Microbe-Host Interactions in Inflammatory Bowel Diseases · Microbe-Host Interactions in...

Microbe-Host Interactions in Inflammatory Bowel Diseases

Hera Vlamakis

Oct 3, 2018

Mowat & Agace 2014 doi:10.1038/nri3738

Stool is proxy for gut microbes

Most of the bacteria in your body are in your gut

HEALTH BENEFITS

Breakdown of polysaccharides

Synthesis of vitamins

Colonization resistance

Maturation of our immune system

DISEASE

Inflammatory bowel diseases

Specific microbes enriched or

depleted

• Do infants acquire bacterial strains from their mother?

• Are different bacterial strains present in disease?

• Are microbial species associated with response to treatment or disease severity?

Today’s Questions:

Early life events shape the microbiome

Koenig et al, PNAS 2011

By age 3 years, the gut microbiome is adult-like.Yatsunenko et al. Nature 2012

Delivery mode affects the newborn’s gut microbiome.Dominguez-Bello et al. PNAS 2010Bäckhed et al., Cell Host & Microbe, 2015

Asnicar et al. mBio 2017

Large-scale paired longitudinal study of

both mother and child samples

Yassour et al., Science Trans. Med., 2016

Vertical transmission of microbes from mother to infants.

Longitudinal mother-infant cohort design

33 families in total = metagenomic sequencing for 264 samples.

Mother

Child

Age (months)

0 1 2 3-1-2

How similar are samples from the same family?

Yassour, Jason, Hogstrom et al. 2018 Cell Host and Microbe

Phylum-level microbial trajectories

ActinobacteriaBacteroidetesFirmicutesProteobacteriaVerrucomicrobia

Phylum:

Family

Birth

14 days

1

mo.

2

mo.

3

mo.

Infant profiles

Rela

tive a

bu

nd

an

ce

Gest.

week

27-28

Birth

3

mo.

Maternal profiles

Family

Rela

tive a

bu

nd

an

ce

Can we find distinctive species that were inherited by the child from the mother?

Do mother and child share their strains?

Yassour, Jason, Hogstrom et al. 2018 Cell Host and Microbe

ChildChildChild

Mother MotherMother

Dominant strain

transferred

Otherstrain

transferred

Secondarystrain

transferred

We are limited to species for which we have enough coverage

for both mother and child samples.

Do mother and child share their strains?

Dominant

strain

transferred

Secondary

strain

transferred

Neither strains

transferred

Z-sc

ore

fo

r se

con

dar

yst

rain

tra

nsf

er

Z-score for dominantstrain transfer

Yassour, Jason, Hogstrom et al. 2018 Cell Host and Microbe

mothersample

childsample

1 2 3 1 2 3

Mother dominant nucleotideMother secondary nucleotideOther nucleotide

z-sc

ore

fo

r s

ec

on

da

ryst

rain

tra

nsf

er

Bacteroides uniformis

Do mother and child share their strains?

Z-score for dominantstrain transfer

Yassour, Jason, Hogstrom et al. 2018 Cell Host and Microbe

mothersample

childsample

1 2 3 1 2 3

Mother dominant nucleotideMother secondary nucleotideOther nucleotide

Transmission pattern varies across species

z-score for dominant strain transfer

z-sc

ore

fo

r s

ec

on

da

ryst

rain

tra

nsf

er

Mostly secondary

strain transmissions

Mostly dominant

strain transmissions

Functional differences in maternal strains may

elicit inheritance mode

z-score for dominant

strain transfer

z-sc

ore

fo

r seco

nd

ary

stra

in t

ran

sfer

MISSING

FUNCTION?

Bacteroides uniformis

Yassour, Jason, Hogstrom et al. 2018 Cell Host and Microbe

z-score for dominant

strain transfer

z-sc

ore

fo

r seco

nd

ary

stra

in t

ran

sfer

MISSING

FUNCTION?

Bacteroides uniformis

Functional differences in maternal strains may

elicit inheritance mode

Yassour, Jason, Hogstrom et al. 2018 Cell Host and Microbe

Functional differences in maternal strains may

elicit inheritance mode

Maternal strains that can utilize human milk oligosaccharides

may be more likely to colonize the infant gut

Starch utilization system (sus) locus

• Do infants acquire bacterial strains from their mother?

• Are different bacterial strains present in disease?

• Are microbial species associated with response to treatment or disease severity?

Today’s Questions:

Intestinal epithelium

Environmental factors

DietHygiene

Microbial community

Genetic susceptibility

Immune systemInflammatory and non-inflammatory

organisms

PathogensAntibiotics

Dendritic cell

Paneth cell

IBD is caused by dysfunction in the composition of and interactionsbetween microbes, intestinal epithelium, and the immune system

Factors that influence development of

inflammatory bowel diseases

Differentially abundant species in IBD

Up in IBD species

Ruminococcus gnavus

Escherichia coli

Streptococcus salivarius

Streptococcus parasanguinis

Haemophilus parainfluenzae

Enterococcus faecium

Down in IBD species

Faecalibacterium prausnitzii

Eubacterium rectale

Ruminococcus bromii

Alistipes finegoldii

Clostridium leptum

Odoribacter splanchnicus

Obligate anaerobe

Facultative anaerobe

Hypothesis: Increased production of reactive oxygen species in IBD causes a decrease in obligate anaerobes and replacement by facultative anaerobes that can tolerate ROS Morgan et al. 2012 (Huttenhower)

Lewis et al. 2015 (Wu) Ballal et al. 2015 (Garrett)

Hall, Yassour et al. 2017 Genome Medicine

Transiently increased abundance of R. gnavus in IBD

Ind

ivid

ual

s

Ind

ivid

ual

s

Hall, Yassour et al. 2017 Genome Medicine

Ge

ne

cluste

rs

Metagenomic samples

Dark blue – presenceLight blue – absence

Clade 2

Pangenome analysis of R. gnavusClade 2 is only found in adults with IBD

Clade 1Metagenomic data from• IBD: LSS, Lewis et al. • Healthy: HMP, 500FG

R. gnavus clade 2 found in IBD patients from 3 clinical centers

Hall, Yassour et al. 2017 Genome Medicine

199 Clade 2 specific genes• Responses to oxidative stress• Mucus utilization• Adherence • Iron acquisition

• Do infants acquire bacterial strains from their mother?

• Are different bacterial strains present in disease?

• Are microbial species associated with response to treatment or disease severity?

Today’s Questions:

Study overview: PROTECT

0 4 12 52

Sample collection weeks:

Pediatric patients often exhibit a more severe clinical phenotype

compared to adults

2 treatment strategies

Strategy 1:

mesalamine

Strategy 2:

corticosteroids mesalamine

Evaluate efficacy

of standardized

initial therapy

405 pediatric, treatment-

naive cohort with new-

onset UC

263 rectal biopsies

949 stool

samples--------------------------

1,212 samples

Schirmer et al. 2018 Cell Host and Microbe

While disease severity improved for many patients, only 34% achieved week

12 remission and 37% achieved week 52 remission.

Severe

n=90 with

follow-up

Moderate

n=139 with

follow-up

Mild

n=75 with

follow-up

Disease progression and treatment response over time

Schirmer et al. 2018 Cell Host and Microbe

Samples cluster by disease severity

Changes in microbial community

composition are associated with disease

severity

Fecal calprotectin

significantly increases

with disease severity

* * *

100

1000

10000

inactive mild moderate severe

Fe

cal

ca

lpro

tec

tin

* * *

Gut microbial composition changes with increased disease severity

Schirmer et al. 2018 Cell Host and Microbe

• Heatmap shows 30/91 most significant OTUs (1,212 samples, FDR < 10-11)

• 75% of severity-decreased OTUs (54) were from the order Clostridiales

• Increase in oral taxa associated with severe disease

Oral

bugs

Do

wn

in

se

ve

reU

p in

se

ve

re

inactiv

e

mild

modera

te

severe

Bifidobacterium (OTU 997439)

Blautia (OTU 1078587)

Lachnospiraceae (OTU 975306)

Collinsella (OTU 147071)

Clostridiales (OTU 509416)

Blautia obeum (OTU 528606)

Blautia (OTU 368950)

Blautia (OTU 531675)

Erysipelotrichaceae (OTU 592616)

Blautia producta (OTU 696563)

Ruminococcus (OTU 199543)

Eggerthella lenta (OTU 682726)

Ruminococcaceae (OTU 309720)

Blautia producta (OTU 589313)

Clostridiales (OTU 562376)

Bifidobacterium (OTU 471180)

Blautia (OTU 580087)

Lachnospiraceae (OTU 195115)

Ruminococcus (OTU 591635)

Bifidobacterium (OTU 484304)

Coriobacteriaceae (OTU 175508)

Neisseriaceae (OTU 904345)

Eikenella (OTU 1026498)

Aggregatibacter segnis (OTU 92231)

Veillonella parvula (OTU 518743)

Pasteurellaceae (OTU 562825)

Fusobacterium (OTU 444857)

Veillonella dispar (OTU 342427)

Haemophilus parainfluenzae (OTU 865469)

Enterobacteriaceae (OTU 1111294)

−4.5

−4

−3.5

−3

−2.5

−2

−1.5

−1

Microbial factors are associated with disease severity

Schirmer et al. 2018 Cell Host and Microbe

• Severe patients achieving week 52 remission started with high levels and displayed a

continuous decrease of H. parainfluenzae

• Mild patients that failed to achieve week 52 remission started with lower levels but

displayed a substantial increase by week 52

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●1e−05

1e−03

1e−01

0 4 12 52

Collection week

OT

U 8

65

469

●

●

●

●

●

●

inactive

mild

moderate

severe

No remission

Remission

Haemophilus parainfluenzae

Longitudinal trends in H. parainfluenzae

implicated in remission

Schirmer et al. 2018 Cell Host and Microbe

Human Microbiome Project 2: Goals and Objectives of this Study

Pregnancy & PretermBirth

InflammatoryBowels Disease

Prediabetes(Type 2 diabetes)

Ramnik Xavier and Curtis Huttenhower

132 subjects; sampled every 2 weeks; 1 year

The IBD Multi’omics DataBase

http://ibdmdb.org

Thank you!

Ramnik Xavier Curtis Huttenhower

Timothy Arthur

Nadine Fornelos

Eric Franzosa

Ashley Garner

Brantley Hall

Larson Hogstrom

Xiaofang Jiang

Jason Lloyd-Price

Tiffany Poon

Melanie Schirmer

Alexandra Sirota-Madi

Moran Yassour

Human Microbiome Project 2

Lita Procter

Jon Braun

Dermot McGovern

Subra Kugathasan

Ted Denson

Janet Jansson

Owen White

Bruce Birren

Chad Nusbaum

Clary Clish

Joe Petrosino

Thad Stappenbeck

ibdmdb.org

…and the labs!

Eeva Jason

Mikael Knip Lab

Georgia Lagoudas

Paul Blainey Lab

PROTECT

Subra Kugathasan

Lee Denson

Jeff Hyams

We are now hiring postdocscontact us if interested