Inflammatory bowel disorders Flashcards
The intestines
GI tract is one of the first lines of defence to infection
Protection from pathogenic bacteria is balanced with maintaining the gut microbiome
Duodenum
20-25cm, receives gastric chyme from stomach (accumulation of food that has been broken down), digestive juices & enzymes from pancreas & gall bladder added, breaks down proteins and emulsifies fats, alkaline mucus produced 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 → villi and microvilli increase surface area for digestion and absorption
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
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
Different types of cells responsible for maintaining structure and forming barrier for protection against bacteria
Gut microbiota
difference in types and number of bacteria
significant increase in bacteria as you move from small to large intestine
gut microbiome shows interindividual (difference between individuals) and intraindividual variation (difference within an individual over a period of time)
Duodenal bacteria
10^1 - 10^3 CFU/ml
Lactobacillus, Streptococcus, Staphylococcus, Enterobacteriaceae
Jejunal and Illeal bacteria
10^4 - 10^7 CFU/ml
Bifidobacterium, Bacteroides, Lactobacillius, Streptococcus, Enterobacteriaceae
Colonic bacteria
10^10 - 10^11 CFU/ml
Bacteroides, Eubacterium, Clostridium, Peptostreptococcus, Streptococcus, Bifidobacterium, Fusobacterium, Lactobacillus, Enterobacteriaceae
Challenges of bacterial exposure
flexible gut microbiome with different exposures between individuals
needs to be prepared to fight bacterial exposure when appropriate
epithelial layer protects against harmful bacteria but can tolerate healthy bacteria → keeps things compartmentalised
Intestinal homeostasis
Exists in a state of “controlled physiological inflammation” → always primed to react
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
occur when balance is lost
disruption to microbiome leads to excessive inflammation and immune response
-Irritable bowel syndrome
-Coeliac disease: autoimmune, allergy to gliadin, inflammation, villous atrophy
- Inflammatory bowel disease (IBD):
- Ulcerative colitis (UC)
- Crohn’s disease (CD)
Clinical features of IBDs
Over 500,000 people suffer from IBDs in the UK
1 in every 123 people in the UK suffer from Crohn’s or Colitis
both generally diagnosed young
Ulcerative colitis
2.2-19.2 cases per 100,000 pa
15-40 years
Continuous inflammation
Superficial, mucosa & submucosa
Pain, diarrhoea, bleeding, weight loss, fatigue
Haemorrhage, bowel rupture, colon cancer
Crohn’s disease
3.1-20.2 cases per 100,000 pa
15-40 years
Most of GI tract
Patches of inflammation
Transmural, all layers of gut wall
Fever, pain, diarrhoea, bleeding, weight loss, fatigue
Abscesses, fistulas, colon cancer
Putative risk factors
Genetics: twin studies suggest significant genetic component CD appears to have a greater heritability than UC NOD2 and IL23R gene mutations implicated in elevated risk
Smoking: elevates risk of CD, protects against UC
Diet: consumption of polyunsaturated fatty acids elevates risk
Hypothesis: inappropriate immunological response to gut microbiota in genetically susceptible individuals
Basic cellular mechanisms in IBD
gut exists in controlled level of inflammation
in IBD, control is overcome and epithelial cell barrier function is overcome
- 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 → pro-inflammatory cytokines target tissues anf further damage barrier, no off mechanism
- If not resolved, then chronic cytokine involvement and tissue destruction
Hypothesis
Controlled physiological inflammation becomes uncontrolled pathological inflammation
The processing and recognition of enteric antigens typically results in immunological tolerance
- usually can determine self from non-self
- begin to recognise self as non-self, triggering immune response
An inappropriate response to the presence of enteric antigens results in IBD
Epithelial cell
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 and microbial particles
Act as APCs
Neutrophil
First responder in inflammation arising from bacterial infection
Destroy bacteria
Macrophage
Phagocytose neutrophils after they have initially tackled invading pathogen
Cells involved in IBD
bacteria engulfed by dendritic cell
endothelial cell layer damage → dendritic cell presents antigen to macrophages
causes inflammation
dendritic cells present antigen to effector T cells
T effector cell stimulates different T cells depending on cytokines
different T cells produce different cytokines
IL-12
Th1 and Th2 cells
IL-23
Th17 cell
Th1 cell
IL-2 and IFN-𝛾
Crohn’s disease
Th2 cell
IL-4, IL-5 and IL-13
Ulcerative colitis
Th17 cell
IL-17A and IL-22
May be involved in development of IBD
Tregs
produce TGF-β, leading to IL-23 production and Th17 production
