Welcome to HOT TOPIC, Evmedreview’s latest special feature of compelling, in-depth articles from major voices in the field of evolutionary medicine, highlighting urgent problems in the world of medicine today that evolutionary medicine has either identified, or upon which it is shedding some new light, and where it may be able to contribute to solutions. This inaugural article is written by Prof. Martin J. Blaser, of the New York University School of Medicine. We have known for some time that overuse of antibiotics can lead to multiple antibiotic resistance. But Blaser here draws our attention to, and describes in fine detail, the way in which over-prescription of antibiotics is gradually depleting human microbiomes and may be seeding a generation-by-generation growth of a wide spectrum of life-shortening diseases in our children. Scroll to the end to see the interesting comments and add your own now, or send us a potential post at [email protected]
The long-term risks of antibiotic treatment in childhood: Antibiotics as panacea, or as opening Pandora’s box?
Muriel G. and George W. Singer Professor of Translational Medicine
Director, Human Microbiome Program
New York University Langone Medical Center
New York, NY 10016
The development of antibiotics was one of the greatest discoveries of the 20th century, and arguably the most important in the field of medicine and health (1). Not only can antibiotics be used to treat diseases that were previously untreatable, but they provide the safety net without which surgery, chemotherapy for cancer, and transplantation would have markedly heightened risk or be impossible.
In consequence, essentially since their widespread introduction in the years following World War II, the notion that antibiotics are miraculous has been a part of the general idiom, to both health professionals and the public alike. Thus, not surprisingly, antibiotics have been used more and more, for all manner of purposes—in the clinic, on the farm, in the aquarium. Their direct use in people worldwide was estimated at more than 70 billion doses annually (2), or 10 doses for every man, woman, and child on Earth. In the United States, about 262 million courses were used in 2011, a rate of 842/1000 population (3), more than five courses for every six people. For young children, rates are even higher, estimated as 1.35/year for US children in the first 2 years of life, representing nearly 3 courses during that time, and about 10 courses by the age of 10 (4).
This enormous use has been predicated on a conceptual framework of few or no substantial risks to the individual from taking antibiotics. As such, any perceived benefit, however small, is considered an indication for antibiotic use. Thus, to both physicians and patients, why not try an antibiotic? “Can’t hurt and it might help!”
2. Bacteria, our ancient companions, as our partners.
Bacteria were here first on this planet, evolving about 4 billion years ago. All known forms of life evolved from bacteria. Further, all of this subsequent life evolved in the presence of bacteria. Thus, the very existence of all plants and animals on earth is based on their ability to control or harness adjacent bacteria, whether in or on them or nearby.
All animal species have their own unique residential microorganisms. These organisms, which we refer to as the microbiota, live in and on their host, and when the intersecting metabolic pathways of microbes and host are included, the constellation has been referred to as the microbiome. In large hosts like humans, each of the multiple physiologic niches includes its own microbiome.
In animals, there is an important vertical component to the inheritance of each host’s microbiome. Stated differently, in addition to our human genome that we inherit from our parents, each of us inherits much of our microbiome from our mother. Recent studies of primates show strong co-speciation of hosts and microbes, representing a span of about 15 million years of hominid evolution (5, 6). This is consistent with studies more broadly across mammals, illustrating similar conservation over even longer time spans (7).
Thus, the genes we inherit from mom are not just human genes, but they are microbial. Viewed in this way, our microbiome represents a portion of our individual genetic endowment, as well as a component of our gene pool (8). The tension between vertical (8) and horizontal transmission of our microbiome is important, but most current data suggest that among long-term microbial residents, vertical predominates (9).
One further point is that even though babies inherit much of their vast microbiota from mom, the initial community structure is quite different from that of adults. However, by the age of 3 years, it becomes much more adult-like in its structure (10). Thus, the first three years of life are when the predominantly vertically acquired microbiome is developing its adult form. It is also the time when babies are developing their immunity, metabolism, and cognition.
As such, the first three years of life are a most critical time for human development. One hypothesis is that the development of a normally maturing microbiome affects physiological processes in salutary ways. We can conceive of a situation in which the initial microbiota may provide contextual instructions to the immune system to distinguish between self and non-self, adding the nuances of grey to a black/white dichotomy. Similarly, the infant must lay down the appropriate amount of adipose tissue, appropriate to its nutritional milieu, that will optimize the relationship between energy utilization and storage that will be a determinant of reproductive success. For example, if a young individual builds greater capacity for energy storage, it can better survive famines, but if it puts more into muscle and bone, it can fight and hunt better; this is a classical trade-off. Similarly, in social animals, the brain of the growing infant must set a cognitive pathway about how open or closed to interpersonal signaling they will be as they mature. There is widening evidence that the early life microbiome is a participant in the dialogue that determines how the host makes these immunologic, metabolic, and cognitive decisions. But the developing microbiome, crucial in the early life window of development, has limited resilience, and is vulnerable to perturbation (8, 11).
3. How antibiotics affect our bacterial partnerships.
We can especially focus on antibiotics as key agents causing micro-ecological change, because their use is so pervasive. Antibiotics were generally designed and used to eliminate single pathogens causing infections; doses were selected to achieve blood levels that inhibit the pathogen’s replication. However, there was little or no consideration of their effects when applied to the diverse microbiota colonizing each host. Such interactions were considered to be off-target, and in the short-term were generally mild, causing GI tract upset, skin rashes, or overgrowth by yeasts, for example. Usually there were no clinical effects at all. It was this apparent safety that lulled professionals and lay-people alike into what we have called ‘antibiotic sleep’ (12).
Yet the question remained, could off-target effects have long-term consequences?
Paradoxically, the answer came 70 years ago, near the beginning of the antibiotic era with strong evidence, and yet until recently it was missed (13, 14). The answers came from the practices of farmers who recognized that feeding antibiotics (generally in low doses for prolonged time periods) to their livestock promoted their growth (15). These widespread and extensively validated effects indicate that exposure to antibiotics changed the development of the recipients. It was a profound point, but the larger implications for human health were missed.
Collectively, the farmers made four crucial observations:
- Antibiotics worked in cows, swine, fish, chickens, and turkeys, among other species. This is a wide swath of vertebrate evolution. That it was not host species-specific indicated that the antibiotic exposure affected a broad and common principle.
- Virtually any anti-bacterial agent was effective, regardless of chemical composition, class, structure, or spectrum, but anti-virals and anti-fungals had no effects. The same anti-bacterial agents worked across multiple animal species, indicating that it was their anti-bacterial effects, not any specific activities of each compound that were the key to their effectiveness.
- Importantly, the younger the animals were when the antibiotics were started, the greater the effects—on growth rate, and on feed efficiency—the ability to convert food calories into body mass, which after all is what farmers are trying to do. This indicates that the process affected is developmental. Conversely, the later in life it was started in the animals, the lower the effect. This observation provides evidence that there may be a crucial ‘window’, the period of time during which an animal is susceptible to the antibiotic effects.
- Agents given orally were more effective for growth promotion than those given parenterally.
- Long-term health risks from perturbing our bacterial partnerships during childhood.
Taken together, these observations point to the importance of the bacteria of the gastrointestinal tract, across animal species, early in life, as the principal targets of the antibiotics, and as the principal intermediates to explain the efficacy of growth promotion. My laboratory has conducted studies in experimental animals that indicate that antibiotic use perturbs the intestinal microbiota and that it is the altered microbiota that is both necessary and sufficient to confer the effects on growth and metabolism (16-19). Parallel studies in other mouse models indicate activities that affect immunological development and disease (20).
In total, these observations are consistent with a role for antibiotics in the rise of many diseases that have their origins in childhood that are affected by altered immunological, metabolic, or cognitive processes. These include (but are not limited to) disorders that are primarily metabolic (obesity and type-2 diabetes), immunologic (asthma, allergies, juvenile (type-1) diabetes, inflammatory bowel disease), and cognition (autism and attention deficit disorder). These in fact are many of the diseases that have increased in incidence or have become epidemic around the world in recent decades.
With this theoretical and experimental background, a growing body of epidemiologic studies of human children have addressed the question of whether in fact antibiotic exposures are associated with the later development of these diseases. In brief, although the many studies differ in the diseases studied, their size, locales, definitions used, study designs, and statistical tools, there is substantial consistency showing positive associations (21-33).
Based on the totality of the evidence, I believe that we will find that every dose of an antibiotic given to young children has a delayed cost. For example, there might be an x% cost of asthma, y% cost of juvenile diabetes, and z% cost of inflammatory bowel disease. Each exposure might confer multiple costs, and my theory is that the costs are cumulative across exposures. However, we do not yet know what is the critical age window, nor the amounts for x, y, and z. Yet data are beginning to clarify the picture. A recent large study, involving all Danish children born over a nine-year period, showed that each antibiotic course was associated with an 18% increase in the risk of childhood-onset Crohn’s disease compared to untreated controls (23). In several epidemiological studies, the highest risks for later illnesses were associated with exposures in the first six months of life (26, 27), which is not surprising.
It is likely that the exact costs will vary in different populations, reflecting the nature of the status quo ante microbiome, which varies across populations (10, 34, 35), effects of maternal pre-partum antibiotics (36, 37), the extent of Cesarean delivery (21-25), the specific antibiotics used (38), and the particular disease risk of highest concern. Further, variations in health outcome may also occur because a perturbed microbiome is not the only factor driving to disease.
- Damage down the generations, and solutions.
Finally, and perhaps most worrisome is that antibiotics given in one generation might affect the health in the next and future generations. We already know that certain medicines given during pregnancy can adversely affect the health of the next generation. There is growing evidence of associations of maternal antibiotic use with particular outcomes (36, 37, 39, 40). However, this must be clearly sorted out since any observed associations might reflect the underlying infections for which the antibiotics were given. Yet, antibiotic use during pregnancy and even before (36, 37) will impact the maternal microbiome, just before the hand-off to the next generation. The girls of today are the mothers of tomorrow, and antibiotic exposures have the potential to affect their microbial compositions in permanent ways. It is important to reiterate that antibiotics are not the only factor that could affect the early life microbiota development and transfer to the next generation. Others include a variety of modern foods and food additives (e.g. emulsifiers, artificial sweeteners) (41, 42), and practices related to pregnancy and delivery (e.g. prophylaxes, Cesarean section, antibacterial washes).
We have hypothesized that the changes in microbiome are cumulative across recent human generations, reflecting a stepping down in biodiversity (14). If this is correct, and evidence is accumulating that it is (10, 34, 43-45), then we must halt the decline, and reverse it through restorative steps (35). I predict that the health practices of the future will involve restoring particular “missing microbes” to young children, based on the microbial needs of all children, and the needs of that specific child (46, 47).
In any event, the doctors of the future will need to take into consideration antibiotic cost data vis a vis the potential benefits in making therapeutic decisions. There are many infections that must be treated, but also a large number for which the benefit is marginal or nil. As in so many other areas of medicine, doctors will need to calculate potential benefit versus potential risk in the patient sitting in front of them, considering the future as well. As our knowledge of the costs becomes more precise, this will become increasingly necessary.
We must alter our views of the “antibiotic umbrella”, under which most of medicine is conducted. Doctors will have to improve their clinical skills to minimize antibiotic exposures unless necessary. There already is enormous heterogeneity in prescribing practices (3, 48-50), so some doctors already are there, while others lag substantially. In Sweden, per capita antibiotic use is about 40% of that in the USA (51), so change is not impossible. But change we must.
Acknowledgments. Supported by R01DK090989 and U01AI22285 from the National Institutes of health, and by the Ziff Family, Knapp, and the C & D funds. I thank Tiffany Archuleta and Joyce Ying for bibliographic support.
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I am grateful for Dr. Blaser’s convincing summary of, and contributions to, this critical field. The loss of bacteria from antibiotic overuse should be a concern for everyone. Antibiotics may also be contributing to a rise in psychopathology. A recent report from the Danish population shows a positive, linear correlation between adult antibiotic use and risk of developing schizophrenia and/or a mood disorder, even after controlling for several confounders, including exposure to antibiotics in childhood (1). Of course, the association does not prove causality: it may indicate that infections directly increase risk or that the same factors that increase susceptibility to infections also raise the risk of severe mental illness. Interested readers can look to great reviews on the topic of mental health and the microbiome (2,3). We desperately need more research into the long-term costs of antibiotic use to know how much harm doctors are doing with these miraculous drugs.
(1) Kohler, et al. “Infections and exposure to anti-infective agents and the risk of severe mental disorders: a nationwide study” Acta Psychiatr Scand 2016: 1–9.
(2) Bested, et al. “Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: Part II – contemporary contextual research” Gut Pathogens 2013, 5:3.
(3) Rook, et al. “Microbial ‘Old Friends’, immunoregulation and stress resilience” J Evolution, Medicine, and Public Health 2013 (1) : 46-64.
In this Hot Topic essay, Martin Blaser incisively describes the profound consequences for general health of disrupting the complex relationships between humans and the microbial world through extensive use of antibiotics in medicine and agriculture. In doing so, he effectively demonstrates that to fully understand and respond to the resulting perturbations of human development and physiology it is helpful to place these phenomena in their broader evolutionary and ecological contexts. Those interested in a fuller treatment of these issues can read his excellent book on the subject (1).
As is well known, another consequence of widespread use of antibiotics is the elicitation of bacterial resistance through the evolutionary processes of mutation and selection. In a recently published commentary (2), I address the need to place this phenomenon as well in a wider evolutionary context while offering pointed criticism of the terminology that currently dominates such discussions in the general media. The unfortunate tendency to refer to bacterial pathogens resistant to multiple antibiotics with the prefix “super” represents a target worthy of opprobrium because it fosters a narrow focus on the relationship between pathogens and our available antibiotics thereby obscuring other factors that may contribute to the evolutionary trajectories of these microbes, the risks of acquiring infection, and interventions other than antibiotics that might be useful to combat such risks.
(1) Blaser, M.J. “Missing Microbes: How the Overuse of Antibiotics is Fueling Our Modern Plagues,” Henry Holt and Company, New York, 2014.
(2) Greenspan, N.S. Greenspan, N.S. “Infectious supercarelessness” in discussing antibiotic-resistant bacteria. Pathogens and Immunity, 2016,1(2):304-307, doi 10.20411/pai.v1i2.160, published online on 12/15/16.