An Update on The Role of Breast Milk in the Ecosystem of the Human Body
The stability of the ecosystem of the human body depends on all components working in harmony
William Parker, PhD Duke University Medical Center Department of Surgery Fannie E. Rippel Foundation Laboratories in Transplant Biology
Microbial Ecology in Health and Disease, 26:26253
Why is the immune system so over-reactive? • 40 % allergy rates
Immune destabilizing factors Hygiene hypothesis
• 8 % autoimmune rates
Biota alteration + Inflammatory diets + Sedentary lifestyle + Chronic psychological stress + Vitamin D deficiency
• 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.
Some results of biota alteration 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
Confirmed • asthma • allergies (all types) some common types of eczema food allergies hay fever or rhinitus • multiple sclerosis • lupus • type 1 diabetes • inflammatory bowel disease • colon cancer
Highly probable
• appendicitis • Graves’ disease • some non-allergic types of eczema • non-tropical Sprue (Celiac disease or gluten enteropathy) • migraine headaches • autism associated with autoantibodies • anxiety disorders • depression • hot flashes • heart disease (in part) • Alzheimer’s • chronic fatigue syndrome • all autism not associated with genetic mutation • schizophrenia • epilepsy • psychopathy Updated from • dandruff Med Hypotheses (2011), doi:10.1016/j.mehy.2011.06.019 • mastitis
Very suspicious
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Ubiquitous factors that, by themselves, do not cause pathology
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Immune hypersensitivity caused by biome depletion and other factors
A three-hit paradigm Bilbo, S.D., Wray, G., Perkins, S.E. & Parker, W. (2011) Reconstitution of the human biome as the most reasonable solution for epidemics of allergic and autoimmune diseases. Medical Hypotheses,77:494-504.
+
2
Environmental stimulus (“triggers”, often reduced by hygiene)
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Genetic predisposition and/or epigenetic effects
+
Hyper-immune associated diseases, including allergy and autoimmunity
(Number 1 advantage) (Number 1 problem with moving forward)
Transient microbiome destruction or alteration
• • • • • • •
No pharmaceuticals needed to address underlying issues
Formula feeding Antibiotics Washing of mother with soap/disinfectant Washing of baby with soap/disinfectant Removal of vernix at birth Cesarean section birth Anti-acid drugs
Where does breastfeeding fit into the picture? • Genetics • Triggers • Environmental factors (a) biota alteration (b) sedentary lifestyle (c) inflammatory diets (d) vitamin D deficiency (e) chronic psychological stress
Brain Behav Immun, 51:14-28.
Immunoglobulin A (IgA) The predominant antibody in milk Bacilli (Turicibacter) Bacilli (Lactobacillus)
Clostridia (Ruminococcaceae)
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Accepted paradigm of Science until 2004: Primary Mechanism of Gut Function
Immune exclusion of bacteria by Immunoglobulin A in the gut
Immune Exclusion An attractive idea •Normal gut bacteria are the most common cause of death in the United States: Something has got to keep these things in check.
SIgA inhibits 50% to 75% of the binding of common Streptococcus species to human gut cells. Inhibition of Bacterial Adherence by Secretory IgA: A mechanism of Antigen Disposal, by R. C. Williams and R. J. Gibbons Published in Science, 1972
On the other hand…. We need our gut bacteria Our gut bacteria need us
•SIgA are made against pathogenic bacteria as well as good bacteria. The SIgA must then be antagonistic to bacteria.
The consistency of “natural” antibody interactions with bacteria, among other things, suggested that a new paradigm was worth consideration.
Indicators of friendly relations in the gut
•Immune components go to a lot of trouble to interact with “friendly” gut bacteria •Bacteria go to a lot of trouble to interact with immune components
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15000 12500 10000 7500 5000
sIgA
sIgA, Igase
0
IgG
2500 BSA
Adherent Bacterial growth (14C incorporation; DPM)
17500
without sIgA
with sIgA
(image not magnified)
Immune Inclusion
Predicted biofilms are observed in the proximal large bowel of rodents.
Biofilms in the frog gut (Proximal large bowel)
Predicted biofilms are observed in the cecum of a non-human primate
Journal of Evolutionary Biology. 22:1984-1999, 2009
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A part of normal biology
Evaluating the model in humans
Biofilms in the earthworm gut (a) Present after washing (b) Present regardless of bacteria in soil (c) Most abundant in the midgut
Pedobiologia 47, 900–903, 2003
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Bollinger, R.R., Barbas, A.S., Bush, E.L., Lin, S.S. & Parker. W. (2007) Biofilms in the large bowel suggest an apparent function of the human vermiform appendix. J. Theoretical Biology. doi:10.1016/j.jtbi.2007.08.0 32.
Apparent function: Storage/maintenance of friendly bacteria for re-inoculation in case of emergency.
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How does breastmilk affect the biofilms in the ecosystem of the gut?
Normal
Infection
Recovery
Apparent function of the appendix
Diarrhea
Recovery
“Safe House”
Human milk causes bacteria to grow in colonies (clumps)
Reminder: secretory IgA in breastmilk causes bacteria to clump together
Number of aggregates 3 - 6 m in diameter
A
adhesin pilus no pilus
adhesin + Man pilus + Man no pilus + Man
7500
5000
2500
Current Nutrition and Food Science, 8:168-176.
0 0
10
20
30
Time (hours)
B
Molecular Immunology, 43, 378-387.
Number of aggregates greater than 6 m in diameter
adhesin pilus no pilus
adhesin + Man pilus + Man no pilus + Man
400 300 200
Human milk contains more than 100 SIgA for modulating bacterial growth
Infant formulas cause bacteria to grow, but not in colonies
0 0
10
20
30
Current Nutrition and Food Science, 8:168-176.
Time (hours)
Figure 1
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Note that cow milk behaves more like infant formula. Current Nutrition and Food Science, 8:168-176.
But what happens to the milk if you pasteurize it? The standard “Holder” method involves heating to 62.5ºC and holding this for 30 minutes
LTLT (Low temperature, long time)
Developing a HTST pasteurization method for laboratory use
Boiling human milk makes it behave more like infant formulas The Holder method seems particularly good.
Current Nutrition and Food Science, in press
72 °C
Current Nutrition and Food Science, in press
4 °C
Some results of biota alteration Confirmed
Review and conclusions
• asthma • allergies (all types) some common types of eczema food allergies hay fever or rhinitus • multiple sclerosis • lupus • type 1 diabetes • inflammatory bowel disease • colon cancer
Highly probable
• appendicitis • Graves’ disease • some non-allergic types of eczema • non-tropical Sprue (Celiac disease or gluten enteropathy) • migraine headaches • autism associated with autoantibodies • anxiety disorders • depression • hot flashes • heart disease (in part) • Alzheimer’s • chronic fatigue syndrome • all autism not associated with genetic mutation • schizophrenia • epilepsy • psychopathy • dandruff Updated from • mastitis Med Hypotheses (2011), doi:10.1016/j.mehy.2011.06.019
Very suspicious
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Immune destabilizing factors Hygiene hypothesis
Biota alteration + Inflammatory diets + Sedentary lifestyle + Chronic psychological stress + Vitamin D deficiency
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.
Acknowledgements
Human milk has a much different effect on the biota growth than infant formulas
Acknowledgements
Darshana Jaint Susan Poulton Erin McKenney Lauren Williamson John P. Jones Sharron Brenner Anna Cheng
Shu S. Lin John Rawls Cindy Pi Ashley Trama Aditya Devalapalli Aaron Lesher Anitra Thomas Jia Liu Kendra Smyth Claire Morton
Collaborators Sarah Perkins: Parasitologist, Cardiff University Michael Muehlenbein: Anthropologist, Indiana University Staci Bilbo: Neuroimmunologist, Duke University Greg Wray: Evolutionary Biologist, Duke University Jeff Ollerton: Evolutionary Biologist, U of Northhampton Rajendra Morey: Psychiatrist, Duke University Janet K. Wilson: Sociologist, University of Central Arkansas
Funding SafeMinds TriCEM Immunity’s Forge
Selected citations for immune inclusion 2003: Human Secretory IgA May Contribute to Biofilm Formation in the Gut. Immunology 109, 580-587. 2004: Microbial Biofilms in the Gut: Visualization by Electron Microscopy and by Acridine Orange Staining. Ultrastructural Pathology, 28, 23-27.
Randy Bollinger Matthew Harker Mary Lou Everett Zoie Holzknecht Parker Whitt Susanne Meza-Keuthen
2004: Immunoglobulin-Mediated Agglutination of and Biofilm Formation by Escherichia coli K-12 require the Type 1 Pilus Fiber. Infection & Immunity, 72, 1929-1938. 2004: Immune Exclusion and Immune Inclusion: a New Model of Host-Bacterial Interactions in the Gut. Clinical and Applied Immunology Reviews, 5, 321-332. 2005: Secretory IgA and Mucin-Mediated Biofilm Formation by Environmental Strains of Escherichia coli: Role of Type 1 pili. Molecular Immunology, 43, 378-387.
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Citations for the appendix 2007: Biofilms in the large bowel suggest an apparent function of the human vermiform appendix. J. Theoretical Biology. 249: 826-831. 2009: Comparative Anatomy and Phylogenetic Distribution of the Mammalian Cecal Appendix. Journal of Evolutionay Biology. 22: 1984-1999.
Citations for therapeutic potential 2009: Altering and Assessing Persistence of Genetically Modified E. coli MG1655 in the Large Bowel. Experimental Biology and Medicine. In Press.
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