Professional Documents
Culture Documents
programming of offspring
neurodevelopment
-
Sex-specific mechanisms
F1
F0
F2
Primordial
Cognitive deficits
Reduced weight gain
Mueller and Bale, 2008, J Neurosci
Morgan and Bale, 2011, J Neurosci
Howerton et al, 2013, PNAS
Howerton and Bale, 2014, PNAS
Corticosterone (ng/mL)
400
350
E-PS
300
250
200
150
100
50
0
15
30
Time (min)
60
Getting a mouthful....
Proteobacteria
Firmicutes
Tenericutes
Bacteroidetes
Prenatal
Postnatal
Childhood
Puberty
Adulthood
Aging
Gastrointestinal tract
Bacterial
colonization
Dietary
transition
Mucosal
thinning
IEC
proliferation
Neuronal loss
Dendritic arborization
Synaptic loss
Neuronal migration
Apoptosis
Synaptic pruning
Excitatory synapses
Inhibitory synapses
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Nonpregnant
Ctrl
Control
Stress
EPS
E7.5
Control
Ctrl
Stress
EPS
PN2
Ctrl
Ctrl
EPS
EPS
20
CTL
EPS
15
10
5
0
-5
-10
-15
-20
-20 -15 -10
-5
10
15
20
E7.5
Time
E7
PN2
PN2
20 40 60 80
Enrichment (-log[P-value])
Lactobacillus
Relative Abundance
0.4
0.3
0.2
0.1
0.0
*
Male
*
Female
Clostridia
Relative Abundance
0.020
0.015
B: Deferribacteraceae
C: Deferribacterales
D: Lactobacillus
E: Lactobacillaceae
F: Clostridiales
G: Clostridium
H: Haemophilus
CTL
EPS
0.010
0.005
0.000
A: Mucispirillum
Male
Female
i
cill
Ba
Ba
cte
roi
de
B
te
5
A: Clostridiales
B:Flavobacteria
C: Bacteroidia
Deferribacteres
E: Leptospirae
F: Gammaproteobacteria
1: Ruminococcaceae
2: Mogibacteriaceae
3: Lachnospiraceae
4: Dehalobacteriaceae
5: Paenibacillaea
17
Clo
str
idi
a
A
G: Deltaproteobacteria
H: Rhiboziales
I: Erysipelotrichales
Erysipelotrichi
H
E
11
10
16
Pro
te
12
15
ob
14
ac
ter
i
13
6: Flavobacteriales
7: Bacteroidia
8: Coriobacterales
11: Leptospirlalles
12: Pasteuellales
13: Desulfovibrionaceae
14: Burkholderiales
15: Burkholderiales
16: Phyllobacteriaceae
17: Eryspelotrichales
10
-1.0
-0.5
0.0
0.5
Propionylcarniti
Isovalerylcarniti
-5
Indolelactic A
Hippuric A
Xanthosi
-20
-10
Creati
Glycerophosphocholi
-15
4-pyridoxic a
GLUCOSE-ALANINE CYCLE
Ribofla
1.0
Variable
Ortho
-10
GLUCOSE-ALANINE CYCLE
1.0
-10
-15
-20
-8
-6
-4
-2
0 2 4 6
EPS component score
PROSTACYCLIN SIGNALLING
1.0
0.0
0.5
-1.0
AMMONIA RECYCLING
INSULIN SIGNALLING
-0.5
0.0
p(corr)
0.5
1.0
MALATE-ASPARTATE SHUTTLE
Carnitine
Imidazoleacetic Acid
-5
0.5
N-acetylaspartate
GLUTATHIONE METABOLISM
GLUCONEOGENESIS
Taurine
1.5
GLYCOLYSIS
GTP
RNA TRANSCRIPTION
Pantothenic acid
INSULIN SIGNALLING
UREA CYCLE
UDP-glucuronate
MALATE-ASPARTATE SHUTTLE
2.0
1.0
UDP-D-glucose
AMMONIA RECYCLING
UDP-N-acetylglucosamine
PROSTACYCLIN SIGNALLING
Energy metabolism
GLUTAMATE METABOLISM
Glutamate
10
MSE
-ketoglutarate
Succinic acid
1.0
15
Sugar
metabolism
1.52.5
Malic acid
CTL
EPSGLUCONEOGENESIS
ADP
GLYCOLYSIS
NAD+
UREA CYCLE
20
Mitochondrial metabolism
Glutathione Disulfide
2.0
Plasma
GLUTAMATE METABOLISM
p(corr)
RNA TRANSCRIPTION
GLUTATHIONE METABOLISM
C
Paraventricular Thalamus
Paraventricular Nucleus
Hippocampus
Alanine
Arginine
Asparagine
Aspartate
Citrate
GABA
Glutamine
Glutamate
Glycine
Histidine
Isoleucine
Leucine
Lysine
Ornithine
Phenylalanine
Serine
Threonine
Tyrosine
Valine
-1
-2
-1
-2
-1
-2
-2
Females
Alanine
Arginine
Asparagine
Aspartate
Citrate
GABA
Glutamine
Glutamate
Glycine
Histidine
Isoleucine
Leucine
Lysine
Ornithine
Phenylalanine
Serine
Threonine
Tyrosine
Valine
-1
Log 2 [FC]
Log 2 [FC]
Log 2 [FC]
Demonstrating causality
Control
EPS
Bacterial Count
Shannon Diversity Index
3
2
1
C
C
-S
-S
ec
ec
tio
tio
n
n
-I
no
cu
la
te
d
Va
gi
na
lly
D
el
iv
er
ed
*
*
Vaginal
o
N
C IC
->
C C
->
E- E
>C
E>E
C
on
tro
EP l
S
Cesaerean
18
Jasarevic et al. (unpublished)
Vaginal
0.1
0.01
0.001
Cesaerean
Lactobacillus
Vaginal
C o
->
C
C
->
E
E>C
E>E
C
on
tro
EP l
S
C o
->
C
C
->
E
E>C
E>E
C
on
tro
EP l
S
0.1
0.01
0.001
0.0001
Cesaerean
19
300
30
20
10
0
Control EPS
200
100
400
CTL
EPS
300
15
30
120
Time (minutes)
40
CTL->CTL
EPS->CTL
CTL->EPS
EPS->EPS
30
20
10
0
CC CE EC EE
200
100
0
0
Caesarean delivered
AUC units (x 1000)
40
Corticosterone (ng/ml)
Vaginally delivered
AUC units (x 1000)
Corticosterone (ng/ml)
400
15
30
120
Time (minutes)
20
Proteobacteria
Firmicutes
Tenericutes
Bacteroidetes
Prenatal
Postnatal
Childhood
Puberty
Adulthood
Aging
Gastrointestinal tract
Bacterial
colonization
Dietary
transition
Mucosal
thinning
IEC
proliferation
Neuronal loss
Dendritic arborization
Synaptic loss
Neuronal migration
Apoptosis
Synaptic pruning
Excitatory synapses
Inhibitory synapses
E18.5&gut&
FC
class
class
class
Amica1
Amica1
Amica1
Camk2b
Camk2b
Camk2b
Mon1b
Mon1b
Mon1b
Piwil2
Piwil2
Piwil2
Limd1
Limd1
Limd1
Aim2
Aim2
Aim2
Pxylp1
Pxylp1
Pxylp1
Snx10
Snx10
Snx10
Ttc39a
Ttc39a
Ttc39a
Cdh4
Cdh4
Cdh4
NA.491
NA.491
NA.491
Fam173b
Fam173b
Fam173b
Ubn2
Ubn2
Ubn2
St6galnac1
St6galnac1
St6galnac1
Cyp2j13
Cyp2j13
Cyp2j13
Rbpms2
Rbpms2
Rbpms2
NA.29
NA.29
NA.29
Snhg18
Snhg18
Snhg18
Tmem204
Tmem204
Tmem204
Prss41
Prss41
Prss41
Fabp6
Fabp6
Fabp6
NA.466
NA.466
NA.466
Eif3j1
Eif3j1
Eif3j1
Dmtn
Dmtn
Dmtn
NA.473
NA.473
NA.473
Retsat
Retsat
Retsat
Iars2
Iars2
Iars2
Gm2115
Gm2115
Gm2115
1700084C01Rik
1700084C01Rik
1700084C01Rik
NA.532
NA.532
NA.532
Ly6d
Ly6d
Ly6d
NA.511
NA.511
NA.511
Gstt1
Gstt1
Gstt1
Yif1b
Yif1b
Yif1b
Krt4
Krt4
Krt4
Dnase1
Dnase1
Dnase1
Rdh5
Rdh5
Rdh5
NA.233
NA.233
NA.233
Dgat2
Dgat2
Dgat2
Cd68
Cd68
Cd68
Igfals
Igfals
Igfals
A930005H10Rik
A930005H10Rik
A930005H10Rik
Paqr4
Paqr4
Paqr4
4933404O12Rik
4933404O12Rik
4933404O12Rik
Rnaset2b
Rnaset2b
Rnaset2b
Atp6v0c
Atp6v0c
Atp6v0c
Rnps1
Rnps1
Rnps1
Rps2
Rps2
Rps2
NA.570
NA.570
NA.570
Hagh
Hagh
Hagh
FC
2
1
0
-1
-2
22
15.MCTL
15.MCTL
15.MCTL
11.MCTL
11.MCTL
11.MCTL
Male Ctrl
23.MCTL
23.MCTL
23.MCTL
19.MCTL
19.MCTL
19.MCTL
5.MEPS
5.MEPS
5.MEPS
Male EPS
13.MEPS
13.MEPS
13.MEPS
Female
10.MEPS
10.MEPS
10.MEPS
Male
222 class
class
class
MCTL
MCTL
MCTL
MEPS
MEPS
MEPS
111
Group
Male Control
000
-1
-1
-1
-2
-2
-2
Male EPS
23
25
SSC-A
33
Ly6G
Ly6C
51
% Ly6G+ Neutrophils
of CD45+ Cells
Male
36
25
20
15
10
5
0
80
% Ly6C+ Monocyes
of CD11b+ Cells
Female
Female
Male
60
40
20
0
Female
Male
CD11b%
Gating on total live singlet's CD45+ and then Ly6G- CD11b+ for bottom
24
Jasarevic,*Weinkopf,*et*al.,*(unpublished)*
EPS
FoxP3
11.3
FoxP3 FMO
5.26
15
Control
10
CD4
25
CON
EPS
2nd
hit
of
stress
reveals
EPS
male
Latent EPS programming to intestinal barrier dysfunction
vulnerability
tovariable
gut permeability
unmasked
by chronic
stress in adulthood
Control-CTL
EPS-CTL
Control-CVS
EPS-CVS
26
Adrenal cortex
Vagus nerve
Gonads
Corticosterone
Catecholamines
Insulin
Glucose
Cytokines
Estrogen
Testosterone
Progesterone
IEC
Microbial
metabolites
Hormones
Neurotransmitters
Immune
cells
EEC
27
28
29
Acknowledgements
Stefanie Bronson, Ph.D.
China Byrns
Jennifer Chan
Jessica Fluharty
Chris Howard
Chris Howerton, Ph.D.
Eldin Jasarevic, Ph.D.
Christopher Morgan
Katie Morrison, Ph.D.
Bridget Nugent, Ph.D.
Carly ODonnell
Ali Rodgers
!
Funding sources:
NIH MH073030, MH091258, MH087597,
SCOR P50-MH099910, MH104184, MH108286
Epigenetics Center
Benjamin Garcia, Ph.D.
Xiaoshi Wang, Ph.D.
CHMI
Dan Beiting, Ph.D.
32
-15
-20
-10
-5
10
-1.0
-0.5
0.0
p(corr)
0.5
Propionylcarnitine
1.0-10
Isovalerylcarnitine
GLUCOSE-ALANINE CYCLE
RNA TRANSCRIPTIO
Indolelactic Acid
-5
GLYCOLYS
Hippuric Acid
GLUCONEOGENESIS
BCAA
catabolite
Xanthosine
Microbial
metabolite
UREA CYCL
ADP
RNA TRANSCRIPTION
Energy
metaboltes
Creatine
10
GLYCOLYSIS
Glycerophosphocholine
15
Vitamin
metabolism
Riboflavin
CTL
EPS
20
Fold Change
(Relative to CTL)
UREA CYCLE
4-pyridoxic acid
Colon
Colon
GLUCONEOGENES
GLUCOSE-ALANINE CYCL
1.0