September 2013
Introduction
The human microbiome is composed of the microbes, as well as their genes and genomes, that live in and on the human body. Scientists are discovering just how important these resident microbes are to our health and well-being, particularly with respect to the roles they play in maintaining our immune systems, contributing to the digestion of our food, and acting as a first line of defense against pathogens. There are many diseases that may be the result of disturbed microbiomes; however, microbiome-based medical treatments and applications are on the horizon.
The Human Microbiome: Our Other Genome
Throughout most of human history we have felt at war with microbes. Bubonic plague, small pox, yellow fever, and typhoid are just a few important examples of historic agents of change, while modern day infectious diseases include malaria, tuberculosis, cholera and HIV/AIDS, to name a few. The scientific study of microbiology, which led to important discoveries such as Louis Pasteur’s “germ theory of disease,” grew out of society’s desire to conquer these pathogens and eradicate infectious diseases. But a new view is emerging in which the metaphors for war (“the only good bug is a dead bug”) are no longer appropriate; instead, we now view humans and microbes as a co-evolved system for the mutual benefit of both the host and resident microbes. But if microbes are germs then how do we benefit from them? In fact, most of the microbes we come in contact with are not germs, but beneficial microbes that digest many things in our diet—like vegetables—that we could not digest without microbial enzymes, provide energy for our metabolism, make essential vitamins, and act as a first line of defense against potential pathogens (i.e., germs). Although we use the general term “microbe,” which is often thought to be synonymous with bacteria, we now know the human microbiome is primarily composed of bacteria, but also includes numerous and diverse viruses, fungi and protozoa.
In current understanding, the human body is made up of about 10 times more microbial cells (~1014) than human cells (~1013). Further, there may be millions more microbial genes than human genes in this human+microbiome system (which is often thought of as a human ‘superorganism’), and it is the ways in which these microbial genes interact with the human host that describe their ultimate role in our health.1 Scientists now believe that infants are sterile (meaning free of microbes) in the womb and receive their first inoculum of microbes from the mother during natural childbirth. This inoculum goes on to colonize the newborn and initiate a succession of events leading to the development of the child’s own microbiome. The newborn relies on this maternal vaginal microbial inoculum and the additional inoculum of microbes from mother’s breast milk for microbial colonization of all exposed surfaces in and on the infant’s body (e.g., oral, nasal/airways, gut, urogenital, skin).2 This is a dynamic process in which microbial abundances increase from effectively zero at birth to over six orders of magnitude (that’s more than a million times!) within just the first few weeks of life, with wide swings in the microbial membership of these communities until the microbiota largely stabilize in composition and numbers after approximately three years of life.3
Figure 1: The characteristics of human microbiota change over time in response to varying environmental conditions and life stages. Image courtesy: US National Library of Medicine. Image source: Ottman N, Smidt H, de Vos WM and Belzer C (2012) The function of our microbiota: who is out there and what do they do? Front. Cell. Inf. Microbio. 2:104. doi: 10.3389/fcimb.2012.00104.
At the same time, the newborn’s gut microbiota trigger development and maturation of the newborn’s immune system. Although there is still a great deal of research needed to understand precisely what happens in this developmental process, it appears the maturing immune system relies on the presence of microbial communities, and especially the presence of these early microbes, to distinguish “self” from “nonself.”4 It is these particular microbes that shape our immune systems. Once the immune system has matured, it will consult its “memory banks” if another microbe is encountered in order to determine if this microbe is considered “self” or “nonself” and to mount defenses against the microbe if it is recognized as a pathogen.5
Figure 2: Diagram of the human body showing the relative abundances of various types of microbes in each region. Image credit: Darryl Leja, NHGRI
Most of these microbes are growing in our large intestine, but each region of our body has its own distinct community of microbes living in or on it. For example, we have a particular kind of microbial community that prefers to grow on our skin or in our nose. Our mouths have a rich mixture of microbes, with specific microbes that prefer our teeth versus those that prefer our gums. Even though your tongue is in constant contact with the roof of your mouth, the microbes growing on the roof of your mouth are, in fact, very different from those growing on your tongue. We’re still trying to understand which factors regulate microbial colonization in areas of the body that are just millimeters apart.
It’s thought that what we eat, combined with our hormones, bodily fluids, skin oils, genetic makeup, where we live, and many other factors, contribute to the colonization and growth of these microbes. Bathing, washing your hair, washing your hands, and brushing your teeth remove some microbes, but they eventually grow back. And it’s thought that each of us has our own personal group of microbial species and strains (meaning microbial subspecies) that make our bodies their only homes. In other words, each of us supports a unique group of microbes that are ours and ours alone. How do you feel about having your own “personal” microbes?
Good Bugs Gone Bad? Or, What Upset the Microbial “Apple Cart?”
At the same time we are beginning to appreciate the microbiome, scientists are also growing concerned about things we are doing that may disturb this delicate system. Antibiotic use is just one example of a common medical practice that may be altering the human microbiome by reducing, removing, or changing fundamental elements. Antibiotics have been in broad use for treating infectious diseases in humans for over 70 years and are also used at subtherapeutic levels to stimulate meat production in livestock. As with vaccines, antibiotics have proven to be a very important medical advance, effectively eliminating many infectious diseases that have plagued human history. Today, as a result of antibiotics and vaccines, children do not die of the infectious diseases that killed them even 50 years ago. However, routine use of antibiotics may cause collateral damage to our microbial flora in two ways: through the unintended death of nontargeted bacteria and through the emergence of antibiotic-resistant bacteria.6
Figure 3: The evolution of antibiotic resistance through natural selection. Image credit: University of California Museum of Paleontology – Understanding Evolution
Antibiotic resistance develops when bacteria are exposed to sublethal doses of an antibiotic that do not kill them but, instead, allow them to develop genetic resistance against the antibiotic. Exposure to sublethal doses of antibiotics occurs when patients don’t take the full regimen of prescribed antibiotics or when the bacteria are exposed to antibiotic doses that aren’t high enough to cause complete bacterial mortality. The development of antibiotic resistance means that microbes aren’t eradicated when exposed to the same antibiotic at therapeutic doses during subsequent infections. Moreover, antibiotics can have unintended consequences and kill off beneficial bacteria in our microbiomes that are not the original target of the antibiotic—so-called “nontarget bacteria.”
There is thought to be a relationship between the theorized disturbance of the human microbiome through antibiotic use and the unexpected rise in autoimmune diseases and allergies, particularly in Western countries. Autoimmunity is the failure of our own immune systems to distinguish “self” from “nonself.” This failure can lead to an immune response being mounted against our own cells and tissues. Examples of autoimmune diseases include rheumatoid arthritis, lupus, diabetes and celiac disease. The current line of thinking is that loss of normal microbiome constituents through antibiotic use may remove the necessary trigger for normal immune system development. As a result, an underdeveloped immune system might possibly allow autoimmune diseases to develop. Currently, much research is being conducted to better understand the relationship between the human microbiome and autoimmune diseases, and to find better treatments and cures.7
Beyond antibiotic use, what might be other possible impacts of modern societal practices on the human microbiome? The “disappearing microbiota hypothesis” postulates that, as a consequence of routine customs in modern societies—such as clean water, sanitation, caesarean birth and antibacterial soaps—practiced over many generations, the normal inoculum on which the newborn is dependent for microbiome and immune system development has become depleted in the mother.8 This hypothesis further suggests that we might be losing key members of our normal microbiome, generation after generation, because of the increasingly impoverished microbiomes of mothers, resulting in a cumulative loss of the normal microbiota needed to support human health. Whether this hypothesis is supported awaits rigorous scientific testing, but it does help frame the question of why we are currently seeing epidemics in autoimmune diseases that have been relatively rare throughout human history. Perhaps disturbances to our microbiome are key to understanding why these diseases are increasing; in turn, this understanding may lead to the treatment and, ultimately, prevention of such diseases.
Medical Applications for the Microbiome Coming Soon
The preceding paragraphs may have painted a gloomy picture for our future health and well-being but, in fact, the future is bright for practical microbiome-based applications that promote human health and treat disease. This promise lies in the key property of the microbiome: its changeability. Our microbiomes are quite dynamic over our lifetimes and change with respect to both the numbers of microbes and their membership. Some appear to be essential members, always present in the microbial communities, while others appear to be transients, coming and going over days, weeks, and even years. Why is this property of changeability so useful? It means we can develop treatments that focus on altering the microbiome from one that appears to be unbalanced, or not functioning optimally, to one that eradicates disease and/or restores health by changing the membership or number of microbes in a deliberate and controlled fashion. Two examples of how scientists have exploited this dynamic property to treat disease and support health illustrate how microbiomes are being incorporated in modern medical practices.
Figure 4: A micrograph showing Clostridium difficile bacteria. Image Courtesy Centers for Disease Control and Prevention Public Health Image Library, Photo credit: Janice Carr.
Many patients in hospitals often acquire secondary infections because they are already sick and have weakened immune systems. In addition, many of these patients are given antibiotics to fight such infections. It is this combination of factors that can lead to a serious gastrointestinal infection from a bacterium known as Clostridium difficile. This bacterium can take over the gastrointestinal tract if resident microbes are eliminated or reduced, such as through antibiotic usage, and cause severe diarrhea and dehydration in the patient. Some patients can recover from C. difficile infections if they stop taking antibiotics, but many do not, and even patients who do recover can experience recurring infections and become weaker with each bout.
A recently-revived medical therapy– bacteriotheraphy or fecal transplants – has had tremendous success in treating patients with C. difficle infections by taking full advantage of the human microbiome’s changeability. Fecal transplants, in fact, are procedures that are just what they sound like: transplants of the gut microbiome, in the form of stool transfers, from a healthy person to a patient. Typically, a fresh stool sample is collected from a healthy family member, blended to liquid, and given to the patient through a colonoscope, an enema or even a tube inserted through the nose. Patients generally appear to show recovery from the C. difficile infection within two weeks. This treatment was first practiced in the 1950s and has recently returned as the treatment of choice for patients with C. difficile infections. Through DNA sequencing, we are now beginning to understand that adding a healthy person’s gut microbiome to a sick person’s gastrointestinal tract leads to a reversal of the bacterial imbalance that caused the disease in the first place, effectively re-establishing the patient’s microbiome to one that can resist attack by C. difficile.9
Fecal transplants illustrate that we have changeable, reversible microbiomes and these treatments appear to have a greater than 90% success rate in treating C. difficile infections. However, because many people find the notion of fecal transplants so unpleasant, scientists are also developing alternative mixtures of microbes thought to be beneficial to humans by isolating them from the human microbiome, thereby creating ‘defined species’ gut microbial transplant mixtures. These mixtures may be superior in treating infections because any potential pathogens have been removed, making the procedure safer in the long run. You can expect to hear more about this medical treatment in the years to come.
Many doctors are learning that patients recover faster if their microbiomes are protected. An excellent example of this comes from research involving the treatment of cancer patients. Radiation and chemotherapy cause collateral damage because they kill healthy cells in addition to cancer cells; this is why these treatments are so difficult to endure, as they also kill the patients’ microbiomes in the process. As doctors have begun to realize this, some have started saving their patients’ microbiomes, a process akin to a patient storing their blood in anticipation of upcoming surgery. In the case of cancer patients, doctors collect and store the patients’ gut microbiomes, again in the form of stool, prior to treatment. Once the cancer treatments are stopped, doctors re-inoculate the patients with their own microbiomes via a procedure similar to the fecal transplants, as described above. In this way, cancer patients receive a fresh inoculum of their own microbiota, allowing their microbiomes to quickly become re-established and shortening their recovery time.
There are many other areas in which the changeable properties of the microbiome are being employed, including vaccine development, pharmaceuticals, and even dietary supplements such as probiotics or prebiotics. These latter two microbiome-based applications will give the reader a taste of what is coming down the road.
Most of us think of yogurt when we think of probiotics. Probiotics are “live microorganisms which when administered in adequate amount confer a health benefit on the host” (as defined by the UN’s Food and Agriculture Organization). However, exactly how yogurt confers a health benefit or how the microorganisms in yogurt interact with the gut microbes to confer a health benefit remain areas of active research. A science-based understanding of how probiotics actually work to confer health is rapidly moving this field forward. As a result of such research, you can expect to see many more sophisticated, science-based probiotic products in your drug store and on your grocery store shelves.
Figure 5: Microbiome products include probiotics and prebiotics. Image source: Science in Our World: Certainty and Controversy, Marisa Cara Fraimow under Creative Commons License
Related microbiome-based products involve prebiotics. According to the International Scientific Association for Probiotics and Prebiotics, a prebiotic is “a selectively fermented ingredient which results in specific changes in the composition and/or activity of the gastrointestinal microbiota, thus conferring health benefits to the host.” Fermentation is a metabolic process carried out by microbes that prefer to grow in the absence of oxygen, such as those bacteria found in the gut. The concept behind prebiotics is that beneficial members of your gut microbiome preferentially use these microbial growth substances. If you consume a favorable prebiotic then you preferentially stimulate the beneficial microbes, thereby promoting improved digestive function. The science-based study of prebiotics is also growing rapidly and employs knowledge of the preferred fermentable substrates used by beneficial microbes to design prebiotics that target these beneficial microbes. The prebiotics in human breast milk are also undergoing intense study, as it is widely believed that breastmilk contains nature’s best prebiotics.
The study of the human microbiome is still in its infancy but already we are seeing products that we can use in our daily lives. We have started to recognize the critical and integral role of the microbiome in our health and well being, as well as the need to consider these resident microorganisms as a part of the human body. Applications from microbiome research are growing at a tremendous rate because we are exploiting the changeable property of the microbiome. The present is a wonderful time to learn more about your body and the trillions of your closest (microscopic) friends. I hope this essay whets your appetite to learn more.
