Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues (38 page)

the relationship of C-section with these other modern plagues:
Other disease risks for which some studies have shown increased risk with C-sections: A. K. Hansen et al., “Risk of respiratory morbidity in term infants delivered by elective caesarean section: cohort study,”
British Medical Journal
336 (2008): 85–87; C. Roduit et al., “Asthma at 8 years of age in children born by caesarean section,”
Thorax
64 (2008): 107–13; H. Renz-Polster et al., “Caesarean section delivery and the risk of allergic disorders in childhood,”
Clinical and Experimental Allergy
35 (2005): 1466–72; P. Bager et al., “Caesarean delivery and risk of atopy and allergic disease: meta-analyses,”
Clinical and Experimental Allergy
38 (2008) 634–42; and C. R. Cardwell et al., “Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: a meta-analysis of observational studies,”
Diabetologia
51 (2008): 726–35. Not every study shows an association with these diseases; some studies are small and underpowered, and others have multiple confounding factors, but there certainly is mounting evidence that the biological costs of C-section are experienced not just during the first month after birth.

14. MODERN PLAGUES REVISITED

disappearing before their second birthdays:
Type-1 DM epidemiology is changing in the United States: T. H. Lipman et al., “Increasing incidence of type 1 diabetes in youth. Twenty years of the Philadelphia Pediatric Diabetes Registry,”
Diabetes Care
36 (2013): 1597–1603; and in Europe: C. C. Patterson et al., “Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–2020: a multicenter prospective registration study,”
Lancet
373 (2009): 2027–33.

babies who gain weight more rapidly in the first year of life:
E. Bonifacio et al., “Cesarean section and interferon-induced helicase gene polymorphisms combine to increase childhood type 1 diabetes risk,”
Diabetes
60 (2011): 3300–306; R. M. Viner et al., “Childhood body mass index (BMI), breastfeeding and risk of Type 1 diabetes: findings from a longitudinal national birth cohort,”
Diabetic Medicine
25 (2008): 1056–61; M. Ljungkrantz et al., “Type 1 diabetes: increased height and weight gains in early childhood,”
Pediatric Diabetes
9 (2008): 50–56; and E. Hypponen et al., “Obesity, increased linear growth, and risk of type 1 diabetes in children,”
Diabetes Care
23 (2000): 1755–60. In classic studies of migrants to England, Bodansky and colleagues showed that the children born in the new place (UK) developed higher rates than those born in the old country (H. J. Bodansky et al., “Evidence for an environmental effect in the aetiology of insulin dependent diabetes in a transmigratory population,”
British Medical Journal
304 [1992]: 1020–22). Together, all of these point to strong environmental influences driving the increased rates of Type 1 diabetes, but farm exposure does not appear to be important (K. Radon et al., “Exposure to farming environments in early life and type 1 diabetes: a case-control study,”
Diabetes
54 [2005]: 3212–16).

But could anything accelerate it?:
NOD (non-obese diabetic) mice are a particular strain of mice that have enhanced susceptibility to developing autoimmune diabetes, with many characteristics that resemble Type 1 diabetes in human children. Affected mice have progressive immune-mediated destruction of the Islets of Langerhans, where insulin is produced. The strain was first recognized in Japan in the late 1970s. (See H. Kikutani and S. Makino, “The murine autoimmune diabetes model: NOD and related strains,”
Advances in Immunolology
51 [1992]: 285–322.) Diabetes develops in 50–80 percent of female mice and 20–40 percent of males. Interestingly, when mice are kept in spanking-clean cages and rooms, they get more diabetes. In rooms with a lot of shared bedding, the rates go down. The general observation is that “dirty protects.” This suggests that there are transmissible agents (microbes) whose presence affects the risk of diabetes development. The sex difference in the NOD mice differs from that of humans but permits analyses of the relevant factors underlying the dichotomy.

allowed us to include both in the experiments:
Ali and I discussed this. Despite the JDRF limitation, we agreed that we would study both PAT and STAT because we wanted two chances for success. Fortunately I had some other funds from a philanthropist that I could use for the additional expenses, and Ali had received support from the Howard Hughes Medical Institute to advance her career. And with the promise of funding from JDRF, I said to Ali, “Your preliminary work is going so well, instead of just taking one year off from medical school, why don’t you take more time off and get a PhD for your work.” This would entail a big change in her career plans. I suggested this to her on a Friday. By Monday, she had decided. “I am going for it!” she excitedly told me, and the NYU MD/PhD program immediately accepted her. She has been an incredible student, already making important discoveries.

more than quadrupling since 1950:
Celiac disease is rising in incidence: T. Not et al., “Celiac disease risk in the USA: high prevalence of antiendomysium antibodies in healthy blood donors,”
Scandinavian Journal of Gastroenterology
33 (1998): 494–98. One in 250 healthy blood donors in the United States: P. H. R. Green et al., “Characteristics of adult celiac disease in the USA: results of a national survey,”
American Journal of Gastroenterology
96 (2001): 126–31. One in 133 adults; 1 in 56, if you include related disorders: J. F. Ludvigsson et al., “Increasing incidence of celiac disease in a North American population,”
American Journal of Gastroenterology
108 (2013): 818–24. One in 141, based on NHANES data: A. Rubio-Tapia, “The prevalence of celiac disease in the United States,”
American Journal of Gastroenterology
107 (2012): 1538–44.

compared
to those who didn’t:
K. Marild et al., “Antibiotic exposure and the development of coeliac disease: a nationwide case-control study,”
BMC Gastroenterology
13 (2013): 109.

led by Dr. Ben Lebwohl at Columbia University:
B. Lebwohl et al., “Decreased risk of celiac disease in patients with
Helicobacter pylori
colonization,”
American Journal of Epidemiology
178 (2013): 1721–30.

people born by C-section also face an increased risk:
K. Marild et al., “Pregnancy outcome and risk of celiac disease in offspring: a nationwide case-control study,”
Gastroenterology
142 (2012): 39–45.

the risk of developing IBD at an early age:
A. Hviid et al., “Antibiotic use and inflammatory bowel diseases in childhood,”
Gut
60 (2011): 49–54.

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

as many as one in fifty children has the condition:
S. H. Sicherer et al., “US prevalence of self-reported peanut, tree nut, and sesame allergy: 11-year follow-up,”
Journal of Allergy and Clinical Immunology
125 (2010): 1322–26.

I was able to find records:
L. Hicks et al., “US outpatient antibiotic prescribing, 2010,”
New England Journal of Medicine
368 (2013): 1461–62.

just for those under two:
G. Chai et al., “Trends of outpatient prescription drug utilization in US children, 2002–2010,”
Pediatrics
130 (2012): 23–31.

highest in the states with the highest obesity:
The CDC data on macrolides were first revealed at a meeting (L. Hicks et al., “Antimicrobial prescription data reveal wide geographic variability in antimicrobial use in the United States, 2009,” presented at the forty-eighth annual meeting of the Infectious Disease Society of America, Vancouver, Canada, October 21–24, 2010), and the abstract is available online at
https://idsa.confex.com/idsa/2010/webprogram/Paper3571.html
. In addition to total antibiotic use, the scientists examined both macrolide use and fluoroquinolone use. Fluoroquinolones include ciprofloxacin, levofloxacin, and others. All three maps—total use, macrolides, and fluoroquinolones—look very similar.

I am focusing on macrolides because fluoroquinolones are not often used for children, whereas macrolides are. Azithromycin was the number-two most-prescribed antibiotic in U.S. children in 2010 (see G. Chai et al., “Trends of outpatient prescription drug utilization in US children”). The CDC data do not distinguish between which macrolides are used in which state, but azithromycin is likely to dominate everywhere because of its remarkable growth in sales. A final caveat is that the CDC maps show antibiotic use across all ages. It is not broken down by year of life, so we do not know whether the relationships observed across all ages also hold for children. Such analyses should be done. Obesity levels source: “Overweight and Obesity” (Atlanta: Centers for Disease Control, 2012), accessed
http://www.cdc.gov/obesity/data/adult.html
.

one in eighty-eight children has autism or autism spectrum disorder:
The generally accepted first written observation of a problem with autism was the paper by Austria-born Leo Kanner, who had established a child psychiatry clinic at Johns Hopkins Hospital (L. Kanner, “Autistic disturbances of affective contact,”
Nervous Child
2 [1943]: 217–50). Since its recognition, there has been much evidence for its rise, despite a trend toward overdiagnosis of autism and its related disorders. See I. Hertz-Picciotto and L. Delwiche, “The rise in autism and the role of age at diagnosis,”
Epidemiology
20 (2009): 84–90; C. J. Newschaffer et al., “The epidemiology of autism spectrum disorders,”
Annual Review of Public Health
28 (2007): 235–58. In 2012, the Centers for Disease Control released an estimate that one in eighty-eight children has an autism-spectrum disorder (
http://www.cdc.gov/media/releases/2012/p0329_autism_disorder.html
).

can affect cognitive development and mood:
Rodent studies of gut signaling to the brain, involving the microbiome: J. F. Cryan and T. G. Dinan, “Mind-altering micro-organisms: the impact of the gut microbiota on brain and behavior,”
Nature Reviews Neuroscience
13 (2012): 701–12; and R. Diaz Heijtz et al., “Normal gut microbiota modulates brain development and behavior,”
Proceedings of the National Academy of Sciences
108 (2011): 3047–52.

the blood of autistic children:
D. Kiser et al., “Review: the reciprocal interaction between serotonin and social behavior,”
Neuroscience & Biobehavioral Reviews
36 (2012): 786–98; and B. O. Yildirim and J. J. L. Derksen, “Systematic review, structural analysis and a new theoretical perspective on the role of serotonin and associated genes in the etiology of psychopathology and sociopathy,”
Neuroscience & Biobehavioral Reviews
37 (2013): 1254–96.

have important bearing on our estrogen status:
We have reviewed this topic (C. S. Plottel and M. J. Blaser, “Microbiome and malignancy,”
Cell Host & Microbe
10 [2011]: 324–35), which includes many of the primary references.

it’s not their genes:
M. C. King et al., “Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2,”
Science
302 (2003): 643–46. According to the U.S. National Cancer Institute, about 12 percent of U.S. women develop breast cancer at some time in their life, but women who have mutations in BRCA1 have a 55 to 65 percent chance, and those with mutations in BRCA2 have a 45 percent chance of developing the cancer before the age of seventy. Ovarian cancer is less common, but having a BRCA mutation increases the risk even more (lifetime risk in the general population is 1.4 percent; the risk with BRCA1 is 39 percent and the risk with BRCA2 is 11–17 percent). Dr. Mary Claire King was one of the discoverers of BRCA1 and has been a pioneer in studies to understand its significance. In her 2003 review in
Science
, she provided data indicating that women who have these mutations develop breast cancers at different ages. However, what was particularly alarming to me is that among women born after 1940, the age curve had shifted to the left. At any given age, women with BRCA1 or BRCA2 mutations who were born after 1940 had a much higher risk of developing breast cancer than women born before 1940. Although comprehensive genetic analyses were not done, such data suggest that there has been a strong environmental risk added to the genetic risk seen in these women.

as we speculated five years ago:
M. J. Blaser and S. Falkow, “What are the consequences of the disappearing human microbiota?”
Nature Reviews Microbiology
7 (2009): 887–94.

brilliant
Silent Spring
:
Rachel Carson,
Silent Spring
(New York: Houghton Mifflin, 1962). I read it when I was thirteen. It greatly affected my thinking about the interconnectedness on our planet.

15. ANTIBIOTIC WINTER

a fifty-six-year-old Brooklyn native:
Peggy Lillis’s family have started the Peggy Lillis Memorial Foundation to promote public education about
C. diff
.

A recent study of nearly 2 million:
R. E. Polk et al., “Measurement of adult antibacterial drug use in 130 US hospitals: comparison of defined daily dose and days of therapy,”
Clinical Infectious Diseases
44 (2007): 664–70.

lead to greater toxin production:
V. G. Loo et al., “A predominantly clonal multi-institutional outbreak of
Clostridium difficile
–associated diarrhea with high morbidity and mortality,”
New England Journal of Medicine
353 (2005): 2442–49; and M. Warny et al., “Toxin production by an emerging strain of
Clostridium difficile
associated with outbreaks of severe disease in North America and Europe,”
Lancet
366 (2005): 1079–84.