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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

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IBD pathogenesis and targeted therapies: How can we improve current management?

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  1. 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

  2. Inflammatory Bowel Diseases CD UC • Segmental inflammation involving full thickness of any part of GI tract • Immunologic ProfileTH1/17: IL-12, 17, 23, IFNg activated innate pathways (IL-1b, IL-6, TNF) • Diffuse inflammation limited to the mucosa of the colon, involves rectum • Immunologic Profile TH2: IL-13, activated innate pathways (IL-1b, IL-6, TNF, IL-12, IL-23) Genes HLA NOD 2 MDR1a ATG16L1 IL-23R IL-23R

  3. 2 patients with Crohn’s disease: similar presentations, different outcomes Onset: Two 12 y/o boys with failure to grow for one year, anemia  weight loss, abdominal pain, nonbloody diarrhea Evaluation: Ileal Crohn’s disease Treatment: Prednisone, 6MP Patient APatient B Benign course Complications: Feels well, no flares intra-abdominal abscess, …………………………. drained, resection of 14” ileum Post op Infliximab

  4. How to predict which patient will: • Have an aggressive course? • Respond to a potential treatment? • Have complications of disease or therapy? Understand mechanisms of disease in an individual at time of diagnosis Genetic, microbial, immunologic profiles and clinical phenotype

  5. B. Sartor Gastroenter. 2010 Fut2 Sartor RB Gastroenterology 2010

  6. Etiologic Hypothesis of Crohn’s Disease (2014) • Chronic intestinal inflammation is due to overly aggressive TH1/17 cell responses to a subset of luminal bacteria • Susceptibility is determined by genes that encode immune responses, mucosal barrier function or bacterial clearance • Onset/reactivation is triggered by environmental stimuli that transiently break the mucosal barrier and initiate inflammation

  7. Crohn’s disease pathogenesis • Microbiota • ↑ Aggressive • ↓ Protective • Environmental Triggers • Infections • NSAIDs • Diet • Smoking • Stress • Genetic Susceptibility • Barrier Function • Bacterial Killing • Immunoregulation • 163 genes! • Immune Response • ↑ TH1 • ↑ TH17 • Defective Innate

  8. 163 confirmed genetic loci in IBD CD genes UC genes 110 IBD loci Common pathways: • Leprosy • Mycobacterialsusceptibility • Other immune-mediated disease 30 CDspecific loci 23 UCspecific loci NOD2 PTPN22 MHC Genes in common Jostins, L. et al. Nature 491, 119–124 (01 November 2012)

  9. 163 gene mutations associated with Crohn’s disease and ulcerative colitis Epithelial Barrier • OCTN 1/2 • organic cation (carnitine) transporter • DLG5 • Scaffolding protein, epithelium • MDR1a (UC) • drug transporter, epithelium • NOD2/CARD15 - intracellular bacterial receptor • XBP1 - endosomal stress response Immunoregulation IL-23R(CD and UC) IL-10 and IL-10R HLA Bacterial killing/processing ATG 16L1-bacterial autophagy IRGM- bacterial killing, autophagy NCF4- NADPH- killing bacteria NOD2- intracellular killing, antimicrobial peptide secretion

  10. Crohn’s disease pathogenesis • Microbiota • ↑ Aggressive • ↓ Protective • Environmental Triggers • Infections • NSAIDs • Diet • Smoking • Stress • Antibiotics • Genetic Susceptibility • Barrier Function • Bacterial Killing • Immunoregulation • Immune Response • ↑ TH1 • ↑ TH17 • Defective Innate

  11. Environmental Triggers of IBD Altered mucosal barrier function and/or immunoregulation Altered microbiota Acute infections Antibiotics NSAIDs IBDOnset and Reactivation Smoking Diet Stress

  12. Mode of delivery profoundly affects early colonization of neonatesDominguez- Bello…R. KnightPNAS 2010Vaginally- delivered babies’ microbiotacontains vaginal dominant organisms (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

  13. 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?

  14. Diet influences Microbiota (Wu et al, Science 2011)

  15. 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) Protective Anti- inflammatory (Fiber, prebiotics) Injurious Pro-inflammatory (Iron, sucrose, fructose, satur. fat) Bacteroides vulgatus, B. theta Enterococcus faecalis E. coli - enteroadherent / invasive Klebsiella pneumoniae Bilophila wadsworthia Bifidobacterium animalis Fusobacterium varium Intestinal Helicobacter species Lactobacillus sp. Bifidobacterium sp. Non-pathogenic E. coli Saccharomyces boulardii Bacteroides thetaiotaomicron Faecalibacterium prausnitzii Clostridium groups IV and XIVA

  16. Crohn’s disease pathogenesis • Microbiota • ↑ Aggressive • ↓ Protective • Environmental Triggers • Infections • NSAIDs • Diet • Smoking • Stress • Genetic Susceptibility • Barrier Function • Bacterial Killing • Immunoregulation • Immune Response • ↑ TH1 • ↑ TH17 • Defective Innate

  17. Gastrointestinal Bacteria in Normal Humans Stomach 0-102 Lactobacillus Candida Streptococcus Helicobacter pylori Peptostreptococcus Duodenum 102 Streptococcus Lactobacillus Distal Ileum 107-108 Clostridium Bacteroides sp Coliforms Jejunum 102 Streptococcus Lactobacillus Colon 1011 Bacteroides Clostridium coccoides Clostridium leptum/ Fusobacterium Bifidobacterium Coliforms (108) Proximal Ileum 103 Streptococcus Lactobacillus

  18. Metabolism in the colonic ecosystem Polysaccharides Oligosaccharides Mucins Proteins Bacteroides clostridia peptostreptococci peptococci Succinate Bifidobacterium Lactobacillus Clostridium IV Clostridium IX SO4-- Clostridium XIVa E. halli R. hominis Sulfate Reducing Bacteria H2S CO2 Lactate Acetogens H2 Ethnogeny Phenols NH4+ Amines Acetate Butyrate Propionate Methane

  19. 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

  20. Anti-microbial Antibody Sum and Disease Behavior P trend < 0.0001 P trend < 0.0001 * 9.5 * 6.1 * 5.0 * 4.2 * 2.2 * 1.7 * 1.0 * 1.0 Inflammatory IP (internal penetrating) S (stenosing) Surgery Frequency of Disease Behavior % 3 N=57 0 N=199 1 N=262 2 N=194 * Odds Ratio Number of Immune Responses Dubinsky MC et al CGH 2008;6:1105

  21. IBD: Patient Stratification by Dysbiosis (abnormal composition) Abnormal Normal Normal Abnormal Frank et al., 2007. PNAS. 104(34):13780-13785 Peterson et al, 2008. Cell Host Microbe. 3:417-427

  22. IBD-dysbiosis subset is characterized by contraction of Firmicutes and Bacteroidetes and expansion of Proteobacteria IBD-Subset No Yes 100 Actinobacteria 80 Proteobacteria Bacteroidetes 60 % of clone libraries Other 40 Bacillus Firmicutes Lachnospiraceae(Clostridia XIVa/IV) 20 0 Frank DN, et al. PNAS 2007;104(34):13780–13785

  23. Faecalibacterium prausnitzii is a putative protective commensal bacterium:Low mucosal concentrations at surgery predict post- operative recurrence in 20 CD Patients No endoscopic recurrence Endoscopic recurrence 10 8 * 6 F. prausnitzii (%) 4 2 0 At surgery At 6 months Sokol H et al. Proc Natl Acad Sci U S A. 2008;105:16731.

  24. Insights from gnotobiotic rodentsNational Gnotobiotic Rodent Resource Center (NIH, CCFA) The stage: A gnotobiotic isolator The actors: Germ-free Selectively SPF/ CONV-R CONV-D conventionalized colonized conventionally (monoassociated) SPF raised Adapted from Jeff Gordon

  25. Essential Role of Commensal Enteric Bacteria in the Pathogenesis of Experimental Chronic Intestinal Inflammation No bacteria Resident bacteria Mice IL-2KO () IL-10KO TCRa KO CD3e26TG MDR1KO SAMP1/Yit () CD45RBhi SCID Rats HLA-B27 TG Indomethacin Guinea pigs Carrageenan Non-human primate Cotton top tamarin Macrophage and TH1/TH17 immune activation No immune activation No colitis Colitis

  26. Differential ability of various bacterial species to induce or prevent experimental colitis All bacterial species are not equal! Aggressive colitis Cecal bacteria HLA B27 transgenic rat Moderate colitis Bacteroides vulgatus Germ free, no colitis No colitis E. coli Cecal bacteria + Lactobacillus GG Protection Rath et al., J Clin Invest 1996;98:945 Rath et al., Infect Immunity 1999; 67:2969 Dieleman et.al., Gut 2003; 52:370

  27. 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)

  28. 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 Protective Probiotic Injurious Pro-inflammatory Lactobacillus sp. Bifidobacterium sp. Faecalibacterium prausnitzii Roseburia species Non-pathogenic E. coli Saccharomyces boulardii Bacteroides thetaiotaomicron Bacteroides vulgatus, B. theta Enterococcus faecalis E. coli - adherent / invasive Klebsiella pneumoniae Ruminococcus gnavus Segmented filamentous bacterium Fusobacterium varium Intestinal Helicobacter species

  29. Crohn’s disease pathogenesis • Microbiota • ↑ Aggressive • ↓ Protective • Environmental Triggers • Infections • NSAIDs • Diet • Smoking • Stress • Genetic Susceptibility • Barrier Function • Bacterial Killing • Immunoregulation • 163 genes! • Immune Response • ↑ TH1 • ↑ TH17 • Defective Innate

  30. B. Sartor Gastroenter. 2010 Fut2 Sartor RB Gastroenterology 2010

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