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Grand Challenges in Environmental Health
Research Could the microbiome be
the missing link?
Andrew D. Patterson Penn State University [email protected]
“It is now recognized that the metabolism of both exogenous and endogenous compounds by conventional animals can be attributed not only to the enzyme of the host but also to the enzyme of the host’s bacterial microflora.” - Peter Goldman, Mark Peppercorn, Barry Goldin The American Journal of Clinical Nutrition November 1974 Vol 27 Number 11
http://www.issx.org/?page=RTWilliams
“Thus it must be emphasized that our conception of the flora is greatly dependent on the techniques used and also that our present knowledge may be both limited and somewhat misleading.” - Ronald R. Scheline Journal of Pharmaceutical Sciences December 1968 Vol 57 Number 12
MICROBIAL
COMMUNITY
STRUCTURE ? METABOLIC
ACTIVITY
HEALTH
DISEASE
Cell Metabolism 2014
MICROBIAL METABOLISM
GI TRANSIT
TIME
ABSORPTION AND
ENTEROHEPATIC
CIRCULATION IMMUNE
SYSTEM
HOST
GENOTYPE
HOST
METABOLISM
CHEMICAL STABILITY
IN THE STOMACH
DIETARY INTAKE
MICROBIAL
INTERACTIONS MICROBIAL GENOTYPE
(STRAIN-LEVEL VARIATION) ENVIRONMENTAL CHEMICALS
???
Cell Metabolism 2014 Nov 20(5) 761-8
Symbiont Evidence for Environmental Chemical Interaction with the Gut
Microbiota
BEAN BUG Riptortus pedestris
PNAS 2012 May 109(22) 8618-22
Fenitrothion degradation by Burkholderia spp.
Symbiont Evidence for Environmental Chemical Interaction with the Gut
Microbiota
COFFEE BERRY BORER Hypothenemus hanpei
Nature Communications 2015 Vol 6 Article 7618
Caffeine degradation by Pseudomonas fulva
(source of Nitrogen and Carbon)
Image: Georg Goergen/IITA Insect Museum, Cotonou, Benin
Intersection of Environmental Chemicals, the Microbiome, and
Human Health
Impact on
Health
Personal Care Products
Persistent Environmental Contaminants
Heavy Metals
Environmental Human
Penn State’s Living Filter
Photo: Emily Woodward
Environmental Contaminants, the Microbiome, and Human Health
Chlorpyrifos (pesticide) • SHIME studies reveal dysbiosis • Intestinal bacteria important for
degradation
Pesticides can interact with and modify the intestinal microbiota
Enviro Sci Pollut Res 2013 Vol 20: 2726-2734; Biotech 2013 Vol 3: 137-142
Environmental Contaminants, the Microbiome, and Human Health
Arsenic (heavy metal) • In vitro cultured human gut
microbiota can metabolize Arsenic to methylated arsenicals and thioarsenicals
Intestinal microbiota can metabolize heavy metals and contribute to presystemic
metabolism
EHP 2010 Vol 118 No 7
EHP 2012 Vol 120 No 3
A - alter absorption via changes in barrier function or transport systems
D - altered distribution via bacterial metabolism
M – contribute to pre-systemic metabolism
E – alter enterohepatic circulation
Environmental Contaminants, the Microbiome, and Human Health
DOSE
EHP 2014 Vol 122 Number 8
FOOD
PESTICIDES
COSMETICS
POLLUTANTS
DRUGS
XEN
OB
IOTI
C
MET
AB
OLI
SM
END
OG
ENO
US
M
ETA
BO
LISM
EXPOSOME
GUT MICROBIOTA
Reconsider What Dose Means?
• Pre-systemic (first pass elimination) vs absorbed dose
• Route of exposure and impact on the microbiome
Antibiotics
Low, Chronic Dose • Promote inflammation,
altered host metabolism, weight gain
• Critical timing window
High, Acute Dose • Improve fatty liver
• Reduce progression of liver cancer ( DCA)
VEHICLE ANTIBIOTICS
JCI 2015 125(1): 386-402 Nature 2013 499(7456):97-101
MOUSE MODELS Conventional and Germ Free
-300
-200
-100
0
100
200
300
-400 -200 0 200 400
t[2
]
t[1]SIMCA-P+ 12.0.1 - 2012-08-07 18:46:17 (UTC-5)
METABOLOMICS NMR, LC-MS, GC-MS
SMALL MOLECULE CHATTER BETWEEN
HOST AND MICROBIOTA
Need Tools Used to Uncover and Decipher Host Gut Interactions
16S rRNA Amplicon Sequencing,
Metagenomics, and Metatranscriptomics
Microbial “Small Molecule” Chatter
Who is listening?
GR MR AR PR ER, VDR TR, RAR,
PPAR, LXR, FXR PXR CAR RXR, HNF4,
ARP-1 COUP-TF EAR2 SCP46 REVERB, SF-1 LRH-1 NGFI-B NURR1 TR2 TR4 RZR, ERR1 Others………
STEROID METABOLIC SENSORS ORPHANS
6 Families 26 Subfamilies > 50 genes
Nuclear Receptor Superfamily
ARYL HYDROCARBON RECEPTOR (AHR)
*not a nuclear receptor but shares many
features*
Aryl Hydrocarbon Receptor
• Xenobiotic Sensor • TCDD
• Dibenzofurans
• Benzo[a]pyrene
• Dietary Sensor • Flavoniods
• Indoles
• Gut Microbiome Sensor • Bacterial Phenazines
• Tryptophan Catabolites
• 7-ketocholesterol
Ve
hi c
l e
TC
DF
0 . 0
0 . 1
0 . 2
0 . 3
0 . 4
Fir
mic
ut
es
/Ba
ct
er
oid
et
es
p = 0 . 0 1 3
Ah
r -/-
Veh
icle
Ah
r -/-
TC
DF
0 .0 0
0 .0 5
0 .1 0
0 .1 5
0 .2 0
Fir
mic
ute
s/B
ac
tero
ide
tes
N S
TCDF Effect
Ahr Effect
16S rRNA Gene Sequencing
AHR Activation Significantly Modulates Gut Microbota Community Structure
ACTIVATION AND GENOTYPE INFLUENCE ON THE GUT
MICROBIOTA
Microbial “Small Molecule” Chatter
Can we tap their line?
Metabolomics
Identification of the chemical fingerprints that biological processes leave behind
Chemical fingerprint is significantly “contaminated” with metabolites of bacterial origin • Indole-containing compounds • Glycine-conjugated compounds • Bile acids (co-metabolites)
Antibiotic Treatment Causes Pronounced Changes in Gut Microbiota Metabolism
p-Cresol glucuronide Antibiotic
p-Cresol sulfate
Vehicle
Anti-Oxidant Tempol Alters the Cecal Community Structure
Genus: Lactobacillus
Tempol kills Lactobacillus spp.
Secondary bile acids – Metabolites produced in the intestine by bacterial enzymes
Lactobacillus
BSH
Deconjugation
TMCA MCA
Dehydroxylation and Deconjugation
β-MCA DCA
γ-MCA CDCA
T-β-MCA
TCA TUDCA
TCDCA
Unconjugated Bile Acids Depleted
Conjugated Bile Acids Enriched
Bile Acid Profiling Fecal Bile Acids Small Intestine Bile Acids
Disruption of Lactobacillus spp. Bile Salt Hydrolase Activity Impacts the Farnesoid X
Receptor (Bile Acid Receptor)
Repression of FXR target genes
Shp (FXR target gene) induction in hepatocytes
TβMCA is an FXR Antagonist
Sayin et al Cell Metabolism 2013
Li et al Nature
Communications 2013
Reducing FXR Activity ( BSH Activity) Can Promote Weight Loss in Mice
Summary Questions
1. Should our considerations of dose include the microbiota? Timing, duration, and route of exposure?
2. How do we best monitor and interpret changes (structural, functional) in the microbiota?
3. How do we assess the “health” of the microbiota?