Inflammatory Bowel

Disease
Joseph Sellin, MD
UTMB
PATHOGENESIS OF IBD
 Do All Causes Contribute Equally?
Genetics Immune
System

Immune
Genetics System

Immune
System
Genetics

Environment

Environment

Environment
Environmental
Infections
Triggers
Antibiotics

NSAIDs
Diet
IBD

Smoking

Stress
Hygiene Hypothesis
 Let them eat dirt
 Limited antigenic exposure in infancy may
lead to later hyper-responsiveness
 Linked to asthma, multiple sclerosis, other
“auto-immune diseases”
Smoking in IBD
 Ulcerative Colitis
 Smoking can protect against UC
 Ex-smokers are more likely to develop UC
 Crohn’s disease
 Twofold risk in current smokers
 Smokers are less responsive to treatment
 Smokers are more likely to develop recurrence
of disease after surgery
Role of Bacteria in IBD
 Search for an infectious etiology
 Mycobacteria paratuberculosis
 Enteroadherent E. coli
 Cold chain hypothesis
 Experimental models
 Sterile gut -> No IBD
 Bypassed segment -> No IBD
 Probiotics
GENETIC INFLUENCE
NOD2 is first Gene associated
with Crohn’s disease
CARD CARD NBD LRR
1 28 124 220 273 577 744 1044

 Located at chromosome 16q12

 Similar to plant disease resistance proteins
 Related to immune response to bacteria
 Activates “down-stream” inflammatory
cell-signals
Significance of NOD2 Risk to
Developing Crohn’s disease
 One copy of Mutated Gene
 1.5-4.0 fold risk
 Two Copies: 15-40 fold risk
 10% of CD patients carry two copies
 28% of CD patients carry one copy
 Actual disease presence with one or
two gene copies is less than 10%
PATHWAYS OF T
LYMPHOCYTE ACTIVATION
BALANCE OF
INFLAMMATORY MEDIATORS
IN THE INTESTINE
ETIOLOGIC HYPOTHESES
 Genes vs Environment
 Hot pursuit of new genes
 NOD2 (CARD15) may be found in 20% Crohn’s
 Four new candidate genes in last year
 But, cannot explain rapid changes in
epidemiology
 Increase in Crohn’s in US
 Rapid changes in Japan, Middle East, India
Systemic Complications
 Extra-intestinal manifestations common, but
not predictable
 Sometimes more symptomatic than bowel
disease
 What does this tell us about the inflammatory
process in the gut? Simply spill-over or….?
Inflammation and Cancer
 Common theme in GI tract:
 Gastric cancer, MALT -> H. Pylori
 Liver Cancer -> Chronic Hepatitis, both viral
and non-viral etiologies
 Pancreatic Ca -> Chronic pancreatitis
 Lymphoma -> Celiac disease
 What’s the connection?
Surgery in Ulcerative Colitis
 Colectomy cures ulcerative colitis
 But people are attached to their colons
 Different plumbing alterations
 Conventional ileostomy
 Continent ileostomy
 Ileo-anal anastamois with J-pouch
 Save lives, not colons
Surgery in Crohn’s
 Not curative
 Specific goals
 Obstruction
 Abscess
 Medical failure
 Recurrence usually at anastamosis
GOALS OF THERAPY
SULFASALAZINE
SULFASALAZINE
METABOLISM
5-AMINOSALICYLATE
VERSUS SULFASALAZINE
TOXICITY
SYSTEMIC CORTICOIDS
RESULTS OF
CORTICOSTEROID THERAPY
FOR CROHN’S DISEASE
Immunosuppressive Rx
 6-mercaptopurine & azathioprine
 Slow onset of action
 Effective for maintenance and steroid sparing
 Monitoring enzyme activity
 Monitoring drug levels
Immunosuppressive Rx
 Methotrexate
 Faster acting than 6MP/Azathioprine
 Maintenance therapy for Crohn’s disease
 Only parenteral rx proven effective
ANTIBODIES TO TNF
NUTRITIONAL THERAPY IN
IBD
NUTRITIONAL THERAPY IN
IBD
Th-17: A novel inflammatory
pathway TGF-b ?

IL-6 ?
Antigen Presenting
Th-17 T-cell IL-23 ? Cell

IL-6 IL-8 TNF G/M-CSF ICAM

•Interleukin-17 stimulates neutrophil generation/recruitment.
•IL-17 has been shown to be an important mediator against several infectious
agents and has increased production to various bacterial antigens.