Inflammatory bowel disorders (Block 5) Flashcards
Major intestinal structures
Duodenum
Jejunum
Ileum
Colon
Duodenum
20-25cm, receives gastric chyme from stomach, digestive juices & enzymes from pancreas & gall bladder added, breaks down proteins and emulsifies fats, alkaline mucus neutralises stomach acid
Jejunum
2.5m, midsection of small intestine, extensive villi and microvilli, products of digestion (sugars, amino acids, and fatty acids) absorbed into the bloodstream
Ileum
3m, final section of small intestine, also many villi, absorbs vitamin B12, bile acids, and other remaining nutrients
Colon
1.5m, principal function is absorption of water
Total length of both intestines together
> 8m
Basic structure of the intestines
Concentric rings of Mucosa, Submucosa, Muscularis externa and Adventitia layers
Epithelium forms part of the mucosa layer, alongside the lamina propria and muscularis mucosa
Folds, villi and microvilli greatly increase the surface area
Gut microbiota
100s of trillions of bacterial cells
Total weight: 1-2kg
More than 95% of human bacteria
Up to 50x smaller than human cells
Outnumber human cells 10:1
Number of bacteria in stomach
10^1-10^3 CFU/ml
Number of bacteria in duodenum
10^1-10^2 CFU/ml
Number of bacteria in Jejunum and ileum
10^4-10^7 CFU/ml
Number of bacteria in the colon
10^10-10^11 CFU/ml
Factors that affect the ut micro biome (variablilty)
** check recording; diagram isn’t on canvas slides
Challenges of bacterial exposure
GI tract had to be prepared to fight bacteria WHEN APPROPRIATE
Protective mechanism -> epithelial layer protects against harmful bacteria, but can tolerate healthy bacteria (gut flora) because it keeps everything compartmentalised. IF something ends up where it shouldn’t then it is recognised and targeted by the immune system
Intestinal homeostasis
Exists in a state of “controlled physiological inflammation”
Normal state, resulting from delicate equilibrium between:
Gut microbes
Gastrointestinal barriers (mucus, epithelial)
Innate immune system that processes and presents antigens
Adaptive immune system that possesses “memory”
Disorders of the intestinal tract
Irritable bowel syndrome
Coeliac disease
Inflammatory bowel disease (IBD)
Coeliac disease
Autoimmune disorder
Allergy to gliadin
Inflammation
Villus atrophy
2 types of IBD
Ulcerative colitis (UC)
Chron’s disease (CD)
How common are UC and CD?
1 in every 123 people in the UK suffer from one or the other
Incidence of UC and CD
UC -> 2.2-19.2 cases per 100,000 pa
CD -> 3.1-20.2 cases per 100,000 pa
Age at onset of UC and CD
15-40 years for both
Sites of CD and UC
UC -> colon only
CD -> most of GI tract
Pathology of UC and CD
UC -> continuous inflammation
CD -> patches of inflammation
Histology of UC and CD
UC -> superficial, mucosa and submucosa
CD -> Transmural, all layers fo gut wall
Symptoms of UC and CD
UC -> pain, diarrhoea, bleeding, weight loss, fatigue
CD -> fever, pain, diarrhoea, bleeding, weight loss, fatigue
Complications of UC and CD
UC -> haemorrhage, bowel rupture, colon cancer
CD -> abscesses, fistulas, colon cancer
Potential risk factors for CD and UC
Genetics
Smoking
Diet
Basically cellular mechanisms in IBD
Controlled physiological inflammation is temporarily overcome
Loss of barrier function
Microbes invade gut wall leading to local immune response
Failure of regulation; loss of protective effects or enhanced pro-inflammatory response
If not resolved, then chronic cytokine involvement and tissue destruction
Theory of what underpins IBD
Controlled physiological inflammation becomes uncontrolled pathological inflammation
The processing and recognition of enteric antigens typically results in immunological tolerance
An inappropriate response to the presence of enteric antigens results in IBD
Cell types involved in IBD
Epithelial cells
T cells
Dendritic cells
Neutrophils
Macrophages
Epithelial cells
Physiological barrier; compromised allowing microbial invasion of gut wall
T cell
Recognition cells of the immune system; determine self from non-self
Dendritic cell
Phagocytose microbes & microbial particles; act as antigen presenting cells
Neutrophils
First responder in inflammation arising from bacterial infection; destroy bacteria
Macrophages
Phagocytose ‘spent’ neutrophils after they have initially tackled the invading pathogen
4 key classes of IBD therapy
Anti-inflammatories
Immuno-suppressants
Antibiotics/Probiotics
Biologicals
Corticosteroids
Steroid drugs used to treat acute inflammatory effects in IBD
Mechanisms include:
Reduced expression of COX enzymes
Reduced prostaglandin synthesis
Reduced cytokine production
Reduced T cell activation and proliferation
Reduced neutrophil chemotaxis
Aminosalicylates
First-line for chronic treatment of IBDs
Used to maintain remission from symptoms
Marginally more effective in ulcerative colitis than in Crohn’s disease
How do aminosalicylates reduce inflammation?
Scavenging free radicals
Inhibiting prostaglandin and leukotriene production
Decreasing neutrophil chemotaxis
Blocking superoxide generation
Immunosuppressants
Used in severe cases of IBD, after failure of aminosalicylates
Drugs more commonly used in rheumatoid arthritis, some leukaemias and organ transplantation
Thiopurines (azathioprine, 6-mercaptopurine)
Methotrexate
Cyclosporin A
Immunosuppressants - examples
Azathioprine: active metabolite is 6-thioguanine, purine antagonist, interferes with DNA and RNA synthesis, inhibits proliferation of T cells and B cells
Methotrexate: inhibits purine metabolism, inhibits T cell activation, down-regulates B cells, reduces production of multiple cytokines
Cyclosporin A: used in ulcerative colitis unresponsive to steroids, reduces T cell activation and reduces release of interleukins
Antibiotics and probiotics
Antibiotics used to treat septic complications (i.e. abscesses) in IBD
Many also be useful in primary disease process in Crohn’s disease but not effective in ulcerative colitis - although used commonly!
Benefits assume bacterial involvement in pathogenesis of the disease and include:
Decreased concentrations of bacteria in the gut lumen
Altered composition of microbiota to favour beneficial bacteria
Decreased bacterial tissue invasion
Treatment of micro-abscesses
Probiotic drinks (i.e. yogurts) suggested to be beneficial
Biologicals - examples
Infliximab: chimera of mouse and human antibodies, human backbone with mouse recognition sites – anti-TNFa
Adalimumab: fully human mAb, less effective than infliximab - anti-TNFa
Certolizumab: human Fab (fragment antigen binding) – anti-TNFa
All such monoclonals are associated with potential for severe adverse effects related to immunosuppression and risk of infection
Biologicals
Treatment of many immune and inflammatory disorders has been revolutionised by use of monoclonal antibodies (mAbs)
Infliximab, adalimumab and certolizumab licensed for treatment of Crohn’s disease and ulcerative colitis
Monoclonal antibodies against TNF-; bind with high affinity to soluble & transmembrane forms of TNF- and prevent interaction with its receptor
Expensive, often restricted to severe IBD that is unresponsive to other medications
Newer therapies
Vedolizumab
Acts T helper cell-specific integrins to inhibit their localisation through the epithelial layer
Thereby stopping excessive inflammation
Ustekinumab
Binds IL-12 and IL-23
Inhibits cytokine binding to receptor on immune cells
Decreases activation of immune system
Risankizumab
Binds IL-23 only
Inhibits cytokine binding to receptor on immune cells (IL23R)
Decreases inflammatory signalling
