Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues (36 page)

strains had double the risk:
Four papers all published in 1991 showed strong associations of having
H. pylori
and developing gastric cancer: J. Parsonnet et al., “
Helicobacter pylori
infection and the risk of gastric carcinoma,”
New England Journal of Medicine
325 (1991): 1127–31; A. Nomura et al., “
Helicobacter pylori
infection and gastric carcinoma among Japanese Americans in Hawaii,”
New England Journal of Medicine
325 (1991): 1132–36; D. Forman et al., “Association between infection with
Helicobacter pylori
and risk of gastric cancer: evidence from a prospective investigation,”
British Medical Journal
302 (1991): 1302–5; and N. J. Talley et al., “Gastric adenocarcinoma and
Helicobacter pylori
infection,”
Journal of the National Cancer Institute
83 (1991): 1734–39. Later we showed that having a
cagA
+
strain just about doubled the risk of gastric cancer development (M. J. Blaser et al., “Infection with
Helicobacter pylori
strains possessing
cagA
is associated with an increased risk of developing adenocarcinoma of the stomach,”
Cancer Research
55 [1995]: 2111–15) and of its precursor, chronic atrophic gastritis (E. J. Kuipers et al., “
Helicobacter pylori
and atrophic gastritis: importance of the cagA status,”
Journal of the National Cancer Institute
87 [1995]: 1777–80).

“the only good
Helicobacter
pylori is a dead one”:
D. Y. Graham, “The only good
Helicobacter pylori
is a dead
Helicobacter pylori
,”
Lancet
350 (1997): 70–71.

This ancient organism:
Evidence that
H. pylori
is ancient: D. Falush et al., “Traces of human migration in
Helicobacter pylori
populations,”
Science
299 (2003): 1582–85; B. Linz et al., “An African origin for the intimate association between humans and
Helicobacter pylori
,”
Nature
445 (2007): 915–18; Y. Moodley et al., “The peopling of the Pacific from a bacterial perspective,”
Science
323 (2009): 527–30; S. Breurec et al., “Evolutionary history of
Helicobacter pylori
sequences reflect past human migrations in Southeast Asia,”
PLOS ONE
6 (2011): e22058: 1–10; and Y. Moodley et al., “Age of the association between
Helicobacter pylori
and man,”
PLOS Pathogens
8 (2012): e1002693: 1–16.

whether his mother has it:
J. Raymond et al., “Genetic and transmission analysis of
Helicobacter pylori
strains within a family,”
Emerging Infectious Diseases
10 (2004): 1816–21.

the human stomach has changed markedly:
M. J. Blaser, “
Helicobacter pylori
eradication and its implications for the future,”
Alimentary Pharmacology and Therapeutics
11, suppl. 1 (1997): 103–7; “Not all
Helicobacter pylori
strains are created equal: should all be eliminated?” 349
Lancet
(1997): 1020–22; “Helicobacters are indigenous to the human stomach: duodenal ulceration is due to changes in gastric microecology in the modern era,”
Gut
43 (1998): 721–27; “In a world of black and white,
Helicobacter pylori
is gray,”
Annals of Internal Medicine
130 (1999): 695–97.

they’re safely across:
M. J. Blaser and D. Kirschner, “The equilibria that allow bacterial persistence in human hosts,”
Nature
449 (2007): 843–49.

10. HEARTBURN

have symptoms every day:
G. M. Eisen et al., “The relationship between gastroesophageal reflux and its complications with Barrett’s esophagus,”
American Journal of Gastroenterology
92 (1997): 27–31; and H. B. El-Serag, “Time trends of gastroesophageal reflux disease: a systematic review,”
Clinical Gastroenterology and Hepatology
5 (2007): 17–26.

progress to the form of cancer called adenocarcinoma:
J. Lagergren et al., “Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma,”
New England Journal of Medicine
340 (1999): 825–31.

first identified in 1950:
In 1950, Norman Barrett, an English surgeon, reported finding abnormal tissue in the esophagus. We now call that abnormality Barrett’s esophagus, and he became Sir Norman Barrett.

in the past three decades:
The incidence of adenocarcinoma of the esophagus is rising, and not just because of better surveillance and reporting. (See H. Pohl and H. G. Welsh, “The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence,”
Journal of the National Cancer Institute
97 [2005]: 142–46.)

eight times more likely:
J. J. Vicari et al., “The seroprevalence of
cagA
-positive
Helicobacter pylori
strains in the spectrum of gastroesophageal reflux disease,”
Gastroenterology
115 (1998): 50–57; and M. F. Vaezi et al., “
CagA-
positive strains of
Helicobacter pylori
may protect against Barrett’s esophagus,”
American Journal of Gastroenterology
95 (2000): 2206–11. Other more recent GERD/Barrett’s studies include: D. Corley et al., “
Helicobacter pylori
infection and the risk of Barrett’s oesophagus: a community-based study,”
Gut
57 (2008): 727–33; and L. A. Anderson et al., “Relationship between
Helicobacter pylori
infection and gastric atrophy and the stages of the oesophageal inflammation, metaplasia, adenocarcinoma sequence: results from the FINBAR case-control study,”
Gut
57 (2008): 734–39. All show inverse associations, with the strongest data from the Corley study showing that people with
cagA
+
strains have a 92 percent reduction in the risk of developing Barrett’s esophagus.

double the rate of esophageal disease:
J. Labenz et al., “Curing
Helicobacter pylori
infection in patients with duodenal ulcer may provoke reflux esophagitis,”
Gastroenterology
112 (1997): 1442–47.

colleagues from around the world:
W. H. Chow et al., “An inverse relation between
cagA
+
strains of
Helicobacter pylori
infection and risk of esophageal and gastric cardia adenocarcinoma,”
Cancer Research
58 (1998): 588–90; R. Peek et al., “The role of
Helicobacter pylori cagA
+
strains and specific host immune responses on the development of premalignant and malignant lesions of the gastric cardia,”
International Journal of Cancer
82 (1999): 520–24; R. J. L. F. Loffeld et al., “Colonization with
cagA
-positive
H. pylori
strains inversely associated with reflux oesophagitis and Barrett’s oesophagitis,”
Digestion
62 (2000): 95–99; and F. Kamangar et al., “Opposing risks of gastric cardia and noncardia gastric adenocarcinomas associated with
Helicobacter pylori
seropositivity,”
Journal of the National Cancer Institute
98 (2006): 1445–52.

and are more damaging:
Two studies that were presented at scientific congresses in the late 1990s were very instructive. In the Eurogast Study (P. M. Webb et al., “Gastric cancer, cytotoxin-associated gene A-positive
Helicobacter pylori
, and serum pepsinogens: an international study,”
Gastroenterology
116 [1999]: 269–76), 2,850 patients in thirteen countries who underwent upper gastrointestinal endoscopy were examined with stomach biopsies, and assessed for blood levels of proteins that are made in the stomach. As was by then expected, people with
H. pylori
had a higher rate of showing a blood-protein (pepsinogen) ratio indicative of atrophic changes than those without the organism, and those with
cagA
+
strains had even more altered blood-protein ratios than those with
cagA
-negative strains. In a contemporaneous study, Y. Yamaji et al. (“Inverse background of
Helicobacter pylori
antibody and pepsinogen in reflux oesophagitis compared with gastric cancer: analysis of 5732 Japanese subjects,”
Gut
49 [2001]: 335–40) showed that in Japan people who had reflux had a pattern of gastric tissue changes and protein production that was the inverse of those with stomach cancer. As the signs of atrophic gastritis—a precursor to gastric cancer—rose, the prevalence of reflux fell. These two studies, done with thousands of patients, provide support for the mixed roles of
H. pylori
vis-à-vis diseases of the stomach and the esophagus.

11. TROUBLE BREATHING

we understood how these strains operate:
Mechanism of action in CagA
+
strains. In 1995 we published the first evidence that
H. pylori
had a Type-IV secretion system that could transport
H. pylori
products into the cells lining the stomach wall, but we did not know what was being exported (M. Tummuru et al.,
Helicobacter pylori
picB
, a homologue of the
Bordetella pertussis
toxin secretion protein, is required for induction of IL-8 in gastric epithelial cells,”
Molecular Microbiology
18 [1995]: 867–76). By 2000, several groups (most notably S. Odenbreit et al., “Translocation of
Helicobacter pylori
CagA into gastric epithelial cells by Type IV secretion,”
Science
287 [2000]: 1497–1500; as well as A. Covacci and R. Rappuoli, “Tyrosine-phosphorylated bacterial proteins: Trojan horses for the host cell,”
Journal of Experimental Medicine
191 [2000]: 587–92) proved that there was a Type-IV system, and that the material it injected was none other than the CagA protein that we (and Covacci) had found a decade earlier, in our case, probing the library of
H. pylori
genes with my serum (see chapter 9). No wonder that I made antibodies to CagA; the
H. pylori
strain that I was carrying was injecting the protein into my stomach wall every day for years.

at the age of seven:
A. L. Kozyrskyj et al., “Increased risk of childhood asthma from antibiotic use in early life,”
Chest
131 (2007): 1753–59.

in May of that year:
M. E. Fernández-Beros, L. Rogers, G. I. Pérez-Pérez, W. Hoerning, M. J. Blaser, and J. Reibman, “Seroprevalence of
Helicobacter pylori
is associated with later age of onset of asthma in urban adults,” abstract presented in May 2005 at the American Thoracic Society Annual Meeting in San Diego, CA.

the subject’s
H. pylori
status:
In the late 1990s Guillermo had run tests on more than eleven thousand people in that study as part of a government contract. He had just received little numbered tubes of serum without any knowledge of any of the characteristics of the people they came from. He was completely blinded, and some of the samples were in fact deliberate duplicates to see how reproducible the assays were. His results were beautifully reproducible, which made the sponsors (and us) very pleased. After the paper was published (J. E. Everhart et al., “Seroprevalence and ethnic differences in
Helicobacter pylori
infection among adults in the United States,”
Journal of Infectious Diseases
181 [2000]: 1359–63), eventually a lot of the data from NHANES III became publicly available in complicated tables and spreadsheets that qualified statisticians could examine. We had earlier examined the relationship of
H. pylori
and obesity using NHANES III (I. Cho et al., “
Helicobacter pylori
and overweight status in the United States: data from the Third National Health and Nutrition Examination Survey,”
American Journal of Epidemiology
162 [2005]: 579–84) and did not find any relationship, but we had practice using the complex NHANES III data set.

my hypothesis was correct:
J. Reibman et al., “Asthma is inversely associated with
Helicobacter pylori
status in an urban population,”
PLOS ONE
3 (2008): e4060: 1–6; and Y. Chen and M. J. Blaser, “Inverse associations of
Helicobacter pylori
with asthma and allergies,”
Archives of Internal Medicine
167 (2007): 821–27.

studies show consistent results:
Y. Chen and M. J. Blaser, “
Helicobacter pylori
colonization is inversely associated with childhood asthma,”
Journal of Infectious Diseases
198 (2008): 553–60.

the modern
H. pylori
–free stomach:
R. Rad et al., “CD25
+
/Foxp3
+
T cells regulate gastric inflammation and
Helicobacter pylori
colonization in vivo,”
Gastroenterology
131 (2006): 525–37; and K. Robinson et al., “
Helicobacter pylori
–induced peptic ulcer disease is associated with inadequate regulatory T cell responses,”
Gut
57 (2008): 1375–85.

as Mueller and her colleagues showed in mice:
I. C. Arnold et al., “
Helicobacter pylori
infection prevents allergic asthma in mouse models through the induction of regulatory T cells,”
Journal of Clinical Investigation
121 (2011): 3088–93; and M. Oertli et al., “DC-derived IL-18 drives Treg differentiation, murine
Helicobacter pylori
–specific immune tolerance, and asthma protection,”
Journal of Clinical Investigation
122 (2012): 1082–96.