Epidemics: Reading #3


The Microbiome


Expanding Our View of the Human Microbiome

Dr. Francis Collins― Director, NIH

National Institutes of Health | September 26, 2017



[1] Many people still regard bacteria and other microbes just as disease-causing germs. But it’s a lot more complicated than that. In fact, it’s become increasingly clear that the healthy human body is teeming with microorganisms, many of which play essential roles in our metabolism, our immune response, and even our mental health. We are not just an organism, we are a “superorganism” made up of human cells and microbial cells—and the microbes outnumber us! Fueling this new understanding is NIH’s Human Microbiome Project (HMP), a quest begun a decade ago to explore the microbial makeup of healthy Americans.


[2] About 5 years ago, HMP researchers released their first round of data that provided a look at the microbes present in the mouth, gut, nose, and several other parts of the body. Now, their second wave of data, just published in the journal Nature, has tripled this treasure trove of information, promising to further expand our understanding of the human microbiome and its role in health and disease. For example, the new DNA data offer clues as to the functional roles those microbes play and how those can vary over time in different parts of the human body and from one person to the next.


[3] The human microbiome consists of a large, but still undetermined, number of microbes. While bacteria make up the majority of the bugs calling our bodies home, other residents include single-celled archaea and fungi. And there are several types of viruses, too, in the nose and gut of otherwise perfectly healthy people.


[4] Collectively, these bugs express millions of microbial genes, called a metagenome. The new data set includes over a million more gene families from the metagenomes than the first HMP data release, as the latest samples captured a wider swath of microbial diversity.


[5] Sequencing metagenomes allowed the researchers to consider the biochemical abilities and potential functions of the human microbiome. Although many genes and pathways in the microbiome are not yet biochemically characterized, 19 pathways were enriched across all of the body sites examined. That means they occur specifically in groups of microbes that are adapted to live in and on human beings.


[6] Those relatively host-specific gene pathways are likely to point the way to functional adaptations important for the microbes’ ability to live in harmony with humans and even to provide benefits to their human hosts. For example, the microbial metagenomes found in multiple body sites appear to have a special ability to synthesize vitamin B12, which is essential to human health.


[7] Other specialized features were specific to particular parts of the human body. For instance, microbes found in the mouth were enriched for genes involved in the chemical modification of nitrates in our diets to nitrites, a process that has been linked to blood pressure regulation and prevention of migraines, among other health conditions. Gut microbes have a special ability to break down mannan, a carbohydrate found in many vegetables.


[8] There were other intriguing observations, too. Haemophilus parainfluenzae has long been known to inhabit the upper respiratory tract and play a role in bronchitis and sinusitis. But the researchers found unexpectedly the bacterium also resides in multiple parts of the mouth. The specific strain varied depending on whether the microbial sample was collected from a person’s cheek, tongue, or tooth surfaces. It suggests the H. parainfluenzae found on my cheek could be more similar to the one found on your cheek than it is to the one on my tongue!


[9] Interestingly, researchers found no characteristic differences in the metagenomes of people in Houston and St. Louis, where study participants lived. Whether this holds for cities across the country will be fascinating to find out. Some of the microbes in a particular person’s gut tended to remain stable over time, while others were much more variable. Surprisingly, however, those core microbes often varied considerably from one person to the next. In other words, the gut microbiomes of people—even those living in the very same city—can contain a highly personalized set of bugs with as-yet undetermined implications for our health.


[10] In total, the new data include an additional 1,631 metagenomes, bringing the complete HMP collection to 2,355 metagenomes. The new metagenomes, gathered from 265 healthy volunteers, represent the complete set of microbial DNA sequences collected from each of six different body sites. These include the edge of the nostrils, inside of the cheek, surfaces of the teeth and tongue, gut, and, in women, a recess of the vagina found behind the cervix.


[11] The latest data release was a true group effort, led by Curtis Huttenhower at the Harvard T.H. Chan School of Public Health, Boston, MA, and The Broad Institute, Cambridge, MA. The team also included Jason Lloyd-Price, also at The Broad Institute, and Anup Mahurkar at the University of Maryland Institute for Genome Sciences, Baltimore.


[12] In addition to our genes, lifestyles, and experiences, our microbiomes are a part of what makes each of us unique. They may also help to explain why some people are more prone to certain illnesses than others. As we learn more in the coming years about the microbial differences that may predispose individuals to good health or illness, one thing is now abundantly clear: microbes are an essential part of us.


Introduction to the Human Microbiome

American Microbiome Institute



[1] The human microbiome refers to the assemblage of microbes that live in the human body.  While these microbes inhabit all parts of our body that are exposed to the environment, such as the skin, mouth, and vagina, most reside in the gut where they have a constant supply of nutrients. Taken collectively, these organisms outnumber our own human cells 10 to 1, making up 5 pounds of our body weight.  We have evolved with these bacteria, passed down from mother to child, for hundreds of millions of years, and scientists are now uncovering the significant role they play in human health.


[2] Nearly every scientific study performed that has attempted to correlate the microbiome with specific traits or diseases has been successful.  In other words studies are finding that our bacteria (or lack thereof) can be linked to or associated with: obesity, malnutrition, heart disease, diabetes, celiac disease, eczema, asthma, multiple sclerosis, colitis, some cancers, and even autism.


Influence on the immune system

[3] In early life the gut bacteria play an integral role in the formation of a strong human immune system, especially during early childhood as our adaptive immune system develops.  During this time the immune system becomes accustomed to foreign antigens in our body and develops a tolerance to them.  Once a homeostasis is established, non-pathogenic microbes and other harmless antigens will not induce an inflammatory response.  It is this inflammatory response that has been linked to autoimmune diseases and allergies.  This concept is especially illustrated in germ-free mice; that is mice which are kept sterile throughout life.  These sterile mice are especially unhealthy and have drastically underdeveloped immune systems.  They suffer from autoimmune diseases and exhibit undesirable traits. 


[4] An important consequence of these findings is that the initial gut microbiome of an infant can have a lasting effect on his or her health.  Scientists have compared babies delivered by C-section, where the newborn is colonizing the mother’s skin biome and babies delivered vaginally, where the newborn is colonizing the mother’s vaginal and gut biomes. Those delivered by C-section have a greater likelihood of developing allergies and obesity than their vaginally-delivered counterparts..


Influence on nutrition

[5] Other research has examined the role the gut microbiome has on nutrition and obesity.  Our gut bacteria are responsible for breaking down many of the complex molecules found in foods such as meats and vegetables.  These bacteria not only harvest energy for themselves from the plants we eat, but also break down the plants into smaller molecules which our body is able to digest.  A simple study in mice showed that certain bacteria were associated with obesity and others with normal weight. 

[6] Surprisingly, when obese mice were given the gut microbiome of normal mice, the obese mice lost weight.  The reverse was also true; that is, when normal mice were given the microbiome of obese mice, the normal mice gained weight.  Similar studies using human twins, disparate in weight, with similar upbringings and identical genomes, showed the same association between obesity and gut microbiome. 


[7] Research has shown a direct relationship between diet and the abundance of certain gut microbial communities.  For example, vegetarians have gut flora that are better equipped to break down plant roughage, making otherwise indigestable molecules such as cellulose available for humans.  During bacterial metabolism of these complex molecules chemical signals are released that end up in our brains and can affect behavior.  This has led some scientists to speculate that the gut microbiome may cause cravings for certain foods and influence dietary choices.


Influence on disease

[8] The gut microbiome is now being implicated in many gastrointestinal diseases, especially those that are symptom based, such as Crohn’s disease, ulcerative colitis, and inflammatory bowel syndrome.  Each of these debilitating diseases has strong links to shifts in bacterial gut populations.  While the microbiome is normally quite robust, the ingestion of antibiotics, as well as sustained diarrhea can permanently alter our flora as new bacteria repopulate the gut.  For example, populations of C. difficile, which are low in a healthy gut, can explode if antibiotics destroy all competing bacteria.  C. difficile infection causes diarrhea and flu-like symptoms that can lead to death if not properly treated.  One therapy to treat C. difficile that has already proven effective is a microbiome transplant from a healthy donor.  As new bacterial populations take hold in the gut, the patient recovers.


Influence on behavior

[9] Recent research is beginning to unveil perhaps the most interesting influence the microbiome has on its host: behavior.  There are many nerve endings that are located around the gut which transmit signals directly to the brain via the vagus nerve.  It is speculated that the metabolites and other small molecules that are released from bacteria can affect everything from taste to mood.  In fact, in one study scientists swapped the microbiome of risk-taking mice with cowardly mice and their risk-aversion swapped as well.  Other studies have hypothesized that the kinds of food we crave and taste good to us may also be dictated by the population in our guts, and may even be related to that population's ability to utilize particular foods for energy.  Finally, diseases such as depression and autism have also been linked to the microbiome.


Why Antibiotics Are Making Us All Ill

Martin Blaser

The Guardian | June 1, 2014


[1] My father had two sisters I never knew. In the little town where they were born, early in the 20th century, they did not see their second birthdays. They had fever. The situation was so dire that my grandfather went to the prayer house to change his daughter's name to fool the angel of death. This happened twice. It did no good.


[2] In 1850, four in 10 English babies died before their first birthday. Lethal epidemics swept through crowded cities, as people were packed into dark, dirty rooms with fetid air and no running water. Familiar scourges included cholera, pneumonia, scarlet fever, diphtheria, whooping cough, tuberculosis and smallpox.


[3] Today, fewer than five of every thousand infants in Britain are expected to die before the age of one – a remarkable improvement. Over the past 150 years, most countries have been getting healthier. Chalk it up to improved sanitation, rat control, clean drinking water, pasteurised milk, childhood vaccinations, modern medical procedures and, of course, 70 years of antibiotics. In today's world, children grow up without deformed bones or "cloudy" sinuses from infections. Nearly all women survive childbirth. Eighty-year-olds, once consigned to the veranda, are swatting tennis balls, often with the help of a metallic hip joint.


[4] Yet recently, just within the past few decades, amid all of these medical advances, something has gone terribly wrong. In many ways, we appear to be getting sicker. You can see the headlines every day. We are suffering from an array of what I call "modern plagues": obesity, childhood diabetes, asthma, hay fever, food allergies, oesophageal reflux and cancer, coeliac disease, Crohn's disease, ulcerative colitis, autism, eczema. In all likelihood, you or someone in your family or someone you know is afflicted. Unlike most lethal plagues of the past that struck relatively fast and hard, these are chronic conditions that diminish and degrade their victims' quality of life for decades. The most visible of these plagues is obesity.


[5] Britain is the fattest nation in western Europe, with more than a quarter of the population ranked obese. The UK figure of 26.1% is more than twice that of France, at 12.9%; the Australian rate is even higher, at 28%. Next time you go to an airport terminal or supermarket, look around and see for yourself. The obesity epidemic is global. As of 2008, according to the World Health Organisation, 1.4 billion adults were overweight; of these, more than 200 million men and nearly 300 million women qualified as obese. Many of these people live in developing countries that we associate more with famine than overeating.


[6] These figures are alarming but what is really shocking is that this global human body fat accumulation has been accelerating not over the course of a few centuries, but in a mere two decades. Yet fat- and sugar-rich foods, so often blamed for all the extra pounds, have been ubiquitous for a good deal longer than that, at least in the developed world, and the new generations of overweight people in the developing world have not suddenly adopted a Kentucky-fried, American-style diet. Epidemiological studies have shown that high caloric intake, while definitely not helpful, is not sufficient to explain the distribution or course of the worldwide obesity epidemic.


[7] At the same time, the autoimmune form of diabetes that begins in childhood and requires insulin injections (juvenile or type 1 diabetes) has been doubling in incidence about every 20 years across the industrialised world; in Finland, where record-keeping is meticulous, the incidence has risen by 550% since 1950. This increase is not because we are detecting type 1 diabetes more readily. Before insulin was discovered in the 1920s, the disease was always fatal. Nowadays, with adequate treatment, most children survive. But the disease itself has not changed; something in us has changed. Type 1 diabetes is also striking younger children. The average age of diagnosis used to be about nine. Now it is around six, and some children are becoming diabetic when they are two.


[8] The recent rise in asthma, a chronic inflammation of the airways, is similarly alarming. There are 5.4 million people with asthma in the UK, affecting one in five households. One in 12 adults is afflicted. One in every 11 children suffers from the wheezing, breathlessness, chest tightness and coughing emblematic of asthma. Two million Australians, 10% of the population, also suffer from the condition. The rate of childhood asthmas increased by 50% from 2001 through 2009 in the US, and the rise in asthma did not spare any ethnicity; the rates were initially different in various groups, and all have been rising.


[9] Asthma is often triggered by something in the environment such as tobacco smoke, mould, air pollution, cockroach droppings, colds and flu. Once an attack begins, asthmatics gasp for air and, without rapid access to medication, are rushed to emergency rooms. Even with the best care, they can die.


[10] Food allergies are everywhere. A generation ago, peanut allergies were extremely rare. Now, if you stroll through any preschool, you will see walls plastered with "nut-free zone" bulletins. More and more children suffer immune responses to proteins in foods, not just in nuts but in milk, eggs, soy, fish, fruits– you name it, someone is allergic to it. Coeliac disease, an allergy to gluten, the main protein in wheat flour, is rampant. More than a third of British teenagers and 15% of Australians suffer from hay fever. Eczema, a chronic skin inflammation, affects more than 15% of children in the US and 30% of Australian infants develop it in their first year.


[11] These disorders suggest that our children are experiencing levels of immune dysfunction never seen before. And then there's autism– a much discussed and debated modern plague that is a focus of my laboratory. Nor are adults escaping these modern plagues. The incidence of inflammatory bowel disease, including Crohn's and ulcerative colitis, is rising. When I was a student, oesophageal reflux, which causes heartburn, was uncommon. But the ailment has exploded in these past 40 years, and the cancer it leads to, adenocarcinoma of the oesophagus, is the most rapidly increasing cancer in many developed countries, and is a particularly nasty problem, especially for men.


[12] Why are all of these maladies rapidly rising at the same time across the developed world and spilling over into the developing world as it becomes more westernised? Can it be a mere coincidence? If there are 10 of these modern plagues, are there 10 separate causes? That seems unlikely. Or could there be one underlying cause fuelling all these parallel increases? A single cause is easier to grasp; it is simpler, more parsimonious. But what cause could be grand enough to encompass asthma, obesity, oesophageal reflux, juvenile diabetes, and allergies to specific foods, among all of the others? Eating too many calories could explain obesity, but not asthma– in which many of the ill children are slim. Air pollution could explain asthma but not food allergy.


[13] Many evidence-free theories are floated to explain each disorder. Lack of sleep makes you fat. Vaccines lead to autism. Genetically engineered wheat strains are toxic to the human gut. And so on. The most popular explanation for the rise in childhood morbidity is the so-called hygiene hypothesis. The idea is that modern plagues are happening because we have made our world too clean. The result is that our children's immune systems have become quiescent and are therefore prone to false alarms and friendly fire. A lot of parents these days try to ramp up their kids' immune systems by exposing them to pets, farm animals, barnyards, or better still, by being pleased when they eat dirt.


[14] I beg to differ. To me, such exposures are largely irrelevant to our health. The microbes carried by soil have evolved for soil, not for us. The microbes in our pets and farm animals also are not deeply rooted in our human evolution. The hygiene hypothesis has been misinterpreted.


[15] Rather we need to look closely at the micro-organisms that make a living in and on our bodies – massive assemblages of competing and co-operating microbes known collectively as the microbiome. In ecology, a "biome" refers to the sets of plants and animals in a community, such as a jungle, forest, or coral reef. An enormous diversity of species, large and small, interact to form complex webs of mutual support. When a "keystone" species disappears or goes extinct, the ecology suffers. It can even collapse.


[16] Each of us hosts a similarly diverse ecology of microbes that, over eons, co-evolved with our species. They thrive in the mouth, gut, nasal passages, ear canal and on the skin. In women, they coat the vagina. The microbes that constitute your microbiome are generally acquired early in life; surprisingly, by the age of three, the populations within resemble those of adults. Together, they play a critical role in your immunity and ability to combat disease. In short, your microbiome keeps you healthy.


[17] And parts of it are disappearing. The reasons are all around us, including overuse of antibiotics in humans and animals, caesarean sections, and the widespread use of sanitisers and antiseptics, to name just a few. Mothers give their microbes to their babies when they pass through the birth canal, but babies born by C-section miss that.


[18] While antibiotic resistance is a huge problem– old killers like tuberculosis are increasingly resistant and making a comeback – there seems to be a separate problem, affecting people with such scourges as Clostridium difficile, a multiple-antibiotic-resistant bacteria of the digestive tract, and Methicillin-resistant Staphylococcus aureus (MRSA), a spreading pathogen. In the presence of antibiotics, the resistant organisms are the ones more fit; it is the pressure of intensive antibiotic use that is increasing the presence of these resistant organisms. The antibiotics I take affect the level of resistance of the bacteria in the entire community. In that sense, antibiotics are unlike all other drugs – my heart medicine does not affect anyone but me.


[19] But as terrible as these resistant pathogens are, the loss of diversity within our microbiome is far more pernicious. Its loss changes development itself, affecting our metabolism, immunity, and possibly even our cognition. Microbes in our guts have a role in the production of some of the building blocks of the brain, as well as the molecules that provide signals from one brain cell to another.


[20] I have called this process "the disappearing microbiota". For multiple reasons, we are losing our ancient microbes. This quandary is my central theme. The loss of microbial diversity on and within our bodies is exacting a terrible price. I predict it will be worse in the future. Just as the internal combustion engine, splitting the atom, and pesticides all have had unanticipated effects, so, too, does the abuse of antibiotics and other medical or quasi-medical practices (eg sanitiser use).


[21] An even worse scenario is heading our way if we don't change our behaviour. It is so bleak, like a blizzard roaring over a frozen landscape, that I call it "antibiotic winter". We know that the "good bacteria" protect us against the "bad" ones, the pathogens that we may encounter over the course of a lifetime. As our populations of good bacteria become depleted, our susceptibility to the bad ones grows. I don't want the babies of the future to end up like my poor aunts. That is why I am sounding an alarm.


[22] But in my lab, we are not waiting; we are working on solutions. We have more than 20 projects, examining how antibiotics affect resident microbes and their hosts, both in mice and humans. In a typical animal experiment, we give mice antibiotics in their drinking water and compare them with mice that do not get the drugs. We start early in life, sometimes just before birth, and then we let the mice grow, studying how fat they become, how their livers are working, how immunity is developing, how their bones are growing, and what happens to their hormones and to their brains.


[23] From seeing the changes induced by these exposures to antibiotics, we have realised that early life is a key window of vulnerability. Young children have critical periods for their growth, and our experiments are showing that the loss of friendly gut bacteria at this early stage of development is driving obesity. We have found this in mice and we have found that human children (in England, participants in the Avon longitudinal study of parents and children) who received antibiotics in the first six months of life were more likely to be fatty at the age of seven years than children who didn't receive antibiotics during that same period, when we took into account other important factors.


[24] Ultimately we hope to apply our findings from mouse studies to humans. We seek to reverse the damage seen in people around the world, including establishing strategies for putting back the missing microbes. A key step in every approach is to reduce overuse of antibiotics in our children, starting now. My odyssey as a doctor and scientist for more than 41 years has given me important perspectives about our modern plagues, and a full slate of solutions. This is a challenge we can and must meet.