1. Crohn’s Disease & Mycobacterial Infections Kimberly Persley, MD October 19, 2005

2. Outline Epidemiology Presumed Etiopathogenesis Antibiotic Therapy Mycobacteria and IBD

3. IBD Spectrum Ulcerative colitis Crohn’s Disease Indeterminant colitis

4. Normal Intestine Vs. IBD Environmental triggers (infection, bacterial products) Moderately inflamed Failure to down- regulate Chronic uncontrolled inflammation = IBD Down-regulate Normal gut controlled inflammation Normal gut controlled inflammation

5. Evidence of Genetic Influence Prevalence varies among different populations risk in increased among first degree relatives greater concordance among monozygotic than diazygotic twins identification of “susceptibility genes” (NOD2/CARD 15)

6. NOD2/CARD15 Intracellular pattern recognition receptors Participates in host defense against microbial pathogens –recognition or molecular pattern present of pathogens –activation of nuclear factor kB –induction and secretion of pro/anti- inflammatory cytokines and chemokines –induction of antimicrobial pathways

7. Defective NOD2 Function Ineffective clearance of intracellular MAP infection Decrease in defensin secretion –permits increased mucosal adherence and epithelial invasion of ingested organisms

8. IBD Treatment Pyramid 5-ASA Antibiotics Steroids Immunomodulators Biologics severityseverity

9. Antibiotics Lack of well-designed, placebo-controlled trials Large “Antibiotic” underground Ciprofloxacin and Metronidazole are the two most widely studied abx Rifaximin may have a promising role in CD Antimycobacterial drugs results are inconclusive

10. Histology Normal SB histology Crohn’s Disease

11. Infection and IBD Histopathology NOD2 mutations High bacterial concentrations in the TI and colon are preferentially involved in IBD Altered composition of commensal enteric bacteria Clinical improvement with antibiotics

12. Detection of MAP from Mucosal Biopsies Sardinia 1.6 million people 3.5 million sheep and MAP infection endemic determine the proportion of MAP infected people Sechi, Leonard et al. AJG 2005:100:1529

13. Prevalence of MAP Germany 100 CD, 100 UC and 100 normals IS900 PCR in resected bowel specimens Autschback F. et al. Gut 2005;54:944

14. Culture of MAP in CD University of Florida 52 patients –28 CD –9 UC –15 Controls presence of viable MAP in peripheral blood of pts with CD Nasser S. et al. Lancet 2004;364:1039

15. Does MAP cause Crohn’s disease? I just don’t KNOW!!! MAP infection may cause CD in a subset of patients MAP colonize ulcerated mucosa of CD but not initiate or perpetuate intestinal inflammation