factors implicated in ibd - American College of Gastroenterology

Stephen M. Collins, MBBS
The Role of the Intestinal
Microbiome in IBD
Stephen Collins
Farncombe Institute
McMaster University
Hamilton, Ontario
Canada
FACTORS IMPLICATED IN IBD
Innate Immunity
ENVIRONMENT
GENES
Adaptive
Immunity
Barrier Function
Bacterial
Recognition
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Stephen M. Collins, MBBS
GENETIC FACTORS
8-10%
44-55%
Ulcerative colitis
• Bacterial recognition
• Reduced epithelial barrier
”THE ENVIRONMENT”
• Impaired bacterial killing
Halfvarson J Gastroenterology 2003
EPIDEMIOLOGICAL STUDIES FAVOR
ENVIRONMENTAL FACTORS
• The impact of urbanization on prevalence of IBD.
• The changing epidemiology of IBD in Japan.
• Increasing prevalence of IBD among young
immigrants to westernized societies.
• Exposure to antibiotics in early life.
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Stephen M. Collins, MBBS
IMPLICATING THE MICROBIOTA IN IBD
• Many IBD susceptibility genes suggest
microbial involvement
• Circulating antibodies to bacterial antigens
in IBD sufferers
• Response to antibiotics in some patients
• Altered microbial composition of the gut in
IBD patients
THE INTESTINAL MICROBIOME
• Home to 10–100 trillion organisms; the most densely packed
ecosystem on the planet; separated by a single cell layer!
•
400m2
Microbial genes outnumber human genes by a factor of 100.
• Bacterial cells outnumber human cells 10:1
• 98% of sequenced bacteria belong to only four bacterial
phyla:
Firmicutes (64%)
Bacteroidetes (23%),
Proteobacteria (8%),
Actinobacteria (3%).
• Instructs the immune system and influences host physiology,
metabolism and brain function
• Subject to environmental influences e.g. diet, antimicrobials
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Stephen M. Collins, MBBS
HOMEOSTASIS
• CONTROLLED RELEASE OF
ANTIMICROBIAL PEPTIDES.
• SHORT CHAIN FATTY ACIDS
SUPPORT EPITHELIAL INTEGRITY.
• MINIMAL PENTRATION OF GUT
WALL BY BACTERIA.
• EFFICIENT KILLING OF INVADING
BACTERIA. NO SEQUELAE.
• CONTROLLED INFLAMMATORY
RESPONSE
Adapted from Sartor RB
Gastroenterology 2010; 139:1816-33
FACTORS CONTRIBUTING TO ALTERED
MICROBIOTA IN IBD
GENETICALLY DETERMINED
FACTORS:
•
Reduced secretion of antimicrobial peptides.
•
Enhanced replication of
mucosal adherent bacteria in
ileum (E.coli).
•
Defective clearance of
invading bacteria due to
impaired intracellular killing
(autophagy); immune
activation
ENVIROMENTAL FACTORS
Reduced acquisition of
microbes :” hygiene
hypothesis”
Loss of ancestral microorganisms: “old friends
hypothesis”
•
Hygiene
•
Diet
•
Antimicrobials
•
Stress
“DYSBIOSIS”
INFLAMMATION & DYSFUNCTION IN HOST TISSUES
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Stephen M. Collins, MBBS
THE MICROBIOTA COMPOSITION IN
IBD & HEALTHY CONTROLS
UC
CD
HC
THERE IS NO
MICROBIAL
SIGNATURE THAT IS
UNIQUE TO EITHER
UC OR CD, OR IBD
IN GENERAL
Principal Component Analysis based on the abundance of 155 species in 14 healthy
controls, 19 Crohn’s Disease patients and 6 patients with Ulcerative Colitis
Qin J et al Nature 2010
COMMENSALS & PATHOGENS
SYMBIONTS
Lactobacilli
Bifidobacteria
F.prausnitzii
Bacteroides fragilis
SCFA, Polysccharide A
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CONDITIONAL
PATHOGENS
Segmented
Filametous Bacteria
(SFB)
PATHOGENS
Clostrium difficile
Certain E.Coli
strains
TH17
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Stephen M. Collins, MBBS
THE MICROBIOTA IN IBD
• REDUCED DIVERSITY AND ALTERED COMPOSITION
Actinobacteria
Proteobacteria
Firmicutes
Bacteroides
Bifidobacteria
Lactobacilli
Clostridium gps IV
XIVa
(F. prausnitzii)
Enterobacteria
Ruminococci
Mucosal
Adherent
Invasive E
Coli
(AIEC) in
ileum of CD
DYBIOSIS & THE LOSS OF
HOMEOSTASIS IN IBD
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Stephen M. Collins, MBBS
BREAKDOWN OF HOMEOSTASIS IN IBD
• Altered microbial
composition
• Impaired barrier
function
• Reduced
autophagy:
Persistent bacterial
presence
• Enhanced immune
response (Th1 &
Th17) and
uncontrolled
inflammation
Adapted from Sartor RB Gastroenterology 2010; 139:1816-33
REDUCTION IN FECALIBACTERIUM PRAUSNITZII
ASSOCIATED WITH ILEAL CROHN’S DISEASE ACTIVITY.
Reduction in
F.prausnitzii in the
ileum when the disease
is active.
F. prausnitzii proportions in the ileal MAM using FISH at the time of surgery and at 6 months according to the
endoscopic recurrence status. *, Significant difference, P = 0.03.
©2008 by National Academy of Sciences
Sokol H et al. PNAS 2008;105:16731-16736
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Stephen M. Collins, MBBS
F. prausnitzii HAS ANTI-INFLAMMATORY
PROPERTIES.
• F.prausnitzii reduces proinflammatory cytokine release
from human monocytes.
• F.prausnitzii increases the ratio
of anti-inflammatory (IL-10) to
pro-inflammatory cytokine (IL12) secretion ratio in human
monocytes.
©2008 by National Academy of Sciences
Sokol H et al. PNAS 2008;105:16731-16736
CONTRIBUTIONS OF MICROBIOTA
TO THE MANIFESTATIONS OF IBD
• Generation of inflammation and tissue
destruction
• Carcinogenesis
• Altered gut function (motility and pain
perception)
• Behavioral changes (anxiety and
depression)
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Stephen M. Collins, MBBS
THE INTESTINAL MICROBIOTA &
COLONIC CARCINOGENESIS
• Germ free animals show reduced carcinogen-induced tumor
formation ( Reddy BS, Cancer Research 1974).
• Reduction in buytrate-producing organisms and an increase in
mucolytic bacteria in CRC patients. (Weir TL et al PLoS One
2103)
• Mucosa-adherent Escherichia coli associated with IBD & CRC in
humans (M Prorok-Hamon et al Gut 2013)
• Inflammation-induced tumor genesis shown to be transferable
via the microbiota in mice; critical role of IL-6 (Hu B et al PNAS
2013).
DYSBIOSIS ALTERS VISCERAL PAIN,
GUT MOTILITY AND BEHAVIOR
Studies in mice…
•
•
•
10-14 days
Antibiotics
Stable
diverse
microbiota
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Motility
Pain
Behavior
Perturbed
microbiota
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Stephen M. Collins, MBBS
EFFECT OF ANTIMICROBIAL TREATMENT ON
BACTERIAL COMPOSITION OF THE COLON IN MICE
Before treatment
Cage
DURING ATM TREATMENT
1
2
-
3
-
4
During treatment
5
-
-
1
+
2
+
3
4
5
6
-
2 WEEKS AFTER ATM TREATMENT
Actinobacteria
G-Proteobacteria
Firmicutes
Bacteroides
Verrumicrobia
Other
CONTROL n=15
ATM TREATED n=19
Bercik P et al Gastroenterology 2011
PERTURBATION OF INTESTINAL MICROBIOTA INCREASED
MPO ACTIVITY IN GUT AND TRANSIENTLY INCREASED
RESPONSES TO COLORECTAL DISTENSION
(A, B) Percentage of colorectal distension (CRD) responses to 30 mm Hg versus day 0 in placebo and
antibiotic treated mice.
©2006 by BMJ Publishing Group Ltd and British Society of Gastroenterology
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Verdú E F et al. Gut 2006;55:182-190
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Stephen M. Collins, MBBS
ANTIBIOTIC-INDUCED CHANGES IN MOTILITY IN
MICE
Antibiotic-induced perturbation of the microbiota (Abx) delayed transit, as
reflected by reduced fecal pellet excretion and altered muscle function.
Similar observations with TLR-4 KO mice (in the absence of antibiotics).
Anitha M et al GASTROENTEROLOGY 2012
PSYCHIATRIC CO-MORBIDITY IN IBD
Kurina LM, Goldacre MJ, Yeates D, et al.
Depression and anxiety in people with
inflammatory bowel disease. J Epidemiol
Community Health. 2001; 55: 716–720.
Lifetime prevalence of major
depression is higher in IBD patients
compared to controls (27.2%vs
12.3%, OR 2.20, 95% CI 1.64-2.95).
Walker JR et al Am J Gastroenterol.
2008 Aug;103(8):1989-97
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Stephen M. Collins, MBBS
DYSBIOSIS ALTERS BEHAVIOR
Latency to step
down (sec)
300
250
200
150
100
50
0
*
Control
Antibiotic treated
2 weeks post
Bercik P Gastroenterology 2011
INTESTINAL DYSBIOSIS IN IBD
• A driver of immune activation and
inflammation in susceptible individuals
• Contributes to altered gut physiology seen
in IBD in during both relapse and
remission
• May influence behavioral changes such as
anxiety and depression in IBD patients
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Stephen M. Collins, MBBS
DYSBIOSIS
CAUSE OR EFFECT ?
Induction of early lesions of Crohn’s by instillation of
faecal material into excluded loops of bowel
3 patients with Crohn's disease
who had undergone a curative
ileo-colonic resection with
ileocolonic anastomosis and
temporary protective proximal
loop ileostomy.
Contact with intestinal fluids for
8 days induced focal infiltration
of monocytes & polymorphs in
LP and epithelium in the
excluded neo-terminal ileum that
was previously normal.
D'Haens GR et al. Early lesions of recurrent Crohn's disease caused
by infusion of intestinal contents in excluded ileum.
Gastroenterology. 1998 Feb;114(2):262-7.
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Stephen M. Collins, MBBS
THE ENEMY IS WITHIN
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