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Infant microbiome in health and disease:
current understanding and future
direction
Dr. Christopher J Stewart, PhD
SIGNEC 2018
October 2018
Disclosures
Support from Danone Nutricia to be at SIGNEC 2018
Agenda
1. Term infant2. Preterm infant3. Looking ahead
Translation
What is the Microbiome?
Micro – SmallBiome – Community that occupies a distinct environment
Proportion of cells in the human body
Gaby D'Allesandro / © AMNH
Aagaard, Stewart, Chu. EMBO Reports. 2016;17(12):1679-1684
Gut microbiome
Stewart CJ et al. Nature. 2018; Vatanen T et al. Nature. 2018.
Development of the gut microbiome early in life
Gut microbiome phases
Stewart CJ et al. Nature. 2018.
Significance and explained variance of 22 microbiome covariates
Metagenomics - Species10,602 samples
783 children
Metagenomics - Module (function)10,602 samples
783 children
Stewart CJ et al. Nature. 2018.
BM increases Bifidobacterium and delays microbiome maturation
Stewart CJ et al. Nature. 2018.
BM increases Bifidobacterium and delays microbiome maturation
Stewart CJ et al. Nature. 2018.
Human milk oligosaccharides (HMOs)
Zivkovic AM et al. Food Rev In. 2013.
Bifidobacterium growth assays
Vatanen T et al. Nature. 2018.
Epidemiological association of breast milk with later life disease
Dogaru et al., Am J Epidemiology (2013)
Allergy - 117 study meta-analysis
Davis et al., Diabetes Care (2006)
Obesity – 15,253 children age 9-14 years old
Agenda
1. Term infant2. Preterm infant3. Looking ahead
Translation
Key differences in microbiome acquisition and development
Term infantPreterm infant
Child
?
Reduced:
Diversity
Stability
Bifidobacterium sp.
Lactobacillus sp.
Bacteroides sp.
Increased:
Klebsiella sp.
Staphylococcus sp.
Escherichia sp.
Enterococcus sp.
1-3 Yearsof age
Full termPreterm
Stewart and Cummings, Taylor & Francis. 2016
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0.0
0.5
1.0
1.5
2.0
0 25 50 75 100DOL
Alp
ha
Div
ers
ity
Disease●
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ControlLOSNEC
DOL
Shan
nonDiversity
4.0
PD1 – 3 Yr
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0.0
0.5
1.0
1.5
2.0
0 25 50 75 100DOL
Alp
ha
Div
ers
ity
Disease●
●
●
ControlLOSNEC
DOL
Shan
nonDiversity
Preterm infants restore diversity post-discharge from NICU
Day of life
Stewart, CJ. et al., Nature Scientific Reports (2016)
Preterm microbiome and NEC
Warner, BB. et al. 2016. Lancet
• Increased Gammaproteobacteria in infants diagnosed with NEC after day 30 of life only• Most NEC is diagnosed prior to day 30 of life
• Shannon diversity generally decreased in NEC
n = 46 NEC casesn = 120 controls
Preterm microbiome and NEC
Pammi, M. et al. 2016. Microbiome
• Potentially some differences between NEC and controls, but not predictive of onset
8 studies (106 NEC cases, 278 controls, 2944 samples)
Microbiome modelling of NEC and LOS
Stewart, CJ. et al. 2016. Microbiome 7 NEC / 7 LOS / 28 matched controls. 747 samples
Bifidobacterium and diversity associated with protection from NEC and LOS
Stewart, CJ. et al. 2016. Microbiome
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Adj. P = 1.7e−13
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Adj. P = 2.9e−61
Observed OTUs Shannon
0
10
20
30
40
50
0
1
2
A B C D E F A B C D E FA
lph
a D
iversity
PGSTletterABCDEF
1 2 3 4 5 6 1 2 3 4 5 6PGCT PGCT
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*** *** ****** ****** *** ****** ***
4%
16%
36%
64%
100%
K.oxytocea
E.coliE.faecalis
S.aureus
Bifidobacterium
Clostr idium_sensu_stricto
Streptococcus
Lactobacillus
Morganella
Veillonella
Re
lative
Abu
nd
an
ce
PGSTletter
A
B
C
D
E
F
123456
A B
C
StatusPGCT
PGCT
K.oxtocea
E.coli
PGCT
S.aureus
E.faecalis
Bifidobacteria
1 2 3 4 5 6
NEC microbiome highly unstable
1
2
3
4
5
6
PGCT
Klebsiella
Staphylococcus
Enterococcus
Escherichia
Klebsiella + Enterococcus
Bifidobacteria
Stewart, CJ. et al. 2016. Microbiome
NEC vs. SIP tissue
Stewart, CJ. et al. Unpublished
13 NEC 16 SIP
Altered alpha- and beta-diversity in NEC
Stewart, CJ. et al. Unpublished
Significantly altered phyla in NEC
Stewart, CJ. et al. Unpublished
Phyla
Genera
Agenda
1. Term infant2. Preterm infant3. Looking ahead
Translation
Preterm enteroids to study host-microbiome in health and disease
Example usesEpithelial integrity
Bacterial translocationInflammatory responses
Collaborative neonatal trials
Speed of Increases in Feeds Trial
SIFT n=2804
Enteral lactoferrin in Neonates
ELFIN n=2204
Interactions between diet and growth outcomes
Exclusive human milk (Prolacta)
INDIGO n=50/100
INDIGO
Mechanisms Affecting the Gut of Preterm Infants in Enteral feeding studies (MAGPIE)
Immune(Transcriptome)
Microbiome
VOCsMetabolome
Stool
Urine
Salvaged blood / Resected tissue
MAGPIE n=481
Collaborative neonatal biobanks
Great North Neonatal BiobankRoyal Victoria Infirmary~700 preterm infants ~10,000 stool samples~3,000 Urine samples~3,000 Serum samples
MAGPIE12 UK centers~500 preterm infants~15,000 stool samples~25,000 urine samples
Future Direction
‘Omics
Discovery Translation
Models
Clinic
Diagnostics/ Therapeutics
Samples
Clinic
HumanInterventions
Joe PetrosinoTatiana FofanovaTommy AuchtungMary EstesSasirekha RamaniUmesh KarandikarJennifer AuchtungAmy Hair
Acknowledgements
Chris LambJohn KirbySophie HambletonRebecca Payne
Janet BerringtonNick Embleton
Tommi VatanenCurtis HuttenhowerRamnik Xavier
Jonathan MansbachKohei HasegawaCarlos Camargo
