Human Interactions with Microbes

In America, and indeed in many other highly developed countries, people tend to be somewhat concerned about the amount of microorganisms they interact with on a daily basis. Ethanol based hand scrubs and antibacterial soap are ubiquitous in American homes and public places, and some people go beyond the reasonable bounds of normal hygiene in an effort to rid themselves of microbes. With the exception of certain people with psychiatric conditions, of course, the majority of these people are hoping to maintain a clean environment in order to avoid getting diseases, as it is well understood that infectious diseases are caused by bacteria, viruses, and other microbial organisms. Scientific studies are, however, demonstrating that the microbes you interact with on a daily basis are not exclusively harmful, and indeed that it is only a small subset of pathogenic microbes that are of concern. The vast majority of microorganisms live in a mutualistic relationship with their hosts and many of the serve important and even essential functions in normal biology. Thus the practice of maintaining a constantly hermetically clean environment out of a misguided germophobia can in fact have consequences for human health and disease that are quite the opposite of the intended and expected outcome.

Pathogenic Microbes

The majority of people, particularly those not familiar with contemporary immunological or ecological research, think of bacteria (and viruses/parasites) as organisms that exist exclusively at a cost to normal health and happiness. While one cannot accurately ascribe malevolent intent to microbes as they exist exclusively to reproduce and they are often able to best reproduce inside of other living organisms, we all anthropomorphize and vilify them from time to time. This is because the microbes that we tend to notice are the ones that make us sick or otherwise impede our normal lives and make us suffer in misery for days or weeks at a time. These are the most salient microscopic life forms we encounter in the world, and they cost millions of lives and billions of dollars in health care costs and lost productivity every year. But how is it that these microbes come to be pathogenic? Indeed the answer is not always trivial, and at times it can be the fault of our own bodies responding to the microbes rather than they themselves that cause us to become sick. It is essential that one understand how the pathogenic species of bacteria and viruses most familiar to us cause disease in order to fully appreciate how it is that so many others cause us no discernible problems whatsoever.

In some cases, bacteria directly cause extensive damage their hosts, and it is this damage that represents the symptoms we feel when we are sick with these organisms. Particularly vigorous examples of such microbes are those that produce toxins that, as the name would suggest, elicit toxic effects on our bodies. For example the cholera bacteria produces the eponymous cholera toxin which acts on the cells of the gut in such a way as to disable certain mechanisms at the cellular level resulting in the release of calcium and sodium ions into the gut lumen. This release triggers the release of water from the surrounding cells, as the water moves in a direction aimed at equalizing concentrations of these ions through a process known as osmosis. This abundant efflux of water into the gut results in the extreme diarrhea and dehydration that characterizes the cholera illness. Similarly, the botulinum bacteria that causes botulism releases a toxin - botulinum toxin, also known by the brand name Botox - that acts on nerve cells in such a way as to shut them down. This can result in systemic paralysis and death as occurs in those affected by botulism, or may be used for therapeutic or cosmetic effects when administered to specific sites in carefully controlled doses. These toxins can have devastating effects owing to their abilities to directly disrupt cellular processes and consequently cause chaotic symptoms.

Other microbes are able to directly cause damage to the body through their life cycles without the involvement of any known toxins. These microbes generally cause extensive damage while they replicate, resulting in a breakdown of normal tissue homeostatic mechanisms. This can result in systemic organ failure and shock if, for instance, bacteria make it into the bloodstream in sufficient numbers. The presence of microbes in a particular body site triggers an inflammatory response that helps to clear the infection. High levels of microbes in the blood trigger this inflammatory in a disseminated fashion throughout the body, causing extensive clotting, multiple organ failure, and septic shock. Viruses can directly kill the cells they infect during their replication cycles. For example, the highly virulent Ebola virus replicates in the cells lining the inside of blood vessels (the vascular endothelium). As it replicates, it takes over the protein production machinery inside these cells and prevents them from functioning normally. Newly formed viral particles then begin to bud from the cells and in the process they destroy these cells. If enough cells are destroyed by the virus in this fashion, there is a loss of vascular integrity which causes the extensive hemorrhages that characterize Ebola infections. This also triggers the body to instigate an inflammatory response that aims to clear the virus but ultimately causes more damage than it prevents.

As alluded to above, much of the damage that originates from infection with pathogenic organisms is the result of the inflammatory responses of the body to infection rather than from a direct action of the virus or bacteria itself. The reason for this is simple - your immune system goes to great length to destroy or neutralize any foreign invading pathogens. In order to effectively remove the offending agent, you need to recruit white blood cells that can actively kill bacteria or, in the case of viruses which can only replicate inside cells, infected cells themselves. This means that dealing with bacteria and other microbes is not as simples as ramping up your immune system so that it can better deal with them, indeed this may have the potential to prove lethal if the virus or bacteria is widespread enough. For example, in a typical year the influenza (flu) virus primarily kills very young and very old people who have a number of physical and immunological deficiencies that render them susceptible to death. Highly pathogenic pandemic flu strains, however, such as the recent H1N1 swine flu virus, disproportionately affect younger people who have very healthy immune systems. This is thought to at least in part result from the fact that the immune system of these young people is so strong that it overreacts to the presence of what it perceives as a particularly dangerous virus, resulting in large amounts of cell death and inflammation in the lung leading to lethal pneumonia.

Thus, as you can see, the pathogenic microbes with which we as a society are most aware of are a real concern that should not be minimized. Pathogenic microbes kill millions of people every year, and have the potential to kill even more during specialized outbreaks where we are unable to contain these deadly organisms. Even so, it is rarely simple to target many pathogenic microbes specifically without doing significant damage to our own bodies in the process. Antibiotics have been very helpful in the fight against bacteria as they do not increase the inflammation inherent in an immune response, however many bacteria are now becoming resistant to antibiotics and it seems unlikely that without more research we will be able to use these antibiotics for too much longer. Our interactions with pathogenic microbes will always be a major concern and problem for the human race, however these are not the only microbes that we encounter, and indeed in many ways they are an exception to the normal rule of what constitutes a microorganism.

Commensal Microbes

Our bodies are filled with microbes - bacteria, viruses, and likely even fungi. Even a very healthy individual carries trillions of bacteria and unknown numbers of viruses at all times - far more bacterial cells than the number of cells composing their own body (bacteria are much smaller than human cells, explaining why we can carry so many of them at all times). These bacteria are isolated to surfaces contiguous with the external environment in healthy people. That is to say, bacteria should not make their way inside your body - instead they are present in large amounts on your skin, in your respiratory tract, and in your digestive tract. They are present at the highest densities in the intestines and colon of the digestive tract, with reduced densities being found in the upper digestive tract which is very acidic and difficult for most microbes to live in. These microbes are present throughout your life, first colonizing you shortly after birth and persisting throughout your entire life. The specific populations of bacteria may shift over time, however there are always new bacteria ready to occupy freshly vacated spots and these microbes play essential roles in normal human immunological growth and development that may surprise people who are used to thinking of bacteria as negative things. These microbes that live with us at all times and that are generally harmless or even helpful in a healthy individual are known by a special name - they are called commensal microbes.

Scientific researchers have been able to generate so-called “germ free” mice that, through a variety of careful steps, are free of any bacteria anywhere on their bodies. These mice may still have some undetected commensal viruses, however research at this point is unable to detect or eliminate these viruses. Even so, these germ free mice allow researchers to study what happens to the body without these normal commensal bacteria and what happens when certain bacteria or types of bacteria are restored to the body, and these mice have yielded some very interesting results over the past decade or so. As it turns out, you need the microbes in your gut to develop a normal immune system - germ free mice lack certain types of T cells, which are important for a normal immune response. This is thought to occur because the microbes in your gut provide some low level stimulation for these cells during development which may allow them to proliferate, although the specifics have yet to be fully clarified. Of course, this process is not as simple as it may seems - some sets of T cells as beneficial, while others can promote autoimmunity by causing your immune system to react to itself rather than to the things it ought to be targeting.

Indeed, research suggest that specific kinds of bacteria can induce specific types of T cells, which may be helpful in specific circumstances. For example, a bacteria known as segmented filamentous bacteria (SFB) is able to induce the replication of a specialized family of T cells known for being inflammatory. You need these T cells to fight off a pathogenic organism like the fungi Candida albicans, yet in the absence of these infection these SFB-induced cells can also have the potential to cause an autoimmune form of the disease arthritis. Conversely, another family of bacteria - the Clostridia group bacteria - are able to induce another group of T cells known for their regulatory capacity. These cells, when present at high levels, can stop autoimmune diseases from developing. Of course, in a healthy adult we will have many bacteria from similar groups and we will have all of these types of T cells. Even so, these results illustrate just how complex our interactions even with our gut bacteria can be, and they suggest the possibility that down the road we might be able to use specific bacteria to, for example, treat people with autoimmune disease by adding the proper stimulatory gut bacteria.

In addition to these long term immunological benefits, commensal microbes are thought to offer a number of more immediate benefits that may explain why we need them in our bodies in order to develop healthily. For one, commensal microbes are able to process a number of nutrients that we cannot process ourselves. Over the millennia of evolution humans have lost the ability to extract nutrients from certain compounds - vitamin A, for example. Our guts instead have bacteria present which are able to metabolize vitamin A into retinoic acid, the metabolite that we need for normal development. Without these bacteria, we would not be able to obtain the needed nutrients from these dietary compounds. Similarly, bacteria are able to process lactose - the sugar found in milk - even though most humans lose the ability to do so shortly after birth. In addition to nutrient benefits, commensal microbes provide us with defenses against potentially pathogenic microbes in the gut. They do this in two ways - for one, they take up space. By occupying niches within our guts in a robust fashion, they do not give pathogens a chance to colonize any open real estate in this crowded environment. In addition, these commensals may produce specific compounds that can target and destroy pathogens. There is evidence to suggest that our bodies have evolved to encourage the growth of commensal bacteria by offering them special nutrient compounds, suggesting just how important these commensal host interactions are to us as a species.

Our interactions with our gut microbial flora run both ways, as the above results suggest - we shape the gut bacterial populations just as they shape us. This can have unexpected long term effects that have important implications for diet and disease. Most notably, mice raised on a high fat diet unsurprisingly grow very overweight. In the process of gaining all this weight, they end up selecting for gut bacteria that are best able to consume all of the fat in the food that they eat, allowing them to extract more nutrients from their food then they would otherwise be able to. If these gut bacteria from these obese mice are transferred into a normal mouse on a low fat diet, then that mouse will still gain much more weight as it will be able to extract more calories from the food that it eats resulting in increased weight gain from the same amount of consumed food. This result is profound, in that it suggests that human metabolic conditions may represent a perpetuating cycle of positive feedback that is difficult to break. Further research is needed to understand how persistent obesity promoting microbe populations may be, and how best we might be able to shape them to deal with human health and disease.

When our body detects a pathogenic microbe in our airways or our bloodstream, it will engage a full scale immune response that causes lots of inflammation and sickness in order to expunge that pathogen from the body. How, then, do we not have a constant state of gut inflammation if we have many more commensal microbes than we do pathogenic ones? The answer is ignorance - the immune system is able to restrain and generally ignore commensal microbes, unless they violate certain criteria which may flag them as potential pathogens. As mentioned earlier, commensal microbes are restricted to the external side of our bodies - this allows the immune system to construct physical and chemical barriers between us and these commensals, which prevents them from being detected by our normal immune defenses. These barrier include mucus - a thick glycoprotein substance that lines our gut and respiratory tract and traps microbes to prevent them from reaching our cells. This mucus is then filled with specialized defense compounds including peptides that can kill microbes and antibodies that can bind and neutralize them without inducing a full immune response.

In this way, our body is able to tolerate the presence of bacteria that, if they were ever to enter the bloodstream, would still trigger an all out immune response, as occurs if they penetrate the body of an immunocompromised individual. Indeed, patients with AIDS that suffer immune deficiencies often die from so called “opportunistic” infections. These infections arise not from pathogens they pick up in the environment, but from commensals that they are no longer able to contain due to their immune deficiency. These opportunistic infections occur in healthier individuals as well. For example, Streptococcus pyogenes and Staphylococcus aureus - two common sources of dangerous bacterial infections in people of all ages - are in fact present in the respiratory tract of anywhere between 5 and 20% of people at any given time without causing any disease. It is only when these potential pathogens (also called pathobionts) enter the wrong site or benefit from some immune deficit as may occur during a flu or cold infection, for example, that they are able to grow and cause the rarer disease for which they are better known. This demonstrates just how important it is to control commensals - and how blurry the line between pathogen and commensal may become.

While most of us are able to control and interact with our commensal bacteria without issue, this is not the case for all individuals. For some people, their bodies perceive the commensal bacteria in their guts as being a threat akin to a normal pathogen at another body site. These patients have an inflammatory disease known as Crohn's disease, which can in a sense be treated as an autoimmune disease as it involves the immune system reacting to a normal part of our bodies that it should be able to tolerate and control. Crohn's disease causes inflammation in the gut as the body tries to eliminate the bacteria it percieves as posing a real threat to survival, and this inflammation can be devastating to the individual affected by it. Crohn's can be a deadly disease in extreme cases, and the constant inflammation that it entails is at the very least quite debilitating. As we increasingly begin to understand the microbiome we are learning more and more about Crohn's disease, however at present we do not know why the immune system of these patients has failed to tolerate the bacteria that are present in their guts. It is likely that this disease results from the combination of a number of genetic and environmental factors, and hopefully in the future we will learn how to target responses to gut bacteria in such a way as to assure that these people do not suffer from these mistargetted immune responses.

While your body may not inappropriately target the bacteria of your gut for destruction, this does not meant that you don't do so anyway without even realizing it. When you have a bacterial infection or surgery, you will be given antibiotics in order to kill off any pathogenic bacteria before they have a chance to kill you. These antibiotics have been very effective and have no doubt saved millions of lives since their 20th century inception. Even so, we are becoming increasingly aware that antibiotics have an unintended effect on our normal microbiome that makes it important to use them cautiously. Currently people use antibiotics far too frequently in antibiotic soaps and other compounds despite a lack of any evidence that these antibiotics offer us any concrete health benefits. Our gut bacteria can be just as sensitive to antibiotics as pathogenic bacteria. This means that every time you take antibiotics, you are killing off both your intended target an many of the microbes in your gut, leaving the niches that they occupied vacant for a short time. This can open you up to infection and can be potentially problematic.

Normally surviving bacteria or similar bacteria will fill the commensal niches left open due to antibiotic treatment. At times, however, these niches may allow for the outgrowth of dangerous organisms. The most infamous of these is Clostridia dificil, a bacteria that can take over the gut after antibiotic treatment or serious gastrointestinal illness, resulting in extreme weight loss, inflammation, and death. Normally your body can control this organism, but the use of antibiotics can eliminate the microbes that typically keep it in check thus allowing it to grow out and devastate the body. At present the best treatment for C. dificil infection is to reintroduce the normal gut bacteria to the person suffering from this infection in a process known as fecal transplant, and though it may sound unpleasant it is remarkably successful. This demonstrates why we need to exercise caution as we interact with bacteria and try to control them - we may trade one pathogen for another and we may devastate our own normal physiology in the process.

Indeed, some hypothesize that our interactions with microbes have fundamentally changed over the last few centuries to the detriment of society as a whole. As our society has become more industrialized there has been a large increase in certain diseases such as asthma and allergies, and a prominent scientific theory suggests that these increases may be the result of our increasing hygiene as a society - indeed, this has been called the hygiene hypothesis. Specifically, researchers postulate that as a society we have largely eliminated our interactions with parasites in Westernized nations, even though our bodies evolved for millions of years to be able to deal with parasites on a regular basis. It has been suggested that in the absence of a parasite to react to, the immune mechanisms that we would normally use to remove a worm from our gut, for example, instead end up being directed inappropriately. These inappropriate responses can cause inflammation and rapid immune reactions that characterize severe cases of asthma and allergies. As such, this hypothesis suggests that once again the unintentional alteration of our normal commensal environment can have profound effects on human health well beyond what was ever intended. This is not to say that the elimination of parasites is necessarily a bad thing and indeed there are many positive effects to removing such organisms from our daily lives. Even so, the ability to properly control potential sources of pathogenesis without damaging our own delicate physiology is clearly a non trivial matter that will require extensive research to perfect.

Hopefully these recent research results make it clear just how complex our interactions with commensal microbes can be. They are both essential for us to live a normal life, and yet they can themselves become pathogens under the right circumstances. Some people are not able to tolerate these microbes as most of us can, and still others will damage their delicate commensal balance in the process of dealing with some other threat. How we as a species need to best handle our internal microbiome is a question that remains to be answered. Research over the next several decades will no doubt uncover new information with regard to how we shape our microbiome and how it in turn shapes us. We still have virtually no understanding of the role of commensal viruses in the body, in part because they are more difficult to study, and new studies on these essential organisms will no doubt add additional layers of complexity to our understanding of host microbe interactions. Hopefully this information will be put to use in order to allow us to maximize the benefits that each person receives from their microbiome without allowing it to be devastated in the process of treating other diseases.


As you can see, the way we as a society think about bacteria and other microbes is a relatively warped view point that is biased by our fears of a small but salient portion of a diverse ecology of microbes. Pathogenic microbes are a real concern for our society as they claim millions of lives each year, however our approaches to eliminating them are not always successful and our societal germophobia may have negative consequences for our actual health. In addition to these thousands of commensal and pathogenic microbial species with which we are becoming increasingly familiar, there are untold billions of unique bacteria, viruses, and other single celled organisms out there in the world that we have never discovered. These organisms dwell in the soil, in the permafrost of Siberia, and most commonly in the ocean which contains a huge biomass of undiscovered unicellular and microbial organisms. These microbes likely won't be able to infect humans, which is why they have largely been ignored by research up to this point. Even so, however, they likely have subtle but potentially profound impacts on our ecology or environments, making it increasingly important that we understand their role in a functioning world.

Going forward, it is important that researchers and individuals recognize that although some microbes are dangerous pathogens, many more are not. Our bodies are finely tuned to respond only to pathogens that they view as posing a true threat, and though at times they may over react or fail to react in time, they are far better at determining the line between friend and foe than are many of our heavy handed pharmaceutical treatments. We need to develop drugs that avoid disrupting the rich and complex microbial ecology within our own bodies while still targeting pathogens if we hope to be able to overcome serious microbial diseases without potentially devastating side effects. Furthermore, we need to understand the role that our internal microbial flora plays in our normal bodily processes, which may allow us to better shape that flora to promote human health. Additionally, we need to investigate just how the trillions of species of microbes in the world affect each other and then environment as a whole. Only by developing such an integrative view of the role of microbes in our world will we ever be able to truly appreciate the complexity of life, and how we might steer that complexity in beneficial directions.

See Also


  • Bai A, et al. All-trans retinoic acid down-regulates inflammatory responses by shifting the Treg/Th17 profile in human ulcerative and murine colitis. J Leukocyte Biol. 2009; 86(4):959-969.
  • Benson MJ, et al. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med. 2007; 204 (8): 1765.
  • Gregg RK, et al. A Sudden Decline in Active Membrane-Bound TGF- Impairs Both T Regulatory Cell Function and Protection against Autoimmune Diabetes. J Immunol. 2004; 173: 7308-7316.
  • Guarner F, Malagelada JR. Gut Flora in Health and Disease. The Lancet. 2003; 361(9356): 512-519.
  • Heuer JG, et al. Adoptive Transfer of In Vitro-Stimulated CD4+CD25+ Regulatory T Cells Increases Bacterial Clearance and Improves Survival in Polymicrobial Sepsis. J Immunol. 2005; 174: 7141-7146.
  • Inzunza J,et al. Germfree status of mice obtained by embryo transfer in an isolator environment. Lab Anim. 2005 Oct; 39(4): 421-7.
  • Jang E, et al. A Positive Feedback Loop of IL-21 Signaling Provoked by Homeostatic CD4+ CD25- T Cell Expansion Is Essential for the Development of Arthritis in Autoimmune K/BxN Mice. J Immunol. 2009; 182: 4649-465.
  • Kang SM, et al. CD4+CD25+ Regulatory T Cells Selectively Diminish Systemic Autoreactivity in Arthritic K/BxN Mice. Mol Cells. 2007; 25(1): 64-69.
  • Lee, et al. Proinflammatory T-cell Responses to Gut Microbiota Promote Experimental Autoimmune Encephalomyelitis. PNAS. 2011; 108: 4615-4622.
  • Lochner M, et al. In Vivo Equlibrium of Proinflammatory IL-17+ and Regulatory IL-10+ FoxP3+ RORγt+ T Cells. J Exp Med. 2008; 205(6): 1381-1393.
  • Lochner M, et al. Restricted Microbiota and Absence of Cognate TCR Antigen Lead to an Unbalanced Generation of Th17 cells. J Immunol. 2011; 186: 1531-1537.
  • McAleer JP, et al. Potent intestinal Th17 priming through peripheral lipopolysaccharide-based immunization. J Leukocyte Biol. 2010; 88: 21-31.
  • Monach P, et al. The K/BxN Mouse Model of Inflammatory Arthritis. Arthritis Research. 2007; 136: 269-282.
  • Mora C, et al. Pancreatic Infiltration But Not Diabetes Occurs in the Relative Absence of MHC Class II-Restricted CD4 T Cells: Studies Using NOD/CIITA-Deficient Mice. J Immunol. 1999; 162: 4576-4588.
  • O’hara AM, Shanahan F. The Gut Flora as a Forgotten Organ. EMBO. 2006; 7(7): 688-693.
  • Qin J, et al. A Human Gut Microbial Gene Catalogue Established by Metagenomic Sequencing. Nature. 2010; 464: 59-67.
  • Smolen JS, Steiner G. Therapeutic Strategies for Rheumatoid Arthritis. Nature Reviews Drug Discovery. 2003; 2: 473-488
  • Steinman L. A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell–mediated tissue damage. Nature Medicine. 2007; 13:139-145.
  • Tartar DM, et al. FoxP3+ RORγt+ T Helper Intermediates Display Suppressive Function against Autoimmune Diabetes. J Immunol. 2010; 184(7): 3377-3385.
  • Umesaky Y, Setoyama H. Structure of the intestinal flora responsible for development of the gut immune system in a rodent model. Microbes and Infection. 2000; 2: 1343–1351.
  • Veldhoen M, et al. TGFβ in the Context of an Inflammatory Cytokine Milieu Supports De Novo Differentiation of IL-17-Producing T Cells. Immunity. 2006; 24: 179-189.
  • Wu HJ, et al. Gut-Residing Segmented Filamentous Bacteria Drive Autoimmune Arthritis via T Helper 17 Cells. Cell – Immunity. 2010; 32: 815-827.
  • Xiao S, et al. Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-β-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J Immunol. 2008; 181(4): 2277–2284.
  • Ziegler SF, Buckner JH. FOXP3 and the Regulation of Treg/Th17 Differentiation. Microbes and Infection. 2009; 11(5): 594-598.\
  • Zotos D, et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell–intrinsic mechanism. J Exp Med. 2010; 207 (2): 365.

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