Immunology Of The Gut Flashcards
Give 3 examples of antigens that the GI tract is exposed to
Resident bacteria
Dietary antigens
Exposure to pathogens
What is required for immune homeostasis and the development of a healthy immune system?
Presence of bacterial microbiota
Define the term ‘Microbiota’
Mixture/blend of microorganisms that makes up a community within an anatomical niche
Define the term ‘Microbiome’
Collective genomes of all of the microbiota, so in all of the different anatomical niches
Why is the GI Tract immune system in a state of ‘restrained activation’?
It balances tolerance of food antigens and commensal bacteria vs immunoreactivity against pathogens
What are gnotobiotic mice?
These are mice which have been colonized to be germ-free
They are used in experiments, e.g. to compare development of the immune system between germ-free and conventionally housed mice
What are the 4 major phyla of bacteria seen in the gut?
Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria
What functions of the gut microbiota make it useful for us humans?
- Provide essential nutrients which we can’t make ourselves
- Digest otherwise indigestible compounds
- Defense against colonization by opportunistic pathogens
- Contribute towards intestinal architecture
Describe how the environment provided by the host can lead to the stimulation or inhibition of the gut microbiota
In general, explain why bacterial content varies as you pass down the GI tract
Chemical digestive factors produced by the host impact viability of the bacteria to survive in different parts of the GI tract
Bacterial content increases as you pass down the GI tract - factors produced are less hostile to bacterial growth (or no DF produced - colon)
List the chemical digestive factors produced by the stomach, liver, pancreas, small intestine and colon respectively
What is Dysbiosis?
Altered microbiota composition
Define the term ‘Symbiont’
Lives with a host but no benefit/harm to either
Define the term ‘Commensals
Microorganisms that benefit from association with the host (nutrients) but don’t affect the host
Define the term ‘ Pathobiont’
Initially acts like a symbiont (doesn’t naturally produce an immune response) but under certain environmental conditions can produce dysregulated inflammation/disease
Describe the proportion of symbionts, commensals and pathobionts during a state of immunological equilibrium and immunological dysregulation
Give 5 factors that can either contribute to the maintenance of healthy microbiota or towards dysbiosis
1) Infection or inflammation
2) Diet
3) Xenobiotics
4) Hygiene
5) Genetics
Give 5 examples of metabolites and toxins which bacteria produce that can cause damage to body systems
TMAO
4-EPS
SCFAs (short-chain fatty acids)
Bile acids
AHR Ligands
What dysfunction can TMAO cause in the body?
TMAO = Trimethylamine N-oxide
Can cause atherosclerosis due to increased cholesterol deposition
What has 4-EPS been associated with?
4-EPS = 4-Ethylphenylsulfate
Increased levels are associated with autism
What are decreased numbers of SCFAs associated with?
SCFAs = Short-chain fatty acids
Decreased numbers of SCFAs are associated with Inflammatory bowel disease
What are increased numbers of SCFAs associated with?
Neuropsychiatric disorders such as stress
What are AHR ligands associated with?
AHR = Aryl hydrocarbon receptor
Increased AHR ligands are associated with MS, Rheumatoid arthritis and asthma
What three different groups make up the mucosal defense of the body?
Physical barriers
Commensal bacteria (occupy an ecological niche)
Immunological barriers
Give an overview of the 2 types of physical barrier the body has towards microbes
Anatomical:
- Epithelial barrier
- Peristalsis
Chemical:
- Enzymes
- Acidic pH
What are two important layers of the epithelial barrier?
Mucus Layer - produced by goblet cells
Epithelial monolayer - with tight junctions in the middle
Where are Paneth cells found and what is their role?
Found in the bases of crypts of Lieberkühn in the small intestine
Secrete antimicrobial peptides (defensins) and lysozyme
What are the 2 immunological defense mechanisms following invasion
MALT (Mucosa associated lymphoid tissue)
GALT (Gut associated lymphoid tissue)
Where is MALT tissue particularly rich?
MALT is particularly rich within the oral cavity (the three tonsils - palatine, lingual and adenoid/pharyngeal)
It is found in the submucosa below the epithelium as a lymphoid mass containing lymphoid follicles
How does the structure of MALT tissue assist its function?
Follicles are surrounded by HEV (high-endothelial venules) postcapillary venules, allowing easy passage of lymphocytes to the tonsils where they can defend against pathogens
What is GALT tissue responsible for?
Responsible for both adaptive and innate immune response
What does GALT consist of?
Consists of B and T Lymphocytes, macrophages, APC (dendritic cells) and specific epithelial and intra-epithelial lymphocytes
Give 2 examples of non-organized GALT tissue
Intra-epithelial lymphocytes
- Make up 1/5th of intestinal epithelium, eg. T-cells, NK cells ( most common)
Lamina propria lymphocytes
Give 4 examples of organized GALT tissue
Peyer’s patches (small intestine)
Caecal patches (large intestine)
Isolated lymphoid follicles
Mesenteric lymph nodes (encapsulated)
Describe how the architecture of the bowel changes as you move through the gut?
Lymphocytes/ immune cells decrease
Goblet cells/mucus-producing cells increase
What are Peyer’s patches?
Aggregated lymphoid follicles covered with follicle associated epithelium ( FAE) —> Found in submucosa of small intestine eg. mainly distal ileum
Act as ‘immune sensors’
What is special about FAE?
No goblet cells, no secretory IgA, lack microvilli
Therefore no barrier to pathogens
Describe the growth of the Peyer’s patches from fetus to teenage years
Peyer’s patches contain an organized collection of naïve T cells and B cells
Development requires previous exposure to bacterial microbiota
Grows over time - 50 in last trimester as a foetus, 250 by teens
How do M cells carry out their function?
Antigen uptake occurs via these M (microfold cells) within FAE
M cells express IgA receptors, facilitating transfer of IgA-bacteria complexes into the Peyer’s patches
Describe the role trans-epithelial dendritic cells play in the immunological response
Dendritic cells can get through tight junction proteins and send dendrites from the outside into the lumen of the intestinal tract where they directly sample bacteria
They can then bring the bacteria back and transport them into mesenteric lymph nodes
Describe the B cell adaptive response
Pathogen uptake via M cell —> Excreted into pocket found on the inner surface of the enterocyte containing APCs —> APCs engulf pathogen and display on their surface using MHC II —> DCs migrate to Peyers patches (and some to mesenteric lymph nodes where they activate more lymphocytes) —>Mature naive B-cells express IgM in these Peyers patches but on antigen presentation switches to IgA -> B cells further mature to become IgA secreting plasma cells -> migrate to/populate lamina propria
- ## T-cells and epithelial cells influence B cell maturation via cytokine production
Describe the formation of secretory IgA within the lumen
Enzymatic cleavage within epithelial cells converts dimeric IgA into secretory IgA which is then released into the lumen
What is the function of sIgA?
Secretory IgA binds to luminal antigen, thereby preventing its adhesion and consequent invasion
Up to 90% of gut B -cells secrete IgA
Describe lymphocyte homing and circulation
NB : BALT = bronchus associated lymphoid tissue
Describe alpha4beta7/ MADCAM-1 adhesion
Allows movement of lymphocytes from circulation back to lamina propria
Lymphocyte expresses alpha4beta7 integrin
High endothelial venule expresses MADCAM-1
Chemotactic stimulation of lymphocytes leads to rolling, then activation, then arrest and internalization into the lamina propria from blood
Why do enterocytes and goblet cells of the small bowel have such a short life-span (36 hours)?
- 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 are 2 protozoal parasitic causes of infectious diarrhoea - Gastroenteritis?
Giardia lamblia - contaminated food or water, can also affect cats and dogs
Entamoeba histolytica- tropical areas
What is Cholera and what agents is it caused by?
Cholera is an acute bacterial disease caused by vibrio cholerae serogroups O1 and O139
Describe the mechanism of Cholera infection
Bacteria reaches small intestine —> makes contact with epithelium and releases cholera enterotoxin
It is internalised by retrograde endocytosis
Increases adenylate cyclase activity -> increased cAMP production
Activates CFTCR causing active secretion of Na+, Cl-, HCO3-, K+ and subsequently water (causing diarrhoea and dehydration)
How is cholera transmitted?
Faecal-oral route
Spreads via contaminated water and food
What are the main symptoms of cholera?
Main: Severe dehydration and watery diarrhoea
Other: Vomiting, nausea and abdominal pain
What investigations do you need to do to reach a diagnosis of cholera?
Bacterial culture from stool sample on selective agar is the gold standard
Rapid dipstick is also available
What is the treatment of cholera?
Oral rehydration therapy is the main management; up to 80% of cases can be treated successfully
Is there a vaccine for cholera?
Yes, Dukoral (oral, inactivated)
Name two types of virus associated with infectious diarrhoea?
Rotavirus (children)
Norovirus
Name five other bacteria associated with infectious diarrhoea?
Campylobacter jejuni
Escherichia coli
Salmonella
Shigella
Clostridium difficile
What class of viruses are the most common cause of diarrhoea in infants and young children worldwide?
Rotaviruses
Describe rotaviruses and which one is the most common in humans?
RNA Virus, replicates in enterocytes
5 types A-E, type A most common in human infections
What is the treatment for a rotavirus infection?
Oral Rehydration Therapy
Before vaccine, most individuals had an infection by age 5, repeated infections develop immunity
Is there a vaccine for this virus?
Live attenuated oral vaccine (Rotarix) against type A introduced in UK July 2013
What type of virus is Norovirus?
It is an RNA virus with an incubation period (time between exposure and when symptoms apparent) of 24-48 hours
What is method of transmission for Norovirus?
Faecal-oral transmission.
Individuals may shed infectious virus for up to 2 weeks
Outbreaks often occur within closed communities ( eg. Cruise ships)
What are some symptoms of norovirus and what treatment is usually offered to patients?
Acute gastroenteritis, diarrhoea, recovery occurs within 1-3 days
Tx is not usually required.
How would you diagnose a norovirus infection?
Sample PCR
What is the method of transmission for Campylobacter and is a high infective dose required to cause illness?
Undercooked meat (especially poultry), untreated water and unpasteurized milk
Low infective dose, a few bacteria <500 can cause illness
What is the treatment for Campylobacter?
Not usually required
Again, oral rehydration therapy
Azithromycin (macrolide) is standard antibiotic
Resistance to Fluoroquinolones is problematic
What is the treatment for Campylobacter?
Not usually required
Again, oral rehydration therapy
Azithromycin (macrolide) is standard antibiotic
Resistance to Fluoroquinolones is problematic
What are the 6 pathotypes of E.coli that are associated with diarrhoea?
1) Enterotoxigenic E.Coli ( ETEC)
- Cholera like toxin
- Watery diarrhoea
2) Enterohaemorrhagic or shiga-toxin producing E.Coli ( EHEC/STEC)
- E.Coli 0157 serogroup, Shigatoxin/verotoxin
- 5-10% get haemolytic uraemic syndrome : loss of kidney function. Therefore, this is the most worrying one.
3) Enteroinvasive E.Coli ( EIEC)
- Shigella like illness
- BLOODY diarrhea
4) Enteropathogenic E.Coli (EPEC)
5) Enteroaggregative E.Coli ( EAEC)
6) Diffusely adherent E.Coli (DAEC)
Do E.Coli species usually cause problems?
Most are harmless
Usually there but don’t cause problems
Is E.Coli gram positive or negative?
Gram-negative intestinal bacteria
How would you manage a patient who has a C.Diff. infection?
- Isolate patient (very contagious)
- Stop current antibiotics
- Give them Metronidazole and Vancomycin (but be cautious, as these can pre-dispose the pt to further C.Diff infections as well!)
- Fecal Microbiota Transplantation (FMT) – 98% cure rate
Recurrence rate 15-35% after initial infection, increasingly difficult to treat
NB : Paradoxically Metronidazole can give you C.diff as well!
