Translational
Gastroenterology Unit and
Children’s Hospital University
of Oxford
The microbiota in inflammatory bowel disease
Holm Uhlig
RCP annual conference: Medicine 2019
Manchester 26.04.2019
Figure 3: Endoscopy and histology.A Endoscopy aphtoid ulcers.
B & C Terminal ileum with granuloma.
D & E Colonic inflammation with granuloma.
A B C
D E
Granuloma
transmural
inflammation
Inflammatory bowel disease
Mendelian disorder
associated IBD(IBD-like phenotype)
>50 disorders
Polygenic IBDCrohn’s disease and
Ulcerative colitis
>230 loci identified
Medical induced
IBD
Uhlig & Powrie
Ann Rev Immunol 2018
Inflammatory bowel diseases
have a complex pathogenesis
epithelial barrier
mesenchymal layer
phagocytes innate
barrier
T cell activation
and regulation
Highest incidence of inflammatory bowel disease
in Western countries
Rising Incidence of Pediatric Inflammatory Bowel Disease
Henderson et al. IBD 2011
Antibiotics
n = 57/447, 13%
on antibiotics during
sample collection Gevers Cell Host Microbes 2014
Darfeuille-Michaud et al. Gastroenterology. 2004
Adherent-invasive
Escherichia coli in Ileal
mucosa of patients with
Crohn‘s disease
reduction of Faecalibacterium
prausnitzii associated with
inflammation and complications
Is there evidence that the change in flora is pathogenic?
Sokol H et al. Proc Natl Acad Sci 2008
Sokol et al. IBD 2009
lower proportion of F. prausnitzii on
resected ileal Crohn mucosa
associated with endoscopic
recurrence at 6 months
in vitro & animal models
Reduction in ecological diversity reduces capacity to adapt
Microbial network disturbances in Crohn’s disease
Microbial co-occurrence analysis of IBD ecosystems
Yilmaz et al. Nature Medicine 2019
Reduced bacterial diversity associated with increased virome richness
Adaptation of the microbiome in early life
Antibiotic Exposure and IBD Development Among Children
A Population-Based Cohort Study
Kronman et al. Pediatrics 2012
Antianaerobic antibiotics
penicillin, amoxicillin,
ampicillin, penicillin/b-lactamase
inhibitor combinations, tetracyclines,
clindamycin, metronidazole, cefoxitin,
carbapenems, and oral vancomycin.
Metronidazole or fluoroquinolone
exposure associated with development of IBD
UK de-identified electronic medical record
data from 464 participating general
practices > GPRD
1 072 426 subjects<17 Year old for analysis
followed up for 6.6 million person years;
748 subjects (0.07%) developed IBD
>2 antibiotics
1-2 antibiotics
no antibiotics
hazard ratio
Normal
salt
diet
High
salt
diet
Normal
salt
diet
High
salt
diet
Animal model Human volunteers
Salt responsive gut commensal flora
Sodium loosing diarrhea shapes the Intestinal Microbiota in
humans and influences the risk of IBD
IBD
related and unrelated
healthy control
Familial
GUCY2C
syndrome
healthy
control
no
Crohn’s
disease
with
Crohn’s
disease
Penagini et al. Nutrients. 2016
Nutrition and IBD
Short chain fatty acids stimulate
regulatory T cells and IL-10 in the intestine
Fibres stimulate fermeting bacteria and effect on epithelial cells and regulatory Treg (Smith et al., 2013)
Bollrath and Powrie Science 2013, Xiong et al. 2014
reduction of butyrat-producing bacteria in IBD Patients (Frank 2007)
Short chain fatty acid butyrate
induces anti-microbial activity in monocyte derived macrophages
Julie Schulthess, Sumeet Pandey
MF0 MFB0
50
100
150
CFU
(x10
4 )
****
MF0
MFB
MF0+B
0
50
100
150
200
CFU
(x10
4 )
*** **
NS
MF0 MFB0
50
100
150
200
250
CFU
(x10
4 )
****
0 30 60 90 1200
50
100
150
200
time (min)
CFU
(x10
4 ) MF0
MFB
MF0 MFBA
B C
Figure 1
MF0 MFB0
20
40
60
80
100
120
% C
FU o
f m
ean
MF0
****
MF0 MFB0
100
200
300
400
CFU
(x10
4 )
***
MF0 MFB0
20
40
60
80
100
120
% C
FU o
f m
ean
MF0
*
D E
control butyrate
Schulthess, Pandey et al. Immunity 2019
MF0 MFB0
50
100
150
CFU
(x10
4 )
****
MF0
MFB
MF0+B
0
50
100
150
200
CFU
(x10
4 )
*** **
NS
MF0 MFB0
50
100
150
200
250
CFU
(x10
4 )
****
0 30 60 90 1200
50
100
150
200
time (min)
CFU
(x10
4 ) MF0
MFB
MF0 MFBA
B C
Figure 1
MF0 MFB0
20
40
60
80
100
120
% C
FU
of
mea
n M
F0
****
MF0 MFB0
100
200
300
400
CF
U (x
104 )
***
MF0 MFB0
20
40
60
80
100
120
% C
FU
of
mea
n M
F0
*
D E
Induction of antimicrobial transcriptional programs
in butyrate treated macrophages
butyrate
Kevin Rue-Albrecht,
Stephen N. Sansom
Butyrate modulates the macrophage metabolism
via AMP AMPK mTOR signalling
AMP AMPK pS6 (surrogate for mTOR)
Induction of LC3 associated antimicrobial activity by butyrate
Control
Butyrate
Schulthess, Pandey et al. Immunity 2019
Fiona Powrie
Julie Schulthess
Isabelle Arnold
Fanny Franchini
Agnieszka Chomka
Nicholas Ilott
Arancibia-Cárcamo
Kevin Rue-Albrecht1,
Stephen N. Sansom
Elisabete Pires
James McCullagh
Sumeet Pandey
Melania Capitani
Inflammatory bowel disease
reduced microbial diversity and dysbiosis
antibiotics food plant fibres salt? iron supplementation
antibiotics
(fistulising
disease)
probiotics
Ulcerative colitisFaecal
transplantation
diet
Sumeet Pandey
Melania Capitani
Tobias Schwerd
Fiona Powrie, Julie Schulthess
Isabelle Arnold
Fanny Franchini
Agnieszka Chomka
Nicholas Ilott
Arancibia-Cárcamo
Kevin Rue-Albrecht1,
Stephen N. Sansom
Elisabete Pires
James McCullagh
Fiona Powrie Oxford University
COLORS in IBD study group
Carl Anderson, Eva Concales
David Wilson
Jochen Kammermeier, Graham Thornton
all Uk collaborators
NEOPICS Aleixo Muise, Christoph Klein, Scott Snapper
Ramnik Xavier, Skip Virgin
Fran Platt & team Oxford
J Kammermeier, Neil Shah, Nikhil Thapar, Great Ormond Street
Hospital
Claire Booth, Kimberly Gilmour GOS London
Mads Gyrd-Hansen, Katrin Bagola, Oxford
