Gastro - Gut Immunology Flashcards
What is the surface area of the GI tract?
200m^2
What part of the body has the most complex + diverse immune system?
GI tract
What is the GI tract exposed to 24/7?
massive antigen load
What is a part of the massive antigen load the GI tract is exposed to?
→ Resident microbiota 1014 bacteria
→ Dietary antigens
→ Exposure to pathogens
What kind of state does the GI tract’s immune system have to be in?
State of “restrained activation”
– Tolerance vs active immune response
– Dual immunological role
What does the GI tract have to have tolerance for?
→ food antigens
→ commensal bacteria
What does the GI tract have to have immunoreactivity for?
pathogens
Why is the presence of bacterial microbiota important in the GI tract?
Immune homeostasis of gut & development of healthy immune system requires presence of bacterial microbiota.
How do you explore the relationship between microbiota + immune system?
using gnotobiotic organisms:
→ germ free organisms that they introduce particular germs to and then compare with conventional house mice
→ can help you identify immunological defects in gnotobiotic organisms
How much gut bacteria do we have?
10^14 compared to 10^13 cells in the body
→ most densely populated ecosystem on Earth
What are the main types of bacteria found?
4 major phyla:
→ bacteroidetes
→ firmicutes
→ actinobacteria
→ proteobacteria
What are the genetic benefits of having gut flora?
Provide traits we have not had to evolve on our own - Genes in gut flora 100 times our own genome.
What promotes bacterial growth in the GI? Why?
→ ingested nutrients
→ secreted nutrients
What reduces bacterial growth in the GI? Why?
→ chemical digestive factors –> leads to bacterial lysis
→ peristalsis, contractions, defecations –> leads to bacterial elimination
What is the bacterial content of the different parts of the GI tract? Why?
What is dysbiosis?
altered microbiota composition
→ when there is an imbalance between symbionts and pathobionts
→ higher proportion of pathobionts will cause inflammation
What is a symbiont?
has no benefits or harm to the host
What is a commensal?
benefits from association with the host but has no effect on the host
What is a pathobiont?
usually a symbiont, but can cause harm when dysregulated
What factors can cause dysbiosis?
→ infection or inflammation
→ diet
→ xeno biotics
→ hygiene
→ genetics
What does dysbiosis cause?
Type 1 Diabetes Rheumatoid Arthritis Atherosclerosis
What is TMAO? What are its effects on the body?
→ Trimethylamine Oxide
→ increases cholesterol deposition in the artery walls
→ increases chances of atherosclerosis
What is 4-EPS? What are its effects?
→ 4-ethylphenyl sulphate
→ associated with autism
What is SCFAs? What are their effects?
→ short chain fatty acids
→ decreased numbers are associated with IBD
→ increased numbers are associated with neuropsychiatric disorders, e.g. stress
What are AHR ligands? What are their effects?
→ Aryl hydrocarbon receptor ligands
→ associated with MS + RA
How does dysbiosis affect the brain?
→ stress
→ autism
→ MS
How does dysbiosis affect the lungs?
→ Asthma
How does dysbiosis affect the liver?
→ NAFLD (Nonalcoholic fatty liver disease)
→ NASH (Non-Alcoholic SteatoHepatitis)
How does dysbiosis affect the adipose tissue?
→ obesity
→ metabolic disease
How does dysbiosis affect the intestines?
→ IBD
→ Coeliac disease
How does dysbiosis cause systemic diseases?
pathogens create bacterial metabolites + toxins
e.g. TMAO, 4-EPS, SCFSAs, bile acids, AHR ligands) which can adversely affect the body
What are the different categories of ways in which the body defends against bacteria?
→ physical (anatomical)
→ physical (chemical)
→ commensal bacteria
→ immunological
How does the body defend itself anatomically?
→ epithelial barrier
→ mucosal defense
→ peristalsis
How does the body defend itself chemically?
→ enzymes
→ acidic pH
How does the epithelial barrier help defend the body?
→ mucus layer produced by goblet cells
→ epithelial mono-layer + tight junctions
→ paneth cells in small intestine
How do Paneth cells defend the body?
→ living in the bases of crypts of Lieberkühn
→ secrete antimicrobial peptides (defensives)
+ lysosomes
How do commensal bacteria defend the body?
occupy an ecological nice and act as an ecological barrier
What is the third line of defense?
immunological
→ MALT (mucosa associated lymphoid tissue)
→ GALT (gut associated lymphoid tissue)
*What is MALT? Where is it found?
→ mucosa associated lymphoid tissue
→ found in the submucosa below the epithelium, as lymphoid mass containing lymphoid follicles
How does MALT help defend the body?
→ lots of lymphoid mass containing lymphoid follicles
→ Follicles are surrounded by HEV (high endothelial venules) postcapillary venules, allowing easy passage of lymphocytes
→ oral cavity is rich in immunological tissue
What is GALT?
→ gut associated lymphoid tissue
→ Responsible for both adaptive & innate immune responses
→ Consists of B & T lymphocytes, macrophages, APC (dendritic cells), and specific epithelial & intra-epithelial lymphocytes
What are the 2 categories of GALT?
→ non-organised
→ organised
*What is the non-organised component of GALT?
→ Intra-epithelial lymphocytes (Make up 1/5th of intestinal epithelium, e.g. T-cells, NK cells)
→ Lamina propria lymphocytes
What is organised GALT?
→ Peyer’s patches (small intestine)
→ Caecal patches (large intestine)
→ Isolated lymphoid follicles
→ Mesenteric lymph nodes (encapsulated)
What are Peyer’s patches? Where are they found?
→ immune sensors
→ Found in submucosa small intestine – mainly distal ileum
What is the structure of Peyer’s Patches? What do they contain?
→ Aggregated lymphoid follicles covered with follicle associated epithelium (FAE).
→ FAE - no goblet cells, no secretory IgA, no microvilli
→ Organised collection of naïve T cells & B-cells
→ sub-epithelial dome contains dendritic cells
How do Peyer’s patches develop?
development. requires exposure to bacterium micro bacterial
How do Peyer’s patches take up antigens?
→ Antigen uptake via M (microfold) cells within FAE
→ M cells express IgA receptors, facilitating transfer of IgA-bacteria complex into the Peyer’s patches
What is an alternative way for Peyer’s patches to pick up antigens?
antigen sampling through trans-epithelial dendritic cells:
→ dendritic cells from mesenteric lymph nodes send dendrites through tight junctions to collect antigens + bring them back
What is the B-cell response in Peyer’s patches?
B-cell adaptive response:
→ Mature naïve B-cells express IgM in Peyer’s Patches
→ On antigen presentation class switches to IgA
→ T-cells & epithelial cells influence B cell maturation via cytokine production
→ B cells further mature to become IgA secreting plasma cells
→ Populate lamina propria
How are secretory IgAs formed + released?
How much of the gut’s B-cells can secrete IgAs?
90%
What is the purpose of the secretory IgAs?
→ binds to luminal antigen
→ prevents the pathogen adhesion + consequent invasions
What is the process of lymphocyte homing + circulation?
v
What is a BALT?
bronchus associated lymphoid tissue
How do lymphocytes undergo the process of gut homing + return to circulation?
What is the average turnover of enterocytes + goblet cells of the small intestine?
about 36 hours, compared to weeks/months for other epithelial cell types
Why is the turnover for small intestine cells so short?
→ Enterocytes are first line of defense against GI pathogens & may be directly affected by toxic substances in diet.
→ Effects of agents which interfere with cell function, metabolic rate etc will be diminished.
→ Any lesions will be short-lived.
*What is the mechanism of cholera infection?
→ acute bacterial disease caused by Vibrio cholerae serogroups O1 & O139
→ Bacteria reaches small intestine
→ contact with epithelium & releases cholera enterotoxin.
→ taken in + increases aneylate cyclase activity
→ increases cAMP
→ causes active secretion of salts, bicarbonates, etc.
→ water follows
→ causes diarrhoea
How is cholera transmitted?
→ Transmitted through faecal-oral route
→ Spreads via contaminated water & food
What are the main symptoms of cholera?
→ Severe dehydration
→ watery diarrhoea
→ Vomiting
→ nausea
→ abdominal pain.
How is cholera infection diagnosed?
bacterial culture from stool sample on selective agar is the gold standard, rapid dipstick tests also available.
How is cholera infection treated?
→ oral-rehydration is the main management
→ up to 80% of cases can be successfully treated
What is the vaccine for cholera?
Dukoral, oral, inactivated
What can cause infectious diarrhoea virally?
→ Rotavirus (children)
→ Norovirus “winter vomiting bug”
What can cause bacterial infectious diarrhoea?
→ Campylobacter jejuni
→ Escherichia coli
→ Salmonella
→ Shigella
→ Clostridium difficile
What can causes infectious diarrhoea parasitically?
→ Giardia lamblia
→ Entamoeba histolytica
What is rotavirus? What are the different types?
→ RNA virus, replicates in enterocytes.
→ 5 types, A – E
→ type A most common in human infections
What is the epidemiology of rotavirus?
→ Most common cause of diarrhoea in infants & young children worldwide
→ Still causes ~ 200,000 deaths/year
What is the treatment for rotavirus?
→ Oral rehydration therapy
→ Before vaccine, most individuals had an infection by age 5
→ repeated infections develop immunity
Does rotavirus have a vaccine?
Live attenuated oral vaccine (Rotarix) against type A introduced in UK July 2013
What is norovirus?
RNA virus
Incubation period 24-48 hours
What is the transmission of norovirus?
Faecal-oral transmission.
Individuals may shed infectious virus for up to 2 weeks
Outbreaks often occur in closed communities
What are the symptoms of norovirus infection?
Acute gastroenteritis, recovery 1 – 3 days
What is the treatment of norovirus?
Not usually required
How is norovirus infection diagnosed?
Sample PCR.
How is rotavirus transmitted?
faecal-oral route
What is campylobacter? What does it cause?
“curved bacteria”, causes food poisoning
What are the common species?
→ campylobacter jejuni
→ campylobacter coli
How is campylobacter transmitted?
→ Undercooked meat (especially poultry), untreated water & unpasteurised milk
→ Low infective dose, a few bacteria (<500) can cause illness
What is the treatment for campylobacter infection?
→ Not usually required
→ Azithromycin (macrolide) is standard antibiotic
What is a problem in campylobacter treatment?
Resistance to fluoroquinolones is problematic
What is the epidemiology of campylobacter infections?
→ Estimated 280,000 cases per year in UK, 65,000 confirmed
→ Commonest cause of food poisoning in the UK
What is E.coli?
→ Escherichia coli
→ Diverse group of Gram-negative intestinal bacteria
→ Most harmless
→ 6 ”pathotypes” associated with diarrhoea (diarrhoeagenic):
What are the 6 types of diarrhoeagenic E.coli?
→ Enterotoxigenic E. coli (ETEC)
→ Enteroinvasive E. coli (EIEC)
→ Enterohaemorrhagic or Shiga toxin-producing E. coli (EHEC/STEC)
→ Enteropathogenic E. coli (EPEC)
→ Enteroaggregative E. coli (EAEC)
→ Diffusely adherent E. coli (DAEC)
What are the symptoms of enterotoxigenic E.coli?
→ cholera like toxin
→ watery diarrhoea
What are the symptoms of enteroinvasive E.coli?
→ shigella like illness
→ bloody illness
What are the symptoms of Enterohaemorrhagic or Shiga toxin-producing E. coli?
→ E. coli O157 serogroup, Shigatoxin/verotoxin
→ 5-10% get haemolytic uraemic syndrome: loss of kidney function
How does C.Diff infect + disturb gut?
v
How is C.Diff infection treated?
→ Isolate patient (very contagious)
→ Stop current antibiotics
→ Metronidazole, Vancomycin
→ Faecal Microbiota Transplantation (FMT) – 98% cure rate
What is one of the biggest causes of C.Diff?
antibiotic over-use or incorrect use
What is the recurrence rate of C.Diff infection?
Recurrence rate 15-35% after initial infection, increasingly difficult to treat.
