Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues (32 page)

“the only good
H. pylori
is a dead
H. pylori
”:
In response to my paper in the
Lancet
(M. J. Blaser, “Not all
Helicobacter pylori
strains are created equal: should all be eliminated?”
Lancet
349 [1997]: 1020–22), David Graham wrote to the editor: “The only good
Helicobacter pylori
is a dead
Helicobacter pylori
” (
Lancet
350 [1997]: 70–71). This became the signature concept for the present era.

our normal gut flora:
Flora
is the old name for the countless organisms that live in humans. We used to call them our normal flora. But bacteria are not plants, and the organisms that live in and on us are both small and diverse. We now call these organisms our
microbiota
. And all of the relationships between the microbiota and ourself, and with each other, are collectively called the
microbiome
.

2. OUR MICROBIAL PLANET

“his middle finger erases human history”:
J. McPhee,
Basin and Range,
book 1 in
Annals of the Former World
(New York: Farrar, Straus & Giroux, 1998).

a few exceptions that reinforce the rule:
H. N. Schulz et al., “Dense populations of a giant sulfur bacterium in Namibian shelf sediments,”
Science
284 (1999): 493–95. But such large microbes are the anomalies in a world dominated by microscopic forms.

the distance between corn and us:
N. Pace, “A molecular view of microbial diversity and the biosphere,”
Science
276 (1997): 734–40. To Carl Woese, Norman Pace, and many others, bacteria were at the very origins of all life on Earth.

240 billion African elephants:
W. B. Whitman et al., “Prokaryotes: The unseen majority,”
Proceedings of the National Academy of Sciences
95 (1998): 6578–83; J. S. Lipp et al., “Significant contribution of Archaea to extant biomass in marine subsurface sediments,”
Nature
454 (2008): 991–94; and M. L. Sogin et al., “Microbial diversity in the deep sea and the underexplored ‘rare biosphere,’”
Proceedings of the National Academy of Sciences
103 (2006): 12115–20.

selection in action:
Plastic-eating bacteria. T. Suyama et al., “Phylogenetic affiliation of soil bacteria that degrade aliphatic polyesters available commercially as biodegradable plastics,”
Applied and Environmental Microbiology
64 (1998): 5008–11; E. R. Zettler et al., “Life in the ‘plastisphere’: microbial communities on plastic marine debris,”
Environmental Science and Technology
47 (2013): 7137–46.

water, and bacteria—loads of them:
T. O. Stevens and J. P. McKinley, “Lithoautotrophic microbial ecosystems in deep basalt aquifers,”
Science
270 (1995): 450–54.

the common intestinal bacterium
E. coli
:
E. coli’s
formal name is
Escherichia coli
, honoring Theodor Escherich, a German doctor who discovered it in 1885 in the feces of healthy people, and called it
Bacterium coli commune.
In the early twentieth century, the name was changed to
Escherichia coli.
Although the best-known bacteria in the human gastrointestinal tract, it usually represents less than one-thousandth of all the bacterial cells present. While most
E. coli
strains are harmless, there are distinct strains that can cause several different types of disease. Because of the ease of growing
E. coli
in culture, it has become a model organism to study the biology, biochemistry, and genetics of cellular life. Many of the five thousand genes in
E. coli
cells have analogues in human cells.

“and ever shall be, until the world ends”:
In 1993 S. J. Gould wrote a review that appeared in
Nature
about E. O. Wilson’s then new book
The Diversity of Life
, in which he indicates that Wilson already knows that rather than an individual age of reptiles or of mammals, these are but parts of the eternal age of bacteria, as he so states. (S. J. Gould, “Prophet for the Earth: Review of E. O. Wilson’s ‘The diversity of life’,”
Nature
361 [1993]: 311–12.)

3. THE HUMAN MICROBIOME

They are symbionts:
Symbiosis, defined in the nineteenth century, is the close relationship of two (or more) species living together, sometimes for most or all of their lifetimes. Although it may mean living together harmfully, neutrally, or helpfully, it also can be used to describe just the mutually helpful relationships. A species party to such a relationship is a symbiont.

Aphids, small insects that live on plants:
N. Moran, “The evolution of aphid life cycles,”
Annual Review of Entomology
37 (1992): 321–48.

more apelike than cowlike:
H. Ochman et al., “Evolutionary relationships of wild hominids recapitulated by gut microbial communities,”
PLOS Biology
8 (2010): e1000546.

Of fifty known phyla:
A phylum is a term in biology referring to the taxonomic classification between kingdom and class. The kingdom Anamalia, encompassing all animals, has about thirty-five phyla, ranging from Arthropoda (insects) to Chordata (having a spinal cord, like humans).

in your mother’s womb, you had no bacteria:
This has been the long-held belief, but evidence is beginning to emerge that even in the womb in many animals microbes are normally present (L. J. Funkhouser and S. Bordenstein, “Mom knows best: the universality of maternal microbial transmission,”
PLOS Biology
11 [2013]: e1001631). However, this is still an area of controversy. We will probably know for sure, one way or the other, in humans in a couple of years.

over the first three years of life:
In a study of the gut microbiota of healthy people in three places—the United States, Malawi, and Venezuela (Amerindians)—Yatsunenko and her colleagues, including my wife, Gloria, catalogued which microbes were present across people of all ages. In early life, there were great similarities between the three different ethnic groups, but as they got older they diverged. Perhaps most important, the composition of the microbiota in infants is very different from that of adults, but gradually it becomes more and more adultlike, reaching adult levels by the age of three! (T. Yatsunenko et al., “Human gut microbiome viewed across age and geography,”
Nature
486 [2012]: 222–27.) Initially I was surprised, but the more I thought about it, the more sense it made—the microbiome develops in parallel with the development of the child. This was consistent with my hypotheses about the importance of the early-life microbiota.

are home to different species:
We did the first survey of the skin using molecular methods beginning in 2004 and showed the incredible diversity but also the symmetry between left and right. (Z. Gao et al., “Molecular analysis of human forearm superficial skin bacterial biota,”
Proceedings of the National Academy of Sciences
104 [2007]: 2927–32.) Then, using more powerful methods, other investigators confirmed and extended the observations, showing more subtle differences between left and right hands, and how our computer keyboards carry the microbial signatures of our fingertips—that is, we can tell your keyboard from mine (N. Fierer et al., “Forensic identification using skin bacterial communities,”
Proceedings of the National Academy of Sciences
107 [2010]: 6477–81). They also showed that each of the three major types of skin—dry, moist, and oily—has its own major populations (E. A. Grice et al., “Topical and temporal diversity of the human skin microbiome,”
Science
324 [2009]: 1190–92), and that a single group of fungi dominate in most of our skin, except for the bottom of our feet (K. Findley et al., “Topographic diversity of fungal and bacterial communities in human skin,”
Nature
498 [2013]: 367–70).

250 healthy young adults:
The large Human Microbiome Project sponsored by the National Institutes of Health made incredible progress in laying out the fundamentals of our microbial composition. In the important study of healthy young adults in the United States (actually in Houston and St. Louis), the outlines of the human microbiome were shown. (C. Huttenhower et al., “Structure, function and diversity of the healthy human microbiome,”
Nature
486 [2012]: 207–14.) In this paper, there were nearly as many authors (me included) as there were subjects, but it was a very complex “big science” national effort that paid large dividends—and that will keep paying as more and more scientists use the trove of information accumulated, from sampling at sixteen sites in men and women, plus three vaginal sites in the women. From that study, for example, we know much more about the populations in the mouth: how the top of the tongue, hard palate, and cheek are more similar to one another than to the gingival crevices.

they don’t like oxygen:
The microbial composition of the gingival crevice is vast: its density is similar to that in the colon, and the variety of bacteria is enormous (I. Kroes et al., “Bacterial diversity within the human subgingival crevice,”
Proceedings of the National Academy of Sciences
96 [1999]: 14547–52; and ibid.). That interface between tooth and gum is where periodontal disease occurs, and the hope is that by better understanding the microbial populations and their dynamics, we will be better able to prevent or treat this major cause of tooth loss.

who is attractive to mosquitoes:
N. O. Verhulst et al., “Composition of human skin microbiota affects attractiveness to malaria mosquitoes,”
PLOS ONE
6 (2011): e28991.

dozens of species living there:
Z. Pei et al., “Bacterial biota in the human distal esophagus,”
Proceedings of the National Academy of Sciences
101 (2004): 4250–55. Until we published our paper, no one thought that the esophagus had any residential bacteria, only transients traveling from the mouth and throat down.

colonic bacteria and in their functions:
Just as we can construct family trees of plants and animals, using new computational tools, we can do the same for the bacterial populations living in different ecological niches. We can compare the composition of microbial populations living in freshwater ponds to those in the oceans. (Not surprisingly, they are quite different.) When such tools are applied to the compositions of the colonic microbes in, for example, mice and humans, we can see enormous parallels (R. E. Ley et al., “Worlds within worlds: evolution of the vertebrate gut microbiota,”
Nature Reviews Microbiology
6 [2008]: 776–88). At higher taxonomic levels, starting at the phylum, we are nearly identical, but as we descend the phylogenic ladder, the differences become greater until, at the species level, mouse and human are highly distinct. In a way, these microbial similarities and differences capture our evolution from a common ancestor to distinct species—
Mus musculus
and
Homo sapiens
—as well as our own genetic inheritance. Yes, even our cohabiting microbes inform us that “ontogeny recapitulates phylogeny,” a concept in evolutionary biology I learned as a high school student, long before I could even guess what evolution was all about.

the activities of your microbes:
W. R. Wikoff et al., “Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites,”
Proceedings of the National Academy of Sciences
106 (2009): 3698–703. Investigators compared germ-free mice (born in bubbles and without any bacteria at all) and more conventionally raised mice. They used very sensitive chemical sampling and detection methods to examine the contents in the bloodstreams of the two groups of mice. Of nearly 4,200 chemical constituents, only 52, slightly more than 1 percent, were seen in the blood of the germ-free animals; the more than 4,000 others were ultimately derived from bacterial metabolism. These studies provided evidence that most of the chemical constituents in the blood of mice (and thus by extension in us) are ultimately derived from having microbiota and from their interaction with our cells.

first chemical processing and then absorption:
H. J. Haiser et al., “Predicting and manipulating cardiac drug inactivation by the human gut bacterium
Eggerthella lenta
,”
Science
341 (2013): 295–98.

at least for a short period:
R. Avallone et al., “Endogenous benzodiazepine-like compounds and diazepam binding inhibitor in serum of patients with liver cirrhosis with and without overt encephalopathy,”
Gut
42 (1998): 861–67.

which is low in protein:
The sweet potato is about 2 percent protein, so an adult would have to eat about five pounds of sweet potato a day to ingest enough protein.

essentially lacks
Lactobacillus:
J. Ravel et al., “Vaginal microbiome of reproductive-age women,”
Proceedings of the National Academy of Sciences
108, suppl. 1 (2011): 4680–87.

gut microbiome is relatively stable:
J. Faith et al., “The long-term stability of the human gut microbiota,”
Science
341 (2013): DOI: 10.1126/science.1237439. By studying the same people over time, often years, Jeff Gordon’s lab showed that although there is turnover in the organisms that can be detected, there also is considerable stability. In their study, about 70 percent of the organisms present in adults on sampling were estimated to be present one year later.

the changes in microbial populations were more significant:
Dr. Nanette Steinle from the University of Maryland presented the data on the dry bean/lentil study at the American Society for Nutrition’s poster session on April 23, 2013. In other work, immediate diet effects on the microbiome were seen, but with long-term stability of overall composition. (See G. Wu et al., “Linking long-term dietary patterns with gut microbial enterotypes,”
Science
334 [2011]: 105–8.)