The Perinatal Microbiome

William Parker, PhD

Duke University Medical Center
Department of Surgery
 Overview

1. The infant’s microbiome: with and

without Western society

2. The role of microbiome alteration in

health and disease
How do bacteria normally work
in our body?

A very important and

useful question!
• Important for digestion
• Important for immune system training
and development
• Important to prevent overgrowth of
some “dangerous” bacteria
without sIgA with sIgA
(image not magnified)

Molecular Immunology (2006) 43:378-387

 Friends of our immune system!

Bacterial
Function identified in 2007:
“safehouse” J. Theoretical Biology. 249: 826-831
How has modern society
modified our microbiota?

Another very important

and useful question!
1860’s:(Thomas(Crapper(makes(
the(toilet(usable:(nine(patents( A(recent(
issued
1880’s(:(Thomas(Crapper(begins(
history(of(
to(install(toilets(for(British( the(toilet
royalty
1890’s:(Scott(paper(company(
becomes(the(first(to(
manufacture(tissue(on(a(roll(
specifically(for(the(use(of(toilet(
paper
1910’s:(Post(WWI,(the(flush(toilet(
gains(popularity(in(the(United(
States
 Worms: MOSTLY LOST
“Old” symbionts that persist in small hunter-gatherer groups
Immune training and regulation

Good germs: DIMINISHED

The microbiome (symbiotic and environmental)
Immune training and regulation

Bad germs: INCREASED

“Crowd infections”
Childhood viruses, measles, smallpox, flu, etc…
Highly inflammatory

View adapted from Graham Rook, Charles Raison and Christopher Lowry,
Clinical and Experimental Immunology, 2013 doi:10.1111/cei.12269
 Changes in the microbiota of the
adult gut are mostly due to diet.

“A typical US diet is rich in protein, whereas diets in

Malawi and Amerindian populations are dominated by corn
and cassava. The differences between US and
Malawian/Amerindian microbiomes can be related to these
differences in diet.”
Yatsunenko et al, 2012. Nature 486:222-228
 Brain Behav Immun, 51:14-28.

Bacilli
(Turicibacter)
Bacilli
(Lactobacillus)

Clostridia
(Ruminococcaceae)
 Breast milk is absolutely necessary for the
development of the body’s normal biome.
Even a small amount of infant formula
causes substantial alterations, and it can
takes weeks to return to normal.

Brown, E. W., & Bosworth, A.W. (1922). Studies of infant feeding

XVI. A bacteriological study of the feces and the food of normal
babies receiving breastmilk. American Journal of Diseases of
Children, 23, 243-258.

Gerstley, J. R., Howell, K. M., & Nagel, B. R. (1932). Some

factors influencing the fecal flora of infants. American Journal of
Diseases of Children, 43,555-565.
 Changes on the skin
microbiota are probably
due to hygiene

1. Humans are less covered with fecal and

soil microbes than other primates.

2. What we consider to be “normal” skin

bacteria may not be normal at all.

Proc. R. Soc. B 2016 283 20152586; DOI:

10.1098/rspb.2015.2586.
 The “cheesy varnish”
after birth:
the vernix caseosa
1. Occurs in at least some aquatic mammals*,
but not in land-dwelling mammals.
Water birthing: (safe, shorter labor (~20% reduction in first stage), 60-
fold reduction in use of surgery (episiotomy), from 23% to 0.38%, and
a 13-fold reduction in requests for an epidural (from 66% to 5%).**

2. A prebiotic, often swallowed by the baby: promotes

growth of healthy bacteria, possibly reducing the risk
of GI problems.***

* Ran-Ressler, Wang, Nilson, Leger & Brenna.

11th Congress of ISSFAL, Stockholm, Sweden, June 2014
** J Matern Fetal Neonatal Med. 2005 May;17(5):357-61.
*** J Pediatr Gastroenterol Nutr. 2015 Mar; 60(3): 294–307.
 Effect of Cesarean birth
on the microbiota
In an infants skin, mouth, nose (at 5
minutes after birth), and feces (24 hours),

Vaginal birth gives babies Cesarean birth gives babies

vaginal bacteria: skin bacteria:
Lactobacillus Staphylococcus
Prevotella Corynebacterium
Sneathia Propionibacterium

Maria G. Dominguez-Bello et al, PNAS vol. 107 no. 26,

11971–11975, doi: 10.1073/pnas.1002601107
No pharmaceuticals needed to address underlying issues
(Number 1 advantage)
(Number 1 problem with moving forward)
 Transient microbiome
destruction or alteration

• Formula feeding
• Washing of mother with soap/disinfectant
• Washing of baby with soap/disinfectant
• Removal of vernix at birth
• Cesarean section birth
• Anti-acid drugs
• Antibiotics
Can bacteria evolve fast
enough for us to be
concerned about?

Pervasive Selection
pressure on the gut
microbiota
 A simple experiment
(unintentional)

Laboratory E. coli

Monitor for
~3 years

Germ free mice

 Laboratory E. coli evolving in the gut

Changing metabolism
APPLIED AND ENVIRONMENTAL MICROBIOLOGY, July 2010, p. 4655–4663
Laboratory E. coli learning to live in the gut

APPLIED AND
ENVIRONMENTAL
MICROBIOLOGY, July
2010, p. 4655–4663

Dead Alive
 But more subtle changes can
happen.
Bacteria evolve and can become
“inflammation-adapted”, potentially serving
as an anchor for the inflammatory state.
Does meddling with the
microbiota make babies
sick?
 Westerners are not healthy
(pathologic inflammation)
• 40 % allergy rates
• 8 % autoimmune rates
• 30 % lifetime risk of cancer
• 43% of children born in the US currently have some
chronic disorder requiring medication.*
• Cognitive disorders that are apparently due to
neuroinflammatory insults, such as depression,
anxiety disorders and autism, are on the rise.**
*ACADEMIC PEDIATRICS 2011;11:S22–S33
**AUTISM RESEARCH AND TREATMENT 2012:910946.
 Immune destabilizing factors
(Rapidly spreading beyond the Western world)

Hygiene hypothesis Biota alteration

+
Inflammatory diets
+
Sedentary lifestyle
+
Chronic psychological stress
+
Vitamin D deficiency
 Reminder: Biota alteration is complex.
Worms: MOSTLY LOST
“Old” symbionts that persist in small hunter-gatherer groups
Immune training and regulation

Good germs: DIMINISHED

The microbiome (symbiotic and environmental)
Immune training and regulation

Bad germs: INCREASED

“Crowd infections”
Childhood viruses, measles, smallpox, flu, etc…
Highly inflammatory

View adapted from Graham Rook, Charles Raison and Christopher Lowry,
Clinical and Experimental Immunology, 2013 doi:10.1111/cei.12269
 Helminths (worms)"and"MS
A"prospective"study,"with"24"patients:"
12"accidentally""colonized"with"
helminths,"and"12"uncolonized (Argentina)

After"colonization,"
3"relapses"in"the"
colonized"group,"
56"relapses"in"the"
uncolonized group
Annals"of"Neurology"(2007)"61:97I108
 gives rise to
Biota alteration Inflammation
+
Inflammatory diets
+
Sedentary lifestyle Autoimmunity
+ +
Chronic psychological stress Allergy
+ +
Vitamin D deficiency Digestive diseases
+
Neuropsychiatric disorders
+
Cancer
 Ubiquitous)factors)that,)by)
themselves,)do)not)cause)pathology
Immune

+
hypersensitivity- Environmental-stimulus-
1 caused-by-biome- 2 (“triggers”,-often-
reduced-by-hygiene)
depletion-and-other-

+
factors

3 Genetic-predisposition-

A-threePhit
and/or-epigenetic-effects

paradigm
Bilbo,-S.D.,-Wray,-G.,-Perkins,-S.E.-
&-Parker,-W.-(2011)-
Reconstitution-of-the-human-
biome-as-the-most-reasonable-
Disease
solution-for-epidemics-of-allergic-
and-autoimmune-diseases.-
Medical(Hypotheses,77:494P504.
Parker et al., Journal of International Medical Research, Published March 2017
 Current model for the induction of autism
BASED ON EXTENSIVE CIRCUMSTANTIAL EVIDENCE

Biota alteration
+ Susceptible genetics and
Inflammatory diets other environmental factors inflammation
+ +
Sedentary lifestyle “oxidative stress”
+
Chronic psychological stress
+ NECESSARY
Vitamin D deficiency
FACTOR

NECESSARY
Use of acetaminophen FACTOR Chemically-induced
(paracetamol) in babies and injury known as
children For many if
not most cases AUTISM
Parker et al., Journal of International Medical Research, Published March 2017
 EXTENSIVE CIRCUMSTANTIAL EVIDENCE
IMPLICATING POST-PARTUM PARACETAMOL
USE IN MANY IF NOT MOST CASES OF AUTISM
A partial list of circumstantial evidence

• 11 studies showing that paracetamol is neurotoxic to the developing

human brain. (Only one of the 11 was conducted in children. The rest
were conducted during pregnancy, when the drug is apparently much
less toxic, but still measurably impairs brain development.)
• Studies in laboratory mice and rats show that the drug permanently
alters brain development and impairs social-related functions when
administered at an early age.
• The observations of many parents. Although parents have blamed
vaccines, the only viable explanation for the parents’ observations
is that paracetamol is a potent inducer of autism.
• Margaret McCarthy, Chair of Pharmacology at the University of
Maryland, has worked out the mechanism of autism induction in
laboratory animals. Her work explains why boys are more susceptible
than girls.
Parker et al., Journal of International Medical Research, Published March 2017
 EXTENSIVE CIRCUMSTANTIAL EVIDENCE
IMPLICATING POST-PARTUM PARACETAMOL
USE IN MANY IF NOT MOST CASES OF AUTISM
A partial list of circumstantial evidence

• The epidemiology of autism tracks well with the epidemiology of

paracetamol use in children (not in pregnant adults). The current
pandemic started when aspirin was identified as the factor responsible
for Reye's syndrome.
• Immediately following the rise in the rate of autism in the early
1980s, there was an apparent shift in the type of autism, toward the
more regressive type, that remains with us today. This suggests some
environmental factor introduced after birth.
• Circumcision is associated with an increased rate of autism. The only
apparent explanation for this observations is that paracetamol is
a potent inducer of autism.

Parker et al., Journal of International Medical Research, Published March 2017

 Immune destabilizing factors
(Rapidly spreading beyond the Western world)

Hygiene hypothesis Biota alteration

+
Inflammatory diets
+
Sedentary lifestyle
+
Chronic psychological stress
+
Vitamin D deficiency
 Reminder: Biota alteration is complex.
Worms: MOSTLY LOST
“Old” symbionts that persist in small hunter-gatherer groups
Immune training and regulation

Good germs: DIMINISHED

The microbiome (symbiotic and environmental)
Immune training and regulation

Bad germs: INCREASED

“Crowd infections”
Childhood viruses, measles, smallpox, flu, etc…
Highly inflammatory

View adapted from Graham Rook, Charles Raison and Christopher Lowry,
Clinical and Experimental Immunology, 2013 doi:10.1111/cei.12269
No pharmaceuticals needed to address underlying issues
(Number 1 advantage)
(Number 1 problem with moving forward)
 Transient microbiome
destruction or alteration

• Formula feeding
• Washing of mother with soap/disinfectant
• Washing of baby with soap/disinfectant
• Removal of vernix at birth
• Cesarean section birth
• Anti-acid drugs
• Antibiotics
 Conclusions
1. Modern humans have so much “environmental
mismatch” (fish-out-of-water issues), that altering
one factor alone may not fix the problem:
2. Major factors that need increasing attention with
increasing Westernization are:

1. DIET
2. STRESS
3. Vitamin D
4. EXERCISE
5. BIOTA (including but not limited to the microbiota)
 Acknowledgements

Collaborators
Sarah Perkins: Parasitologist, Cardiff University
Michael Muehlenbein: Anthropologist, Indiana University
Staci Bilbo: Neuroimmunologist, Harvard University
Greg Wray: Biologist, Duke University
Jeff Ollerton: Biologist, U of Northhampton
Erin McKinney: Biologist, North Carolina State University

Funding
SafeMinds
TriCEM
Immunity’s Forge