Your immune system is a junkyard dog. It can be your best friend, the ultimate protector of your health, and a lifelong partner to the end, supporting every tissue in your body, or it can make you sick and sometimes kill you. That may come as a bit of a shock.
We tend to think that the immune system is the only thing standing between you and certain death from infections. That is true as long as your immune system is functioning well and is well trained. When it is not, it can easily kill you. My own research on and teaching about the immune system beginning in the 1970s is not so much the happy story about the immune system and all the great work it does. Mine is the flip side. Mine is the story of natural disasters caused by an immune system gone so far rogue that it is literally blowing up the body. It can look much like a scene from a Bruce Willis, Arnold Schwarzenegger, or Dwayne “The Rock” Johnson action movie or one of your favorite disaster films (The Perfect Storm, Independence Day, San Andreas, Titanic . . .). Except in this case the location is your body.
“When Things Go Wrong” is the name of the block of lectures I give in Cornell’s Basic Immunology course. Most students taking the Basic Immunology course do so as juniors or seniors but with only a cursory prior exposure to the immune system. You might say that my scientific career gig within immunology has two basic areas of focus: (1) what goes wrong with the immune system and how that leads to disease and, of course, (2) how to keep people out of harm’s way and off a disease-filled path in life. As a result, my lectures cover allergic and autoimmune diseases with a pinch of inflammatory diseases and conditions (e.g., obesity, some forms of heart disease, some forms of cancer, and depression) thrown in for good measure. Some of the diseases can be a type of personal natural disaster for many people, forcing their way of life to change dramatically.
Natural disasters come in many forms. During my time with the Cornell Center for the Environment, I had the pleasure of working with a distinguished Cornell engineering professor, Walter Lynn, whose expertise was in global natural disasters. Whenever there was an earthquake, volcanic eruption, tsunami, flood, or massive forest fire, he was usually on a plane to go lend his much-needed expertise. Among many leadership appointments, he served as chairman of the board on natural disasters for the US National Research Council. I have been hoping that a bit of Walter Lynn rubbed off on me as I seem to be dealing with more and more natural disasters, particularly those located within our bodies.
For many students, my part of the immunology course is a bit of a harsh reality. I start the first lecture by polling the students, asking how many have family members (including themselves) or friends who face different categories of noncommunicable diseases, focusing on allergic and autoimmune diseases and conditions. There are very few hands unraised. I do the same thing when I guest lecture in one of Cornell’s largest freshman-level biology courses. The response is the same. It is the same with the veterinary students I teach. As students look around these classrooms at the raised hands, they become increasingly aware that these diseases touch virtually every student at Cornell in some way. They have grown to become such a part of our societal fabric that until we tally up exactly who carries these diseases and conditions and the toll they take on our lives and those of friends and families, we are almost numb to their increasing existence.
Part of the reason that these diseases can travel under the radar is that we tend to use a name-and-divide strategy within medicine that can make it difficult to see the forest for the myriad of trees. New diseases and conditions are given various levels of official designations almost every day. Just look at the propagation of autoimmune diseases and conditions between 1970 and today. As often told by Noel Rose, Johns Hopkins professor and famed autoimmune researcher, his early days were spent with barely double-digit numbers of recognized autoimmune conditions. Today there are many more than one hundred, and the number is growing. This is reflected in new drug development to treat all of these new autoimmune conditions, which disproportionately affect women more than men.
Similarly, if you look at the neurobehavioral arena, a good way to track the growth in the number of different conditions is to consult each new version of the psychological manual for diseases and conditions called the Diagnostic and Statistical Manual of Mental Disorders (DSM). With each updated version, the DSM grows with new entries.
Of course, there are reasons why. A contributing factor to this growth is that we find more ways to partition dysfunctions within the human body. First, our detailed knowledge of physiological systems and organs, along with improved ways of imaging and analyzing their functions, allows for greater distinctions to be made. The result is that one prior disease may be divided into two new distinct diseases. Second, new drugs can be developed for each new officially named disease. Therefore, it is in the interest of the drug companies to eliminate gray areas around diseases and conditions and have new diseases defined whenever possible. A potential new drug that did not reach a level of efficacy for a broad disease may be more useful if the diseases are refined. If you doubt this, just look at the expansion of neurobehavioral conditions and the growth of prescription drugs administered to address childhood behaviors that were unnamed one or two decades ago. Drugs are prescribed based on their government-regulated, label-approved use connected to physician-diagnosed diseases and conditions. With more diseases, there are more possible opportunities for an existing or new drug to be used. This is at least partly why the list of diseases and conditions and their acronyms increases each year.
I used a story about a real peanut allergy in Part One of this book. Let us return to that topic now to illustrate exactly how far and how fast public health has deteriorated due to a dysfunctional immune system and NCDs. Probably the two most influential people to raise the visibility of peanuts as a healthy and useful alternative crop are George Washington Carver, famed agronomist and inventor, and President Jimmy Carter, the former peanut farmer from Georgia. Carver was instrumental in helping poor farmers find a sustainable farming future using alternatives to cotton such as peanuts. At the same time he researched and developed many new uses for peanuts that helped to expand the demand and markets for the increased crop production. This was a win-win for agriculture in the southern states and helped to produce greater yields for what was viewed as a healthy food.
For anyone alive in the 1970s, Jimmy Carter’s emergence on the US political landscape, first as the governor of Georgia and later as president, was a surprise not only because of his relatively short duration of political experience but also since his profession was peanut farming rather than law. It was also a boon to the peanut industry as more and more people had their attention drawn to this crop and its uses in a wide variety of foods and nonfood products (e.g., cosmetics). In fact, Carter’s grassroots campaigners were nicknamed the Peanut Brigade, and they used such visuals as peanut-shaped campaign clasps with Carter’s name on the front to help convert his campaign push into election and boarded buses called the Peanut Special for a subsequent Peanut Inauguration Parade, for which commemorative plates exist. In the Carter era of the late 1970s, consumption of peanuts in schools soared. How quickly things have changed.
Peanuts are being banned from some schools and/or nut-free zones established, and airlines are deliberating whether to ban them from flights. Anaphylaxis at 30,000 feet is not a good thing. The risk of bystander exposure is becoming too great for peanuts to appear in close quarters. This food is on a path where it might be enjoyed only in the confines of your own home, and even then with warnings or consent statements needed for visitors.
Peanut allergy is the poster child for what has gone wrong with our bodies starting with the microbiome and the immune system. How did peanut consumption become eerily similar to cigarette smoking in terms of ever-increasing restrictions on when and in what specific spaces the product can be used? Would Jimmy Carter dare call his grassroots campaign the Peanut Brigade today?
Clearly, humans have changed since even the 1970s. If you look at food allergies and intolerances, we are seeing prevalences and intensities of adverse reactions that are both alarming and a reflection of our body’s natural present disasters. Food certainly has changed as well (as discussed in Chapter 9), but our altered love affair with peanuts in only three to four decades reflects a major environmental shift in us. With 70 percent of our immune system residing in the gut, it makes biological sense that the front line of determining tolerance versus allergy to foods like peanuts involves our gut microbes and what happens in our gut.
So stepping away from President Carter and the 1970s and back to that present-day undergraduate immunology course, the present-day students, via their extended families and their friends, are touched by the very diseases I cover in my lectures. It’s not just peanut allergy or the larger category of food allergies. It is also asthma, type 1 diabetes, celiac disease, multiple sclerosis, autism spectrum disorders, autoimmune thyroiditis, lupus, arthritis, atopic dermatitis, Crohn’s disease, ulcerative colitis, allergic rhinitis (hay fever), psoriasis, and on and on. When something goes wrong with the immune system, the result is disease, which can show up in any tissue at any age. How is that possible?
Well, a little-known secret of biology and immunology is that immune cells are residents in virtually all of your tissues. They are placed there early in development and become so different from their cellular kin in other tissues that they are often given their own names. For example, what do microglia cells in the brain, Kupffer cells in the liver, and skin macrophages have in common? They are all macrophages. But their appearance and features are quite different. They morph while residing in the different tissues to take on their special characteristics. These resident immune cells exert significant control over what happens in those tissues. Ever wonder how you are able to see skin tattoos and why they last a very long time? It is because you are actually staining skin macrophages—they are the ones who take on the task of keeping the dye from reaching your internal tissues.
It is important to keep in mind that when these resident immune cells are happy and functioning well, the tissue usually functions well. But when the resident immune cells of a tissue are dysfunctional, that tissue is likely headed to a future of pathology and disease.
The common factors are that the immune system methodically attacks things it should not be attacking or that the response is completely uncontrolled. The response is often either completely over the top in intensity and/or never-ending instead of temporary. All of those types of inappropriate responses by the immune system result in pernicious damage to tissues and organs.
How can the immune system of the 1970s and before have been OK with peanuts, OK with the thyroid, OK with the skin and gut, but the immune system of the twenty-first century is misfiring anywhere and everywhere? The answers lie in how the immune system is trained in early life. Our first-genome human mammalian genetics today are not that different than those of the 1970s or even the 1920s. There are some genetic variants there that can affect the risk of developing an allergy or multiple allergies (called atopy). They contribute a small portion to the risk of immune problems. But what changed massively between forty and a hundred years ago is the early-life experience of our immune system. It is one reason some allergists are suggesting consumption of peanuts during pregnancy and early infancy and also having a dog in the house during the pregnancy and early infancy if you ever intend to have one. What your baby’s immune system sees during this training period is what counts. But as we will see, potential allergens are only part of the story. There is much more at stake affecting whether the immune system will misfire during life and produce damage and disease, and that involves the baby’s microbiome. Missed training of the immune system, which occurs all too often in today’s babies, is a program for a different kind of natural disaster.
In a prior book coauthored with my wife in 2008–09 and published in early 2010, we described how the immune system develops and what things were known to affect its development. Development of the immune system includes two key aspects: maturation of the different cells of the immune system and education of the immune system in how, when, and where it should react. Because the immune system is widely dispersed in the body and very complex in terms of having many different specialized cells, it is very sensitive to developmental disruption. However, not every minute of prenatal or postnatal development is equally important for development of the immune system. There are different periods when major developmental events are occurring or immune school is in session, and there are other periods when immune development is comparatively quiet or school is on vacation. The most sensitive periods of immune development are called critical windows of immune vulnerability.
During these critical windows of immune vulnerability, the immune system is hypersusceptible for programming later-life dysfunctional responses and diseases. Disruption then means the immune system becomes unbalanced in cell populations and/or fails to learn how it should respond when challenged. Events disrupting immune development can include environmental exposures to chemicals or drugs, or intense or persistent maternal or infant stress. If a maturational step is missed or the education of the immune system is interrupted, the entire system of distinguishing friend from foe can go very wrong. An improperly trained immune system is almost guaranteed to eventually produce disease. Some combination of three things is likely: (1) failure to react to a real threat, (2) reacting to a threat with the wrong kind of defense, and/or (3) attacking our own tissues. Immune-related disease is often life-threatening.
While many environmental factors affecting immune education were laid out and even prioritized in the book I coauthored in 2009, the significance of the microbiome was not evident. Its role was only beginning to emerge at that time. Now in 2015 the picture of immune education during developmental windows would look quite different precisely because of the impact of the microbiome. That is how fast the biology of immune development and its impact on health is changing.
The impact of the microbiome on immune education is so critical and so all-encompassing that it is key to protecting the immune system of children. It is not just another environmental factor. The ramifications of environmental exposures and immune programming must now be seen through the lens of our microbes and recognition of you as a superorganism.
Remember, the microbiome is your body’s ultimate gatekeeper. However, sitting between the microbiome and most of the rest of your body is the immune system, which is the next line of communication with the world outside of you. Yes, there are epithelial cells and linings in several of the sites such as gut and airways, but once you get past the skin, the immune cells are always just on the other side of the barrier. They are your mammalian cell greeting party, the welcome wagon as it were.
Not surprisingly, some of the most primitive, least sophisticated immune cells (representing your innate or natural immune system, as opposed to your acquired immune system) are the very cells in closest and most frequent contact with the microbes inhabiting each portal of your body (i.e., gut, skin, airways, urogenital region). They have a temper, are highly mobile, and you don’t want to upset them. In fact, consider them as the very core of that junkyard dog. They need careful, early-life training, or they can be unpredictable and dangerous. Close friendship and contact with a complete microbiome is very important in the immune system’s education. This happens both from physical interactions (almost the equivalent of hugs or cuddles) and from chemical signals that are present in the metabolites of the microbiome. If the immune cells do not see enough of the microbes and get the right microbial signals in their early, formative period of education (shortly after birth), the immune system goes very wrong. It is almost a matter of when, not if, problematic immune responses will happen. The BFFs need to be together throughout infancy. In the end, your immune system is the arbiter of what gets attacked and what is tolerated. It largely controls your risk for having allergies, autoimmune disease, and/or a host of other inflammatory diseases and cancers.
The innate immune cells, your most primitive, are found in the most primitive and ancient organisms. There are some organisms that do not have the types of responses immunologists call acquired or adaptive immunity, essentially immune responses to vaccines. They lack those necessary immune cells. But if they have any immune cells at all, they have innate immune cells such as some form of macrophage. This is not just coincidence. If microbes have been living with and communicating with host defenses of vertebrate and invertebrate animals since the start, then macrophages are going to be in all those animals, even if more sophisticated immune cells (e.g., certain types of lymphocytes) are missing.
A great deal is known about invertebrate immunology from the foundational work of Edwin Cooper of UCLA and his trainees. In invertebrates such as earthworms, there are innate immune defenses but not acquired immunity as we know it in mammals. Even amoebae have macrophage-like activity and can attack bacteria using macrophage-based functions when needed.
To emphasize the point about the BFF relationship between the microbiome and innate immune cells, Czech researchers recently found differences in the microbial-driven innate immune responses of two closely related species of earthworms that live in quite different natural composts. The species that lives in a manure-based compost that is rich with pathogens and needs robust immunological defenses had a much higher level of innate immune activity than that of the closely related species of earthworm living in forest mulch compost (with fewer pathogens). The scientists concluded that the microbial environment was the primary driver of the status of what were quite comparable innate immune systems. The fact that the immune system is primitive should not discount its importance within humans.
The common view of the past decades is that the immune system establishes a fortress wall and defends our mammalian body against invading microbes. That is what I was taught in college. The other thing I was taught in college was that the immune system (1) resides in a limited number of body sites that are specialized lymphoid organs (thymus, spleen, bone marrow), (2) travels in blood and lymph, and also (3) samples our portals of entry for exposure to invading bacteria and viruses. There was virtually no mention of the gut as the main location of immune cells, despite the fact it has a majority of our immune cells, or the fact that virtually every tissue and organ of our body has its own mini immune system permanently residing there. This led to some misconceptions about what the prime directive of the immune system actually is. It is not just sitting in all our tissues to sample for the first invasion of microbes—after all, the liver and brain are not the first sites where microbes gain entrance to infect. Instead, the immune system is sitting in the liver, brain, and other tissues and organs to control their integrity and to help control the balance of function in our specialized tissues.
Ironically, the groups of immune cells living within our different organs (brain, liver, kidney) are so radically different in appearance and some properties that scientists weren’t even certain they were immune cells when I went to college. But these highly specialized immune cells are in our specialized tissues for a purpose other than just microbe hunting. We now know that microbes aren’t the only threat. Internally developed cancers are something the immune system must deal with as well. Plus, the immune system clears us of all dead and dying cells much like an overnight building custodian who wants to disrupt normal operations as little as possible.
So, in addition to pathogen hunting, the immune system is analogous to an environmental and security control system in an office building. It is an integral part of virtually all of your organs, ensuring that the conditions are met and maintained for effective organ function. When the immune residents in your organs function well, your organs are likely to do so as well. But if those immune cells go rogue, your organs are in serious jeopardy. Inappropriate immune responses within the organ cause organ damage, loss of organ function, and the increased chance of cancer involving that organ or tissue. The resident immune cells are also likely to signal for help from external immune cells, which come rushing into the organs, attaching to our normal cells. This can cause organs like the thyroid and pancreas to become more of an immune organ than an endocrine organ in a comparatively short time (e.g., autoimmune thyroiditis, diabetes).
Why would your immune cells do this? Why would they divert from protecting the integrity of our organs and tissues to inflicting harm on us? There are several reasons why this could happen. But I will argue here that the most significant reason for immune-inflicted noncommunicable diseases is the loss of a higher order of self-integrity involving our microbiome. If the immune system matures in an environment where we do not self-complete and are missing our intended microbiome, our immune system gets programmed for haphazard, inappropriate responses. It is then only a matter of when and in what tissue disease will show up. Will it be in our brain, causing neurobehavioral and neurodegenerative issues; our liver, causing metabolic issues; the gut, causing digestive-inflammatory issues; our endocrine organs, causing hormone/metabolic problems; our bones, causing osteoporosis; our mouth, causing dental cavities; our blood vessels, causing cardiovascular disease; or in any of these locations, causing cancer?
Remember those macrophages I discussed earlier that reside in all our tissues. They appear to be able to morph into different forms, are given different names, and can operationally control tissue function, plus potentially destroy the tissue if they so choose. I have told my students half jokingly that macrophages rule the world, and if only we knew how to control macrophages, it would be a better world. Of course now we do know how to control macrophages . . . It is through the microbiome.
Most people have probably heard of asbestos, even if they are a little fuzzy about why. They may have seen danger signs in hallways or on the outside of old buildings announcing asbestos remediation areas or have seen one of countless TV ads from law firms about class action suits, asking if you or a loved one has been diagnosed with mesothelioma caused by exposure to asbestos. There is even a 900-plus-page book intended as a guide for lawyers concerning asbestos health litigations. Some people may have come across a recent article in Scientific American asking parents if their child may be coloring with crayons containing asbestos, including comments on the dangers of such exposures from a leader in children’s health protection, Dr. Philip Landrigan of Mount Sinai’s Kravis Children’s Hospital in New York City. I have memories of specific asbestos products from my younger days. In fact, for a period of time, you could walk into any well-equipped research laboratory and find pairs of asbestos-lined gloves. They were the gold standard for handling hot lab ware from sterilization ovens. For the majority of the twentieth century the health risk was simply not known. It was thought that they protected lab workers without presenting a significant health risk.
There are other parallels right in the research laboratories. The immune-toxic, cancer-causing chemical benzene was used in twentieth-century chemistry labs as the go-to solvent for cleaning glassware. Only later did the health risks become apparent. Benzene went from being a common type of liquid detergent to something stored and used under the most highly contained lab conditions and with workers fully protected. In mid-twentieth-century homes carbon tetrachloride was a common cleaning aid ready at hand when your guest spilled a drink on your beautiful new sofa or your pets had an accident. But no more. Its use in consumer products was banned in the 1970s.
So asbestos was not alone in being almost a miracle material in widespread use in the twentieth century that was later recognized and regulated as a significant environmental health hazard once its action on humans was fully understood. But exactly what is asbestos and how does it affect our health via the immune system?
Asbestos is a series of naturally occurring mineral fibers that can be separated into thin threads. It is mined much like the metals gold and uranium. It was extensively used in construction materials and car parts and could be found in some gardening products and even some products designed for children. Among the hot spots for asbestos exposure were mining operations near Libby, Montana, for the production of vermiculite. Between the late 1970s and today, there have been a series of bans on asbestos use in different products, and this has led to a significant reduction in its annual production in the United States. What does asbestos do that makes it so dangerous? Actually, asbestos is primarily toxic and carcinogenic via the immune system.
By themselves, the fibers don’t do a great deal. The problem is they don’t easily degrade or go away. That is a problem when they end up on innate immune sentry cells like macrophages in your lungs (called alveolar macrophages). These macrophages, along with cells of the airway linings, engulf and accumulate the asbestos fibers. But the macrophages can’t digest them. So they respond in several ways. They accumulate near the airway borders and mount a massive, never-ending inflammatory response featuring damaging oxygen radicals that overwhelms your antioxidative defenses. If this goes on long enough, cancer can and does result. Mesothelioma is one of the predictable outcomes.
At the same time, macrophages and other innate immune cells lead a repair effort as lung tissue damage builds up in the area. But the repair effort has two critical features: First, the repair uses biological materials that fill the lung space but don’t replace lost function. In other words, the repair does not help you to transfer oxygen to the blood as is needed. Also, the repair blunts anti-tumor responses by other immune cells. Macrophage changes in the lung with asbestos also allow for autoimmunity and for cancers to survive better. This is especially bad news since, after the decades of oxidative damage, the risk of tumors forming in the lungs is high. The innate immune attack against asbestos led by macrophages can result in several forms of lung disease. In the end, because these cells cannot digest the asbestos, they lash out, and the lungs pay the price.
This is precisely the type of scenario that happens over and over in our bodies when the immune system does not cope well with environmental exposures. Only, instead of asbestos, it could be exposure to truly innocuous factors that cause dysfunctional or untrained immune cells to produce self-damaging, inappropriate, inflammatory reactions in the brain (neurodegeneration), the reproductive tract (sterility), the pancreas (diabetes), the gut (inflammatory bowel disease), the lungs (asthma), the skin (psoriasis), the heart (myocarditis), the skeleton (osteoporosis), or the liver (several forms of hepatitis).
Finally, a lingering question is whether there is a role of the lung microbiome in asbestos-related lung disease. Researchers recently suggested that one of the factors affecting the risk of asbestos-related cancer is whether the fibers penetrate the lining of the airways and reach the alveolar macrophages. They hypothesize that one of the determining factors in penetrating the lining may be whether lung microbes secrete proteins that punch holes in the epithelial cells providing the lining border. That would confirm the idea that the microbiome is our gatekeeper, controlling what actually reaches our internal cells. It remains to be determined if this is a major factor in internal asbestos concentration.
A wonderful and health-promoting discovery uncovered between the years 1979 and 1984 may, in the long run, end up being viewed as a tipping point for the fallout over the twentieth-century war on microbes and overuse of antibiotics. Barry Marshall, the Australian physician, and his collaborator Robin Warren reported the link between a spiral-shaped bacterium, only found in humans, named Helicobacter pylori (H. pylori), infections of the stomach, and peptic ulcers. Their report was first published as letters in 1983 with a full report in 1984 published in the medical journal Lancet. Prior to that time a diet of spicy foods and mammalian genetics were thought to be the major factors determining who got ulcers and gastric cancer. For their discovery, Marshall and Warren were jointly awarded the 2005 Nobel Prize in Physiology or Medicine. The solution seemed simple enough: Eradicate H. pylori with massive antibiotic therapies anywhere and everywhere it showed up. That was in keeping with the widely held twentieth-century view that the only good bacteria are dead bacteria should they dare to come into our bodies.
Yet at the same time as the Marshall and Warren discovery, other researchers held a slightly different view. In his book Missing Microbes, Martin Blaser describes his lengthy, contrasting research into the health-promoting activities of H. pylori as a stomach resident. How could the same information be taken to different conclusions? It happens because the whole human is an ecological system, as discussed in Part One of this book. Not every cohabiting species within or on us is innocent of causing potential harm, nor are potential pathogens always without any redeeming value to us as a superorganism. It can be situational. H. pylori has been associated with humans for thousands of years, having been found in mummies from northern Mexico dating to before the arrival of Columbus in the New World. Balance is needed, combined with broader understanding of who and what we are. It turns out that H. pylori and its multiple effects probably fit into an immunological idea known as the hygiene hypothesis, first described in 1996 by David Strachan of the UK.
When it comes to microbes, just as with environmental chemicals, here’s a prescription for good health: the right place (specific body location), the right amount (dose), the right time (developmental, menstrual cycle, or circadian cycle timing), and compatible with our mammalian self. The flip side is equally a path toward pathology and disease. The wrong place, the wrong amount, the wrong time, or incompatible with our mammalian self often causes significant health problems.
Why might you want some H. pylori, which in some circumstances can produce peptic ulcers or stomach cancer? Because purging the body of H. pylori is equally associated with other NCDs, and we have a good idea about the mechanism of how this happens. It turns out that the persistent presence of H. pylori helps the immune system become more tolerant and reduces the risk of asthma, allergies, and inflammatory diseases such as inflammatory bowel disease (IBD), beginning with immune cells called dendritic cells that sample the environment. Partly through H. pylori’s effects on dendritic cells, there is an increase in the maturation and numbers of regulatory T cells called natural Tregs, and these are critical to avoiding the inflammation that supports numerous NCDs such as asthma, allergies, and IBD.
This example illustrates that we need microbes in place that will educate and train our developing immune system, or we are likely to face a plethora of different inflammation-driven NCDs. If it is not H. pylori, then some microbial equivalent needs to be in place in our microbiome to ensure that our immune system does not go rogue and accepts both our own tissues and the harmless things in our environment.
A prime example of the importance of early education of the immune system by the microbiome comes from the collaborative immunology and gastroenterology efforts of Dennis Kasper and Richard Blumberg and their laboratories at Harvard Medical School. These groups used the C57 Black 6 strain of mice, which is a standard research model for immunology, to investigate the effects of commensal bacteria and their metabolites on early immune maturation and susceptibility to later-life noncommunicable disease. In this case, the disease was colitis, which is similar to ulcerative colitis in humans (one of the two parts of inflammatory bowel disease). In this strain of mice, the lack of commensal bacteria makes the mice highly susceptible to colitis when they are exposed later in life to oxazolone. The immunological mechanism for this colitis is well described, with specific immune cell populations and immune hormones leading the way to produce disease. The dysfunctional immune process in mice appears to be similar, if not identical, to that which produces human ulcerative colitis.
What the two research groups at Harvard did that was so intriguing is they asked four important questions about the microbiome, immune dysfunction, and susceptibility to colitis. Their first question was whether a single commensal gut bacterium could protect against later-life colitis. The answer was yes, and the bacterium that provided resistance to the disease was Bacteroides fragilis. This bacterium is rod-shaped, does not need oxygen to grow, and is usually one of the immune system’s friends as long as it stays put in its region of the gut.
The Harvard researchers then went a step further and asked if there was a critical developmental window when the bacterium had to be in the newborn mouse to produce resistance to colitis. The answer was it had to be there by one week of age. After that, the addition of B. fragilis could not prevent colitis.
Next, they asked how the bacterium made the mice resistant to disease in the newborn. The answer was it blunted the proliferation of a specific population of gut-innate immune cells called invariant natural killer T cells (iNKT cells). In the absence of the bacterium, these cells had a burst of proliferation in the infant mouse, and that burst was what made the mice susceptible to colitis for the rest of their lives. If the bacterium was present in the gut, the burst was significantly lessened and the mice were resistant to colitis for the rest of their lives. It was a remarkable finding about the importance of an early developmental window for the immune system and the need for the microbiome to be in place to avoid later-life disease.
Finally, the researchers asked whether the entire bacterium was needed or if a metabolite of the bacterium could produce the same beneficial effect on the developing immune system. They found that a particular type of lipid made by B. fragilis, given at just the right developmental window, could suppress the amount of iNKT cell proliferation and make the mice resistant to colitis. This is one gut bacterium, one immune change, and one NCD. Imagine the opportunities to reduce the prevalence of NCDs when the entire microbiome can be effectively managed to support the best possible cultivation of your immune system.
It is obvious perhaps, but this fact about death from infection needs to be emphasized. Unless the infection causes immediate failure in vital organs or blood vessels, such as with the Ebola virus, risk of death usually comes down to how the immune system responds to the infection. The Spanish flu pandemic of 1918–19 took an estimated 21.5 million lives globally, including approximately 675,000 in the United States. But many people were infected and survived. In fact, if you look at who died and who got infected but didn’t die during the pandemic, it came down to which individuals mounted responses that, in attempting to kill the virus in the lungs, led to complications that compromised lung function. It is thought that they mobilized an unhelpful, aberrant inflammatory response. The immune system can save your life, or it can kill you. It just depends. In the case of that flu, it appears that an overzealous, unrelenting immune attempt to purge the body of the virus led to many deaths, particularly among healthy young adults.
The same thing can and has happened with bacterial infections. Wiping out bacteria with the use of antibiotics does not mean a patient automatically survives. Some pathogenic bacteria carry what are called toxins. These toxins are chemicals in the bacteria’s outer cell makeup that cause immune cells such as macrophages to go just a little crazy and start shooting first and asking questions later. This is a part of what we usually refer to as the inflammatory response. The inflammatory response is a good thing if it is in the right place, of the right kind, at the right level, and ends when it is no longer needed. Anything other than that is a problem.
Bacteria are usually not a huge problem if the bacteria are few in numbers and localized to one place in the body. But even if the bacteria die, such as after exposure to antibiotics, their outer layers or shells carrying the toxins must be cleared from the body. This is a job for macrophages and their friends. There are two major categories of bacteria: gram-positive and gram-negative. For our purposes the important thing to know is that each carry different sets of toxins. Gram-negative bacteria are powerful direct activators of innate immune cells (e.g., cells such as macrophages and neutrophils that are capable of a generic type of immediate response to pathogens). Some gram-positive bacteria have toxins that cause massive T lymphocyte (thymus-derived lymphocyte) activation, producing a storm of immune hormones known as cytokines. This cytokine storm, in turn, activates macrophages for destruction. An example of this in humans is toxic shock syndrome.
If the toxins have actually made it into the blood at high enough levels, innate immune cells in the blood go crazy and start shooting there. That is never a good idea. It destroys the blood vessels and produces what is call septic shock. This is very serious, and patients often have only minutes to receive treatment or they will die. Sometimes the toxin levels are so high it is difficult to save the patient. That is why physicians like to kill bacteria slowly with antibiotics (over one to two weeks) and not all at once. Here again the dead bacteria are not killing the patient. The bacteria are already dead. Innate immune cells responding to the perceived threat are killing the patient. Does this actually lead to death? Yes. Your host defense system can unintentionally destroy itself. In fact, Dr. Kevin Tracey has catalogued numerous examples of why what are usually nonfatal infections can lead to immune-inflicted death in his 2006 book Fatal Sequence: The Killer Within.
An improperly educated, dysfunctional, or out-of-control immune system can make you very sick and kill you. You need the immune system to develop appropriately, to function in a controlled manner, to function in balance, and to recognize and respond to actual threats but tolerate and leave alone your healthy cells and tissues as well as innocuous environmental factors (e.g., foods and allergens). The best way to ensure this happens is to connect the immune system with a healthy microbiome from birth to have the immune system properly educated and brought into balance. We now know that protecting our microbiome has this essential purpose.