The Microbiome and Immune System in Environmental Risk of Infectious...
Transcript of The Microbiome and Immune System in Environmental Risk of Infectious...
The Microbiome and Immune System in Environmental Risk of Infectious Disease
Rodney Dietert
Cornell University
Appreciation
• To the workshop organizers for my inclusion in the program
• To my editor and wife, Janice Dietert
Disclosures
Recent and Current Positions Held and Financial Support:
• Professor of Immunotoxicology at Cornell University
(Now Professor Emeritus)
• Consultant – in Education and Translational Research for Seed (a 2018 start-up company)
• Author at Dutton Penguin Random House
Disappearing Dogmas of the 20th Century
1. The newborn is fully prepared immunologically to fight all diseases.- (The newborn must postnatally co-mature with the microbiome to be
immunologically balanced and prepared to fight diseases).
2. Species barriers are chromosomally gene driven.- (Immune-microbiome incompatibility can also determine species barriers)
3. Most microbes are a threat to human health.
- (Some microbes are required for human health.)
4. The human mammal is the target of environmental health risk assessments (e.g., toxicological safety).
- (The human superorganism is the most relevant target for assessment/evaluation/safety determinations).
The Complete Human: Three Domains of Life
Eukaryota
Archaea
Bacteria
Majority-Microbial Humans
(based on cell and gene numbers)
Domains of Life Genomes
First~ 25,000 genes
Approximately 57%-90% microbial
by cell number
Second ~ 10 million genes
Superorganism
Mammalian
MicrobialEukaryotes
Adapted from: Dietert and DietertHealthcare 3(1), 100-129; 2015.
~ 3.3. million microbial genes in a individual
Routes of Exposure, Portals of Entry, and Microbiome Sites Converge
Main Toxicological Routes of Exposure
See: Damalas and Koutroubas,
Toxics 2016, 4(1), 1; doi:10.3390/toxics4010001;.
Skin Break Urogenital
Infectious Agents - Major Portals of Entry
InhalationDermal Oral
Major Body Sites for the Microbiome
Hologenomic Speciation Determined by the Microbiome and Immune System
See: Brucker, R. M. & Bordenstein, S. R. Science 2013; 341 (6146): 667-669Flintoft, L. Nature Reviews Genetics 2013; 14: 598 (Photo : Bordenstein Lab)Wang et al. Nature Comm 2015; 6, Article number: 6440 doi:10.1038/ncomms7440Sutherland et al. Immunol Rev. 2016 Mar;270(1):20-31. doi: 10.1111/imr.12384
Nasonia sp. wasp House Mouse in Europe
(note: generalized wasp depicted)
Postnatal Immune Maturation(Note: 1,000 day concept on postnatal developmental windows)
• Environmental exposures and adaptations are required for full immune maturation (the newborn does not equal adult immunologically). The prenatal environment has a Th2 preferential bias).
• Gut microbes at mucosal surfaces drive the newborn’s stereotypic immune development. Microbial dysbiosis impairs immune maturation.
• Some aspects of inflammation must be ramped down and others made more selective as per innate immune responses. Macrophage polarization and regulation must be altered to better protect the infant from infections (e.g., via cell signaling factors - IRF5).
• Peripheral T cell helper and regulatory populations must change for balanced responses
• B cell, Natural killer cell, and dendritic cell maturation is affected during first 3 months of life
• Specialized innate immune populations (e.g., microglia, invariant NKT cells) must mature, expand, contract in tissues to provide immune homeostasis
See: Olin et al. Cell 174: 1277–1292. 2018
Lenz and Nelson, Front. Immunol., 13 April 2018 | https://doi.org/10.3389/fimmu.2018.00698
Zeissig and Blumberg, FEBS Lett 588(22): 4188-4194. 2014
Schneider et al. Front. Immunol., 11 July 2018 | https://doi.org/10.3389/fimmu.2018.01597
Examples of Neonatal “Critical Windows”Involving the microbiome and immune system
•Modulation of proliferative burst of invariant Natural Killer T cells (iNKT cells) in the gut –(determines risk of G.I. inflammatory disease)
(An et al. Scharschmidt et al. Immunity 43, 1011–1021, 2015)
•Neonatal timed influx of FoxP3+ T regulatory cells (Tregs) into the skin (determines tolerance to skin commensals)
(Scharschmidt et al. Immunity 43, 1011–1021, 2015)
A Systems Biology Unit: the Microimmunosome
Adapted from Dietert, Reprod. Toxicol. 2017
Microbes
Barrier
Specialized
Immune Cells
Barrier integrity and
bi-directional
communication
leading
to immune
homeostasis is critical
2/3rds of
your
immune
cells are
in the gut
near the
gut barrier
Responses of the Microbiota to Environmental Exposures
Environmentalpollutants
(e.g., metals, organics)DrugsDiet
1. Sequestration2. Avoidance/Exclusion3. Metabolism4. Specific Signaling5. Selective Microbe Death6. Selective Microbe Expansion7. Translocation
Adapted from: Dietert R. The microbiome in early life: self-completion and microbiota protection as health priorities. Birth Defects Res. Part B. 101(4): 333-340, 2014.
Gut Microbiota and Xenobiotics
• Increase or decrease drug available for absorption
• Directly metabolize drug
• Inhibit detoxification
• Biotransform common food components, drugs, and xenobiotics
• Generate aryl-hydrocarbon receptor agonists
• Convert a pro-drug into an active drug
• Respond to one drug/xenobiotic by inactivating host enzymes for an unrelated drug
• Regulate host metabolism
From: Klaassen and Cui, Drug Metab Disp. 2015; 43(10): 1505-1521
See: Clayton et al. Proc Natl Acad Sci U S A. 2016 Sep 13; 113(37): 10376–10381;
Lekshmi et al., Microorganisms 2017, 5, 11; doi:10.3390/microorganisms5010011;
Kristensen K1, Henriksen L, J Allergy Clin Immunol. 2016 Feb;137(2):587-90; Kristensen et al.
Pediatr Infect Dis
J. 2015 Feb;34(2):145-8.
Captivity
Reduced
microbiota
diversity
Humanized
microbiome
- from animal
handlers
Microbiome Destruction – What happens next?
Elective Cesarean delivery
More hospital-
associated
microbes
seeding the
neonatal gut
Altered
infant
cytokine
production
Howler monkeys
(Food and lifestyle restricted)
Prophylactic use of antibiotics
for growth promotion
in food-producing animals
Increased antimicrobial
resistance
and zoonotic risk from
pathogens (e.g.,
Campylobacter spp.,
Salmonella spp.,
Escherichia coli and
Staphylococcus aureus)
Elevated risk for several
diseases associated with
the mucosal immune
system
From:
National Research Council,
Environ Health Perspect,
74: 3-9, 1987
Current Biomarkers Model for Health Risk Assessment (1987)
The Microbiome Filters Virtually All Exposuresand Directly Participates in Epigenetic Alterations
Proposed New Environmental Health Assessment Model
Adapted from: Dietert and Silbergeld, Toxicol. Sci. 2015 Apr;144(2):208-16.
Microbiome
Colonization ResistanceGeneral factors: competitive exclusion (Gauses’ Law in ecology, Nurmi Concept), host gut motility, mucus layer regulation, epithelial barrier integrity
Specific processes: Inter-bacterial interactions
• Nutrient limitation (e.g., need to block simple sugar availability for pathogens)
• Including blocking inflammation-associated nutrient shifts (e.g., nitric oxide)
• Bile salts metabolism (secondary bile salt inhibition of pathogens)
• Short chain fatty acid (SCFAs) production (note: loss of butyrate production triggers increased oxygen and nitrate release in the lumen)
• Bacteriocin production
• Cell-cell contact-dependent inhibition
• Type VI secretion systems (e.g., B. fragilis blocks enterotoxigenic B. fragilis)
• LgX proteins
See: Sobara and Pamer, Mucosal Immunology 12: 1-19 (2019)
Nurmi and Schneitz, Int J Food Microbiol. 15(3-4): 237-240.
Wiles et al. PLoS Biol. 2016 Jul; 14(7): e1002517.
Cornick et al. Tissue Barriers. 2015; 3(1-2): e982426.
Importance of Commensal Microbes to Block Pathogens
Information adapted from: Keith and Pamer, J. Exp Med.DOI: 10.1084/jem.20180399 Published October 11, 2018
Treg
cell
Barrier structural and
functional integrity
Inner mucus layer
Outer mucus layer
B. fragilis + opportunistic pathogen
Immune population
mix and status
Exposure to
environmental
chemicals,
drugs,
stress, and/or
dietary changes
Loss of inhibition
capacity –
increase in
susceptibility
Barrier
damage
likely
LPS signal
to underlying immune cellsInflammatory
attack
Pathogens: Minimum Microbiota Necessary for Effective Competitive Resistance
• Metagenomic tools were used to construct a minimum consortium of gut microbiota that would protect mice from infection with the human enteric pathogen Salmonella enterica serovar Typhimurium (S. Tm).
• An installed combination of 15 specific gut bacterial strains were equivalent to a complete microbiome in effective colonization resistance.
From: Brigiroux et al. Nat. Microbiol. 2:16215 · November 2016
Utility of BiomarkersFrom Altered Microbiota to Disease
Clinical Disease
Altered
Gut Microbiota
Loss of
Colonization
Resistance
Physiological
System/
Immune
Dysbiosis
Infectious Disease
Non-communicable Disease
Barrier
Function
(Is it useful to Flip this information?)
Arsenic Presystemic Metabolism via the Microbiome• Sulfate-reducing colon microbiota can thiolate methylated arsenic producing
highly toxic metabolites.
• There is individual human variation in the presence of these bacteria potentially affecting individual risk.
• Arsenic exposure can also change gut microbiome composition and microbial genes.
• Arsenic exposure is associated with increased risk of certain human infections (e.g., hep B). - NHANES
• Infections can change both microbiome composition and arsenic metabolism (mouse study).
• Components of the gut microbiome can protect the immune system from arsenic toxicity (mouse study)
See: Rubin et al. Environ Health Perspect. 2014 Aug; 122(8): 817–822.
Luk et al. Chem Res Toxicol. 2013 Dec 16;26(12):1893-903.
Gokulan et al. MBio. 2018 Aug 14;9(4). pii: e01418-18. doi: 10.1128/mBio.01418-18.
Chi et al. Toxicol Sci. 2017 Dec 1;160(2):193-204.
Coryell et al. Nat Commun. 2018 Dec 21;9(1):5424.
Zhang et al. Curr Med Sci. 2018 Aug;38(4):610-617.
Arsenic “Ages” the Immune System
1. Prenatal and early childhood arsenic
exposure is inversely associated with telomere length and
signal joint T- cell receptor excision circle (sjTREC)
at 9 years of age. Fewer naive T cells with aging.
Immunosenesence - Mannan et al. Associations of Arsenic Exposure
With Telomere Length and Naïve T Cells in Childhood-
A Birth Cohort Study.
Toxicol Sci. 2018 Aug 1;164(2):539-549.
2. Low to moderate levels of arsenic disrupt T cell development.
Both genotoxic (oxidation) and non-genotoxic
(IL-7 signaling are involved) processes are involved.
The earliest T cells are the least capable of pumping
out arsenic and are at the greatest risk. - Xu et al.
Toxicity of environmentally-relevant concentrations of arsenic on
developing T lymphocyte.
Environ Toxicol Pharmacol. 2018 Sep;62:107-113.
Case Scenario for Cumulative Environmental Health RisksChildhood Incompleteness of the Microbiome
Bereavement
Maternal stress
Environmental tobacco smoke
Air pollution/
PAHs, others
F1 immune programmingReduced Tregs
Antibioticsadministered
Cesareandelivery
Reduced microbial seeding
Depletedmicrobiome
Altered metabolites& Immune development
BPA, heavy metals, certain food additives
Improper control of inflammation;Inadequateinnate
immune training
Inflammatorypromotionof
metabolic syndrome& carcinogenesis
Elevated risk of allergy,autoimmunity, obesity,CVD
Formula feeding
Missing prebioticsand microbes
urbanization
Reduced colonization resistance;Increased risk of infectionAdapted from:
Dietert, R. NeoReviews 2018 19(2):e78-e88.
Summary
• The microbiome is the lens through which we see our external environment (chemicals and pathogens). It is also our first line of defense from external threats and it is malleable.
• The microbiome and immune system must be sufficiently matched and must co-mature together to ensure host integrity and effective immune function (e.g., self tolerance and host defense against infectious diseases). The immune system, absent a “healthy” microbiome, is a disease inflictor rather than a protector.
• Optimizing colonization resistance is a key to improved health protection even as we work to reduce external health threats (chemical and microbiological).
• Managing the microbiome-immune interface should be a significant part of future preventative and therapeutic health.