digest the fibers in an apple that has passed through your small intestine and turn them into food—primarily to feed themselves—but some of their products, especially molecules called short-chain fatty acids, are released and actually feed you, starting with the cells in the wall of your colon. They nourish you, their innkeeper. Up to 15 percent of the calories present in your food are extracted by the guest bacteria in your colon and used to feed you. Like all our resident microbes, they are more than casual or random guests; we coevolved to help each other. Among all mammals, even ones that separated from one another tens of millions of years ago, there are remarkable similarities in the types of colonic bacteria and in their functions. The gut environment is warm, wet, and oozy, with numerous different neighborhoods occupied by specialized microbes. Some that make particular vitamins might live in particular niches, whereas ones that turn starches into simple sugars may live in much larger neighborhoods. There is competition. As in cities, prized parking spaces and spots in private schools are desirable. Many bacteria hungry for the same nutrients are equipped with identical enzymes and, like lions and cheetahs stalking the same prey, compete vigorously for similar foods. It seems to me that many want to lay their heads on the same soft layers of mucus and use the same limited number of hiding spaces protected from the harsh rain of stomach acid or bile. Meanwhile, many cells lining your gastrointestinal tract are sloughed off every day, so today’s hiding place may be tomorrow’s sinking ship. By the end, 29
when the last products of digestion leave your body as feces,a mixture of bacterial cells is swept away along with the worn-out cells of your intestinal tract.Together, they and their fragments and water constitute the bulk of your stool. To give you a sense of their importance in your metabolism,consider that nearly all of the chemicals present in your bloodstream are derived from the activities of your microbes.Bacteria also digest lactose,make amino acids,and break down the fibers in strawberries or,if you eat sushi,the fibers in seaweed. Through their products,your microbes help you maintain stable blood pressure via specialized receptors located in your blood vessels (oddly,also found in your nose).These sensors detect small molecules created by the microbes that line your intestine.Responding to these molecules affects blood pressure.Thus,after eating your blood pressure may go down.Could we one day have better treatments for high blood pressure by harnessing these bacteria?Very possibly Bacteria metabolize drugs.For example,millions of people around the world take digoxin,derived from the foxglove plant,to treat various heart conditions How much of the drug reaches the bloodstream depends on the composition of each person's microbiome;the gut is where digoxin undergoes its first chemical processing and then absorption.Variations in the chemistry have consequences.If levels are too low,the drug does not work.If levels are too high,a patient can experience additional heart problems,changes in color vision,and upset stomach. In the future,doctors may be able to gain control over how much digoxin reaches the blood by taming or augmenting gut microbes. Some of your bacteria make vitamin K,which is necessary for your blood to clot but which is not made by your own cells.It may have been more efficient for the human body to rely on bacteria to produce vitamin K than to go through all of the metabolic costs in manufacturing it ourselves.so our ancestors who acaured vitamin K-producing bacteria were selected over cousins who had to invest in either making it or harvesting a substantial amount from plants.In a sense,our forebears outsourced a key metabolic function to our bacteria.We feed them and house them;they help clot our blood-a wonderful trade Some of your microbes even make an endogenous "Valium."People dying of liver cancer often fall into a coma.But if they are given an agent that inhibits benzodiazapines(such as the drug Valium),they wake up.This is because a healthy liver breaks down a natural form of Valium made by microbes in the gut,but a sick liver does not,and the homegrown Valium goes straight to the brain and puts the person to sleep.Other microbes known to live in New Guinea highlanders allow their hosts to live on a diet that is 90 percent sweet potato,which is low in protein. Like bacteria that thrive on the roots of legumes,gut microbes in these New Guinea tribes are able to make proteins from sweet potatoes.They convert or "fix' atmospheric nitrogen found in the highlanders'guts to make amino acids. 30
when the last products of digestion leave your body as feces, a mixture of bacterial cells is swept away along with the worn-out cells of your intestinal tract. Together, they and their fragments and water constitute the bulk of your stool. To give you a sense of their importance in your metabolism, consider that nearly all of the chemicals present in your bloodstream are derived from the activities of your microbes. Bacteria also digest lactose, make amino acids, and break down the fibers in strawberries or, if you eat sushi, the fibers in seaweed. Through their products, your microbes help you maintain stable blood pressure via specialized receptors located in your blood vessels (oddly, also found in your nose). These sensors detect small molecules created by the microbes that line your intestine. Responding to these molecules affects blood pressure. Thus, after eating, your blood pressure may go down. Could we one day have better treatments for high blood pressure by harnessing these bacteria? Very possibly. Bacteria metabolize drugs. For example, millions of people around the world take digoxin, derived from the foxglove plant, to treat various heart conditions. How much of the drug reaches the bloodstream depends on the composition of each person’s microbiome; the gut is where digoxin undergoes its first chemical processing and then absorption. Variations in the chemistry have consequences. If levels are too low, the drug does not work. If levels are too high, a patient can experience additional heart problems, changes in color vision, and upset stomach. In the future, doctors may be able to gain control over how much digoxin reaches the blood by taming or augmenting gut microbes. Some of your bacteria make vitamin K, which is necessary for your blood to clot but which is not made by your own cells. It may have been more efficient for the human body to rely on bacteria to produce vitamin K than to go through all of the metabolic costs in manufacturing it ourselves. So our ancestors who acquired vitamin K–producing bacteria were selected over cousins who had to invest in either making it or harvesting a substantial amount from plants. In a sense, our forebears outsourced a key metabolic function to our bacteria. We feed them and house them; they help clot our blood—a wonderful trade. Some of your microbes even make an endogenous “Valium.” People dying of liver cancer often fall into a coma. But if they are given an agent that inhibits benzodiazapines (such as the drug Valium), they wake up. This is because a healthy liver breaks down a natural form of Valium made by microbes in the gut, but a sick liver does not, and the homegrown Valium goes straight to the brain and puts the person to sleep. Other microbes known to live in New Guinea highlanders allow their hosts to live on a diet that is 90 percent sweet potato, which is low in protein. Like bacteria that thrive on the roots of legumes, gut microbes in these New Guinea tribes are able to make proteins from sweet potatoes. They convert or “fix” atmospheric nitrogen found in the highlanders’ guts to make amino acids. 30
In women,bacteria colonize and protect the vagina.Until recently medical scientists believed that only one group of bacteria,called lactobacilli,safeguarded the vagina in women of reproductive age from pathogens such as those that cause yeast infections.Indeed,lactobacilli shield the vagina by producing lactic acid, which lowers the pH of the vagina,making it slightly acidic and less hospitable to pathogens.It was assumed that those women whose vaginas are populated by different bacteria would be more prone to vaginal disorders.But now that DNA sequences of the vaginal bacteria from hundreds of healthy women are available. we know that there are five major types of vaginal microbiota,only four of which are dominated by a particular Lactobacillus.The fifth type essentially lacks Lactobacillus.A woman within this type has several other co-dominant bacterial species in her vagina,but contrary to long-held beliefs this does not make her more likely to develop vaginal disorders,and she is not part of a small minority.About a third ofall women have this so-called abnormal mix of vaginal microbes Women without lactobacilli have a slightly higher vaginal pH,but their bacteria are just as good as lactobacilli at creating an environment unfriendly to intruders This kind of functional substitution is probably occurring at sites all over the body, with different bacteria getting the same jobs done in different people. In addition,we have learned that the bacterial populations in each woman's vagina shift over time.For example,the bacterium L.iners may dominate during most of the month,but when a woman has her period,another bacterium,L.gasseri, will bloom,only to recede when her menses end.Seems straightforward enough but this sort of pattern is an anomaly.The most common pattern is that there is no obvious pattern.Sometimes bacteria shift dominance in the middle of a woman's cvcle and the next month late in the cvcle.Sometimes there are no changes.At other times Lactobacillus species take turns dominating the vagina in leapfrog fashion. And in some cases the "abnormal"bacteria dominate,only to disappear without apparent cause.We are still untangling the mystery of what drives these dramatic changes. Probably the most important service your microbes provide is immunity. In fact,your microbes constitute an important third arm of the immune system. First,there is innate immunity,based on the fact that most of the microbes with which we are in contact have structural patterns that are "seen"by proteins and cells that guard our surfaces.Then adaptive immunity is based on the recognition of highly specific chemical structures.And microbial immunity is based on the microbes that are already in your body,your long-term residents,inhibiting outsiders through various mechanisms.We'll explore each of these in more detail in 31
* * * In women, bacteria colonize and protect the vagina. Until recently medical scientists believed that only one group of bacteria, called lactobacilli, safeguarded the vagina in women of reproductive age from pathogens such as those that cause yeast infections. Indeed, lactobacilli shield the vagina by producing lactic acid, which lowers the pH of the vagina, making it slightly acidic and less hospitable to pathogens. It was assumed that those women whose vaginas are populated by different bacteria would be more prone to vaginal disorders. But now that DNA sequences of the vaginal bacteria from hundreds of healthy women are available, we know that there are five major types of vaginal microbiota, only four of which are dominated by a particular Lactobacillus. The fifth type essentially lacks Lactobacillus. A woman within this type has several other co-dominant bacterial species in her vagina, but contrary to long-held beliefs this does not make her more likely to develop vaginal disorders, and she is not part of a small minority. About a third of all women have this so-called abnormal mix of vaginal microbes. Women without lactobacilli have a slightly higher vaginal pH, but their bacteria are just as good as lactobacilli at creating an environment unfriendly to intruders. This kind of functional substitution is probably occurring at sites all over the body, with different bacteria getting the same jobs done in different people. In addition, we have learned that the bacterial populations in each woman’s vagina shift over time. For example, the bacterium L. iners may dominate during most of the month, but when a woman has her period, another bacterium, L. gasseri, will bloom, only to recede when her menses end. Seems straightforward enough, but this sort of pattern is an anomaly. The most common pattern is that there is no obvious pattern. Sometimes bacteria shift dominance in the middle of a woman’s cycle and the next month late in the cycle. Sometimes there are no changes. At other times Lactobacillus species take turns dominating the vagina in leapfrog fashion. And in some cases the “abnormal” bacteria dominate, only to disappear without apparent cause. We are still untangling the mystery of what drives these dramatic changes. * * * Probably the most important service your microbes provide is immunity. In fact, your microbes constitute an important third arm of the immune system. First, there is innate immunity, based on the fact that most of the microbes with which we are in contact have structural patterns that are “seen” by proteins and cells that guard our surfaces. Then adaptive immunity is based on the recognition of highly specific chemical structures. And microbial immunity is based on the microbes that are already in your body, your long-term residents, inhibiting outsiders through various mechanisms. We’ll explore each of these in more detail in 31