Crohn’s Disease &

Mycobacterial InfectionsKimberly Persley, MD

October 19, 2005

Outline

• Epidemiology

• Presumed Etiopathogenesis

• Antibiotic Therapy

• Mycobacteria and IBD

IBD Spectrum

Ulcerative colitis Crohn’s Disease

Indeterminant colitis

Normal Intestine Vs. IBD

Environmentaltriggers (infection,bacterial products)

Moderatelyinflamed

Failure to down-regulate

Chronic uncontrolledinflammation = IBD

Down-regulate

Normal gutcontrolled inflammation

Normal gutcontrolled inflammation

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)

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

Defective NOD2 Function

• Ineffective clearance of intracellular MAP infection

• Decrease in defensin secretion– permits increased mucosal adherence and

epithelial invasion of ingested organisms

IBD Treatment Pyramid

5-ASA

Antibiotics

Steroids

Immunomodulators

Biologicsseverity

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

Histology

Normal SB histology

Crohn’s Disease

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

Detection of MAP from Mucosal Biopsies

0%10%20%30%40%50%60%70%80%90%

Crohn's

IS900PCRCulture

• 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

Prevalence of MAP

0%

10%

20%

30%

40%

50%

60%

IS900 PCR

CDUCNormal

• Germany• 100 CD, 100 UC and

100 normals• IS900 PCR in resected

bowel specimens

Autschback F. et al. Gut 2005;54:944

Culture of MAP in CD

0%5%

10%15%20%25%30%35%40%45%50%

pos culture

CDUCcontrol

• 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

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