IBD pathogenesis and targeted therapies: How can we improve current management? R. Balfour Sartor, M. D. CCFA Chief Medical Advisor Midget Distinguished Professor of Medicine, Microbiology & Immunology Director, Multidisciplinary IBD Center and National Gnotobiotic Rodent Resource Center University of North Carolina- Chapel Hill
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IBD pathogenesis and targeted therapies: How can we improve current management?
IBD pathogenesis and targeted therapies: How can we improve current management?. R. Balfour Sartor, M. D. CCFA Chief Medical Advisor Midget Distinguished Professor of Medicine, Microbiology & Immunology - PowerPoint PPT Presentation
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IBD pathogenesis and targeted therapies: How can we improve current
management?
R. Balfour Sartor, M. D.CCFA Chief Medical Advisor
Midget Distinguished Professor of Medicine, Microbiology & Immunology
Director, Multidisciplinary IBD Center and National Gnotobiotic Rodent Resource Center
University of North Carolina- Chapel Hill
UCUC CDCD
Diffuse inflammation limited to the mucosa of the colon, involves rectum
(lactobacillus species), while C. section babies have predominant skin organisms
(Staphlococcus species)
C. section associated with risk of celiac disease, IBD, NEC, asthma, atopic
dermatitis
Antibiotic use in childhood is a risk factor for developing Crohn’s disease
(Anders Hviid et al, Gut 60:49-54, 2011)
Prospective, nationwide cohort study of children born between 1995 – 2003 in Denmark (N= 577,622)Findings:•Relative risk increased for IBD (1.84), and selectively for Crohn’s disease (RR 3.41), but not UC•Time and dose response: dx within 3 months (RR 4.43) and >7 courses of antibiotics( RR 7.32)
Conclusion: Unknown causal relationship or association with IBD symptoms before diagnosis?
Diet influencesMicrobiota(Wu et al, Science 2011)
Diet determines the composition of gut bacteria Growth and function of aggressive species by refined sugars and iron;
protective bacteria by complex carbohydrates (fiber, prebiotics)
Injurious Pro-inflammatory
(Iron, sucrose, fructose, satur. fat)
Bacteroides vulgatus, B. thetaEnterococcus faecalis
E. coli - enteroadherent / invasiveKlebsiella pneumoniaeBilophila wadsworthia
Clinical evidence (mostly correlative)that enteric bacteria, viruses or fungi can induce
Crohn’s disease
• Disease located in areas of highest bacterial populations• Increased mucosal association and translocation• Abnormal composition commensals- dysbiosis• Certain CD- associated genes alter gut microbiota and
bacterial killing• Infections can induce flares of IBD (C. diff toxin, CMV)• Fecal stream diversion prevents CD relapse, disease
recurs upon restoration of fecal flow• Manipulating bacterial populations treats certain subsets• Microbe-specific serologic and T cell responses
0
20
40
60
80
100F
req
ue
ncy
of
Dis
ea
se B
eh
av
ior
%
Number of Immune Responses
Anti-microbial Antibody Sum and Disease BehaviorInflammatoryIP (internal penetrating)
S (stenosing)
* Odds Ratio
0N=199
1N=262
2N=194
3N=57
Surgery
P trend < 0.0001
*2.2
*1.0
*5.0
*9.5
*1.7
*1.0
*4.2
*6.1
P trend < 0.0001
Dubinsky MC et al CGH 2008;6:1105
IBD: Patient Stratification by Dysbiosis (abnormal composition)
Peterson et al, 2008. Cell Host Microbe. 3:417-427Frank et al., 2007. PNAS. 104(34):13780-13785
No
rma
l Ab
norm
al
AbnormalNormal
IBD-dysbiosis subset is characterized by contraction of Firmicutes and Bacteroidetes
and expansion of Proteobacteria
Frank DN, et al. PNAS 2007;104(34):13780–13785
0
20
40
60
80
100
% o
f clo
ne li
brar
ies
No
Lachnospiraceae(Clostridia XIVa/IV)
YesIBD-Subset
Bacillus
Other
Bacteroidetes
Proteobacteria
Actinobacteria
Firmicutes
Faecalibacterium prausnitzii is a putative protective commensal bacterium:
Low mucosal concentrations at surgery predict post- operative recurrence in 20 CD Patients
Sokol H et al. Proc Natl Acad Sci U S A. 2008;105:16731.
10
8
6
4
2
0
F. p
rau
snit
zii (
%)
At surgery At 6 months
No endoscopic recurrenceEndoscopic recurrence
*
Insights from gnotobiotic rodentsInsights from gnotobiotic rodentsNational Gnotobiotic Rodent Resource Center (NIH, CCFA)National Gnotobiotic Rodent Resource Center (NIH, CCFA)
Essential Role of Commensal Enteric Bacteria in the Essential Role of Commensal Enteric Bacteria in the Pathogenesis of Experimental Chronic Intestinal Pathogenesis of Experimental Chronic Intestinal
InflammationInflammation
Mice
IL-2KO () IL-10KO
TCRKO
CD326TGMDR1KO
SAMP1/Yit () CD45RBhi SCID
RatsHLA-B27 TG
Indomethacin
Guinea pigsCarrageenan
Non-human primateCotton top tamarin
Differential ability of various bacterial speciesto induce or prevent experimental colitis
All bacterial species are not equal!
Cecal bacteriaHLA B27
transgenic rat
HLA B27
transgenic rat
Bacteroides vulgatus
E. coli
Cecal bacteria + Lactobacillus GG
Aggressive colitisAggressive colitis
ProtectionProtection
No colitisNo colitis
Moderate colitisModerate colitis
Rath et al., J Clin Invest 1996;98:945Rath et al., Infect Immunity 1999; 67:2969 Dieleman et.al., Gut 2003; 52:370
Germ free, no colitis
Functionally altered E. coli are present in ileal Crohn’s disease
Adherent/invasive E. coli
•Adhere to/invade epithelial cells•Persist within EC, macrophages•Increased in ileal Crohn’s disease (Darfeuille- Michaud, et al.Baumgart, Simpson, ISME J. 2007)
•Bind to CEACAM 6 on ileal epithelial cells Barnich et al, JCI 2007)
Intestinal inflammation vs. homeostasis depends on the relative balance of beneficial vs. detrimental bacteria: This balance is unique in each individual and each individual responds differently to various bacterial species
Injurious Pro-inflammatory
Bacteroides vulgatus, B. thetaEnterococcus faecalis
E. coli - adherent / invasiveKlebsiella pneumoniaeRuminococcus gnavus