Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues (31 page)

The differences were stark and almost paradoxical. The 157 North Americans had only a few taxa that were unique to them, while the 12 Amerindians had more than a hundred unique species that were not present in most of the U.S. subjects. Plus they had more taxa than the U.S. subjects by far, even though many species were found in low numbers. How to explain this asymmetry? One interpretation is that many of the microbes they carried had disappeared from us as a result of our exposures to antibiotics and other aspects of medical care and, indeed, of modern life.

Here, too, was important evidence supporting my nearly twenty-year-old hypothesis. The graphs were visually beautiful and the contrasts clear. It did not take complex statistical analyses to see the major differences between the samples from the two populations. Someday these ancient microbes, missing from us, might be used to protect our children from the modern diseases now plaguing them and that the villagers are not suffering from. One day we might give them back to our babies to fill the modern void.

*   *   *

As with fecal transfer, the idea is to somehow restore the missing microbes. They might come from faraway places or from your own family. I can imagine grandmothers who have not taken so many antibiotics in their lifetime giving their bacteria to their grandbabies.

I imagine that babies in the future might undergo a new kind of workup. For the one-month checkup, the doctor will examine the baby along with its poop and urine. In the lab, the bacteria will be sequenced and counted, and the urine analyzed for particular metabolites. Out will come a statement: baby doing fine but need to supplement with
Bifidobacterium
. And for another baby it might be
Allobaculum,
and for the third
Oxalobacter.
So the doctor will order up from the formulary the optimal culture for that child. And for another child, the composition of the cultures likely will differ.

Maybe these microbes will be applied to the mom’s nipple so that the baby can take them in with mom’s milk. Or maybe they will get a special dosage of formula, let’s say with some cells of
Oxalobacter
and oxalate, the nutrient that this microbe loves but that we can’t digest. Such a “synbiotic” approach will help get the strain started: the probiotic with its prebiotic. These are not just random organisms. In my lab at NYU, we are studying each of these and their relationship with humans.

In 1998 I predicted in the
British Medical Journal
that we would one day be giving
H. pylori
, a disappeared organism, back to our children. Since then, the support for this idea has only grown deeper and the list of disappeared organisms longer. But these are early days in the discovery process; most of the workings of the mechanisms are still secret.

EPILOGUE

Karl Benz, Henry Ford, and the other automotive inventors in the late nineteenth and early twentieth centuries made a monumental contribution to human life. They invented, perfected, and mass-produced the internal combustion engine, a machine that enables us to drive to work, to carry large loads, to go on holidays, to explore the world, and much more. Human existence has changed as a result: we are more interconnected, we can war at longer range, we can meet people of all different ethnicities and cultures.

We already know that the internal combustion engine also has spawned a host of new problems or worsened those we already had: air pollution, vehicular homicide, traffic jams. Perhaps Ford could have anticipated these; although they were unintended, they could have been imagined. Cities with horse-drawn carriages had traffic tie-ups, and all of the excreta was not exactly pleasant. As such, many of the problems that followed the widespread introduction of the internal combustion engine were extensions of the known.

Yet imagine that about a hundred years ago someone told Henry Ford that every time a person turned the ignition in his or her car, the ice cap in Greenland would melt a little. It would have been unfathomable, and Ford likely would have dismissed it immediately. What if someone told
you
that same thought about thirty years ago? You probably also would have thought that it was ridiculous. How could those two occurrences be related? Yet we know how the unconnected become connected. This is one example of how our successful inventions are transforming our “macroecology,” the status of our planet.

The story I have told concerns how we are changing our “microecology” with well-intended and indeed life-saving measures like antibiotics and Cesarian sections. That the resident microbes living in us are changing with disastrous results may seem as foreign as global warming would have been to Ford. But now, more than forty years after the “Earth” movement began, I believe that we are finally primed to contemplate and address these changes.

The ill effects in this story may be no less profound than those related to global warming and, in fact, may be operating on a shorter time frame. I do not wish to ban antibiotics or Cesarian sections any more than anyone would suggest banning automobiles. I ask only that they be used more wisely and that antidotes to their worst side effects be developed. The truth is always obvious in retrospect. How could people really have thought that the sun revolves around Earth or that Earth is flat? Yet dogma are powerful and to their adherents infallible.

Once the question, Do antibiotics have a biological cost as well as clear benefits? is even posed, the horizon begins to shift. The answer is that, of course, our powerful antibiotics could affect our friendly bacteria. Of course, changing the mechanics of labor and delivery from the ancient ways to the modern in a third or half of our births today could have effects. Of course, purposely removing our natural microbial inhabitants is likely to have complex consequences.

The logic is inescapable. Our ancient microbes are there for a reason; that’s how we evolved. Everything that changes them has a potential cost to us. We have changed them plenty. The costs are already here, but we are only just beginning to recognize them. They will escalate.

The moment for substantive change is now. But change takes time, and reversal of the losses takes even longer. As with global warming, there is the risk that the status quo is “locked in.” Yet I am optimistic. The changes in human microecology have been going on for only about a century and especially the past sixty to seventy years. This is the blink of an eye in the totality of human experience. Change that comes fast can depart just as rapidly.

We stand at the proverbial crossroads. We have medicines and practices that have served us well but have had unintended consequences. With powerful agents of any kind, there always are unintended consequences, so it should be no surprise. But the wake-up call is that we are not talking about uncommon events. The practices that endanger our children are at the core of modern health care.

We have made so much real progress in combating and eradicating terrible diseases. But now perhaps our efforts have peaked, and the fruits of discovery have left their seeds, indigestible and toxic. We must act, for the consequences are beginning to swallow us, and stronger storms lie ahead.

Yet many types of solutions are available. And with some of these, there may be synergies, combining the effects of two approaches, like curtailing both C-sections and antibiotic use, and eventually replacing disappeared organisms. For the future of our children and theirs, it is time for us to begin implementing them in earnest.

NOTES

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1. MODERN PLAGUES

have been getting healthier:
In ancient times, one-third to one-half of children did not survive until the age of five. (See T. Volk and J. Atkinson, “Is child death the crucible of human evolution?”
Journal of Social, Evolutionary and Cultural Psychology
2 [2008]: 247–60.) Childhood death rates remained high through the nineteenth century. Even by 1900, in some U.S. cities up to 30 percent of infants died without seeing their first birthday. (See R. A. Meckel,
Save the Babies: American Public Health Reform and the Prevention of Infant Mortality, 1850–1929
[Baltimore: Johns Hopkins University Press, 1990].) By the twentieth century, improved public health started to make a huge difference; infant mortality went from about 100/1,000 in 1915 to about 10 in 1995 (
Morbidity and Mortality Weekly Report
48 [1999]: 849–58). Childhood mortality rates have continued to fall in the last half century (G. K. Singh and S. M. Yu, “U.S. childhood mortality, 1950 through 1993: trends and socioeconomic differentials,”
American Journal of Public Health
86 [1996]: 505–12).

worldwide obesity epidemic:
Although increased body mass ultimately reflects more calories in than out, obesity is a complex issue. The question of whether all food calories are equal in terms of human metabolism is controversial. Issues such as physical and psychological stress and lack of sleep may affect
(increasing)
food intake. Lack of exercise may play a role in weight gain disproportionate to its direct effect on calorie expenditure. Maternal smoking, prenatal environment, hormone disruptors, and salted-food addiction all have been postulated as causative, and even chemical toxins have been considered to play a role. (P. F. Baillie-Hamilton, “Chemical toxins: a hypothesis to explain the global obesity epidemic,”
Journal of Alternative and Complementary Medicine
8 [2002]: 185–92.)

has risen 550 percent since 1950:
In developed countries, juvenile (Type 1) diabetes has been steadily rising. (V. Harjutsalo et al., “Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study,”
Lancet
371 [2008]: 1777–82.) Although, after more than fifty years of continued growth and a recent period of accelerated growth, the incidence appears to be leveling off, possibly because of public-health activities. (V. Harjutsalo et al., “Incidence of type 1 diabetes in Finland,”
Journal of the American Medical Association
, 310 [2013]: 427–28.) Worldwide, the annual increase in Type 1 diabetes in recent years has been about 3 percent. (P. Onkamo et al., “Worldwide increase in incidence of Type I diabetes—the analysis of the data on published incidence trends,”
Diabetologia
42 [1999]: 1395–403.)

resemble those of adults:
T. Yatsunenko et al., “Human gut microbiome viewed across age and geography,”
Nature
486 (2012): 222–27. In this study, after comparing the gut microbiota from people in the United States, Malawi, and Venezuela (Amerindians), researchers found that the compositions in infants were markedly different from those in adults. But as children matured, their microbiomes became more and more adultlike. Importantly, the age at which this happens is three. The transition from no microbiota to an adultlike microbiota is all accomplished during the earliest stages of life, just as many functions in the host are developing.

the “disappearing microbiota”:
The disappearing-microbiota hypothesis evolved over a number of years. A few of my key papers that develop the theme include: “An endangered species in the stomach,”
Scientific American
292 (February 2005): 38–45; “Who are we? Indigenous microbes and the ecology of human disease,”
EMBO Reports
7 (2006): 956–60; with my very distinguished colleague Stanley Falkow, “What are the consequences of the disappearing microbiota?”
Nature Reviews Microbiology
7 (2009): 887–94; “Stop killing our beneficial bacteria,”
Nature
476 (2011): 393–94.

“cloak of invisibility”:
The discovery of the stealth mechanisms of
Campylobacter fetus
involved a progressive series of experiments conducted over nearly twenty years. A few of the key papers include: M. J. Blaser et al., “Susceptibility of
Campylobacter
isolates to the bactericidal activity in human serum,”
Journal of Infectious Diseases
151 (1985): 227–35; M. J. Blaser et al., “Pathogenesis of
Campylobacter fetus
infections. Failure to bind C3b explains serum and phagocytosis resistance,”
Journal of Clinical Investigation
81 (1988): 1434–44; J. Dworkin and M. J. Blaser, “Generation of
Campylobacter fetus
S-layer protein diversity utilizes a single promoter on an invertible DNA segment,”
Molecular Microbiology
19 (1996): 1241–53; J. Dworkin and M. J. Blaser, “Nested DNA inversion as a paradigm of programmed gene rearrangement,”
Proceedings of the National Academy of Sciences
94 (1997): 985–90; Z. C. Tu et al., “Structure and genotypic plasticity of the
Campylobacter fetus sap
locus,”
Molecular Microbiology
48 (2003): 685–98.

and house cats (
Felis catus
)
: Unfortunately, taxonomy is often complicated because our house cats also have been classified as
Felis silvestris
, within the species of wildcats, or sometimes called
F. silvestris f. catus
. Still, a cat by any other name would meow.

natural defenses against it:
Based on our studies of variation in campylobacters and host responses to them, we began to study the same for the gastric campylobacter-like organism (or GCLO), which for a time was called
Campylobacter pyloridis
, then
Campylobacter pylori
, before eventually its current name,
Helicobacter pylori
, was agreed upon. Our first papers about this were: G. I. Pérez-Pérez, and M. J. Blaser, “Conservation and diversity of
Campylobacter pyloridis
major antigens,”
Infection and Immunity
55 (1987): 1256–63; and G. I. Pérez-Pérez, B. M. Dworkin, J. E. Chodos, and M. J. Blaser, “
Campylobacter pylori
antibodies in humans,”
Annals of Internal Medicine
109 (1988): 11–17. From these studies we developed a blood test (which is the basis for most of the blood tests used today in the United States) to diagnose whether or not a person has
H. pylori
in his or her stomach.