Microorganisms in the Gastrointestinal Tract in Health and Disease Flashcards
What is commensal bacteria?
❖ From latin commensalis: « com » = sharing, « mensa » = table —> « those that eat at the same table » ❖ = Normal inhabitant of the human body, living in communities = « Microbiota » ❖ ~1012 bacteria per gram of colon contents ❖ Neither the host (human) or the microbe is harmed, they both derive benefits
Where do we get our commensal microbiota?
- Effect of maternal exposures to environment, antisepsis, antibiotics, diet, other hosts, epigenetics
- Oral (pre-mastication of food)
- Mammary, through breastfeeding (selection)
- Cutaneous (contact with skin)
- Vaginal (passage through birth canal)
- Dental amalgam
- Bottle feeding
- Early/ extensive bathing
- Caesarean section
- Early-life antibiotics
Examples of opportunistic bacteria
E coli and other enterobacteria (urinary tract infections, wound)
-Bacteroides fragilis (anaerobes)
What factors affect the GI ecosystem?
- pH
- Flow rate (high at top of gut, low at bottom)
- Mucus (protective layer- inner and outer)
- Competition with other bacteria= colonisation resistance
- Presence of bile and digestive enzymes
- Intestinal microbiota
- M cells and Peyer’s patch
- Antimicrobial peptides
- Redox potential/ oxygen tension (bottom of gut= anaerobic)
What are the pathogenic mechanisms?
- Adherence mechanisms (avoid being flushed through)
- Toxin production (proteins, enzymes)
- Motility (swimming action to burrow through mucus layer)
- Site of pathogenicity (stomach/ intestine= adherence, colon= penetrate gut wall)
- Resistance to bile and digestive enzymes
- Avoidance of immune mechanisms (secretory antibody IgA, capsules and lipopolysaccharides)
- Immunopathological mechanisms
Describe Helicobacter pylori
- Curved/ spiral, Gram-negative, microaerophile (small amount of air needed)
- Motile= mucus layer
- Causes gastritis, and gastric and duodenal ulcers (and gastric carcinoma)
- Produces urase (urea to ammonia) to protect itself from acid= urea breath test
- Very common, well-adapted pathogen
- Present in up to 50% of western adults and 100% in developing world
- Several putative virulence factors but with no simple correlations with pathogenicity
Describe Vibrio cholerae
- Gram-negative, comma-shaped bacterium- motile with polar flagellum
- Water-borne pathogen (faeces) or seafood
- Sensitive to drying out, sunlight and acid so high bacterial load needed
- Causes cholera
- Cholera toxin (CT) and toxin co-regulated pilus (organelles of adherence, projections)
- CT- bacteriophage encoded (without virus is not pathogenic)- lysogenic
- Watery diarrhoea: rice-water stools (mucus in clear solution)
- Severe dehydration
Describe the mechanism of the cholera toxin
- 5 B subunits and one A unit (A1 and A2)
- A bipartite, ADP-ribosylation toxin (ribosylates proteins involved in adenyl cyclase system so ATP to cyclic AMP)
- cAMP builds up so sodium pump reversed so little sodium and chloride intake and stops absorbing water
- Crypts that normally produce mucus= water pour out more, more chloride secreted
- 5 x B subunits Bind to GM1 ganglioside in enterocytes
- A subunit is Active part
What are the types of Shigella?
-S. dysenteriae
-S. boydii
-S. flexneri
-S. sonnei
Members of Enterobacteriaceae
Lactose-negative, non-motile, facultatively anaerobic, gram-negative rods, low infectious load
Bacteria dysentery
What is bacterial dysentery?
- Bloody diarrhoea
- Invasion of mucosa by shigellae
- S. dysenteriae causes most severe disease- only one to produce shiga toxin
- S. sonnei least severe disease
Describe the pathogenesis of shigellae
- Mainly disease of colon, sometimes an initial phase of watery diarrhoea in the ileum
- Bacteria enter mucosal cells via M-cells, ingested by macrophages
- Macrophages killed by apoptosis- release of cytokines- inflammation- tissue destruction
- Actin polymerisation pushes progenies through to multiply
Describe clostridium difficile
- The most common cause of nosocomial (hospital/ community acquired) diarrhoea, with a severity spectrum ranging from asymptomatic carriage, mild to moderate diarrhoea, to life-threatening pseudomembranous colitis
- Flagella= highly motile
- Gram-positive, spore-forming
- Anaerobic
- Increasingly resistant to antibiotics
Describe CDI
A spectrum from -Asymptomatic carriage -Diarrhoea/ simple colitis -Pseudomembranous colitis -Fulminant colitis A combination of direct cellular damage and immunopathology -A disease of hospitalised elderly
What are the necessary stages in pathogenesis of clostridium difficile?
- Colonisation resistance compromised by antibiotics
- Gut becomes susceptible to colonisation by C. difficile
- C. difficile evades immune response and multiplies, producing toxins A and B
What is the mechanism of clostridium difficile?
- Soluble toxin inside cell by receptor-mediated endocytosis, transfers glucose from UVP glucose
- Translocation from endosome
- Rho and other small GTP-binding proteins glycosylated, GTPases cause collapse
- Cytoskeletal involvement
- Collapse= cytopathic effect
- Rounding with neurite-like protrusions remaining
- Toxins can penetrate into lamina propria= monocytes= TNF, IL8, inflammatory cytokines, neutrophil chemotaxis through tight junctions into gut
Describe the UK hyper-virulent strain of clostridium difficile
- 027s from Stoke Mandeville
- PFGE variants
- Same tcdC gene deletion (negative regulator)
- tcdR alternative sigma factor- positive regulator of toxin production
- tcdE encodes a holin-like protein
- Toxins transcribed on entry to stationary phase
- Hyper-toxin producers
- Resistant to quinolone antibiotics
What is the treatment of CDI?
-Kill bacterium
-Neutralise toxins
-Prevent attachment of toxin or bacterium
-Modulate inflammatory response
=Antibiotics= metronidazole/ vancomycin (fidaxomicin= drug of choice, clostridium specific)
What are the benefits of commensals?
-Nutrient and micronutrient (e.g. vitamin)
availability/energy extraction from food
❖ Terminal postnatal differentiation of mucosal
structures (epithelial brush border)
❖ Physical barrier function
❖ Immune system development (Ag stimulation)
❖ Regulation of metabolism
❖ “colonization resistance” against
pathogens
Examples of opportunistic pathogens
All pathogens are “commensals” when contained
within GI tract
❖ When they cause a disease, they become « pathogens »
❖ Disease is not required for survival —> accident !
-Examples in the gut:
❖ Escherichia coli
❖ Bacteriodes fragilis
❖ Enterococcus faecium/faecalis
What are pathogens?
Also called « obligate pathogen »: Need to cause disease
to transmit between hosts (—> evolutionary survival)
❖ Can produce asymptomatic infection (but ≠ commensal)
❖ Infections are not necessarily more severe than with
opportunistic pathogens
Examples of pathogens
❖ Escherichia coli
❖ Shigella dysenteriae
❖ Salmonella Typhi
❖ Campylobacter jejuni/coli
What are zoonotic microorganisms?
❖ Commensal or pathogen in animals ❖ Transmitted to humans < Insect vector < Direct contact (animal/product) ❖ Disease causation in humans is accidental and not necessary for evolutionary survival. ❖ Examples: ❖ Yersinia pestis ❖ Borrelia burgdorferi
What are environmental microorganisms?
❖ Present in the environment (water, soil, plants,…) ❖ Transmitted to humans < contacts or ingestion ❖ Disease causation in humans is accidental and not necessary for evolutionary survival ❖ Examples: ❖ Clostridioides difficile ❖ Vibrio Cholerae
What are the pathogenic mechanisms?
- Antacid drug on redox potential/ oxygen tension
- Ileus- Appendicitis on flow rate
- Adherence mechanisms/ motility on mucus layer
- Antibiotics on intestinal microbiota
- Sepsis, invasion and toxin production on barrier function
- Immunosuppression and avoidance (capsule/ LPS) on the immune system
- Opportunistic and obligate pathogen on Peyer’s patch
What is Diarrhoea?
❖ > 3x/day
❖ Liquid: more than
80% of water
❖ > 300g/24h
What are the types of diarrhoea?
-Secretory= Secretion or lack of reabsorption of water & electrolytes
=Ex: V. Cholerae, S. Aureus, ETEC, C. difficile
-Inflammatory= Release of proteins, blood, WBC, mucus < inflammation of the epithelium
=Ex: most of bacterial infections, IBD
Describe vomiting
- Reflex, mechanism of protection
- Humoral or neuronal stimuli
- Ingested toxins, gastrointestinal tract
Treatment for clostridium difficile
- Infection= removal of spores of C. difficile from the hospital environment (cleaning)
- Antibiotic stewardship= restriction of antibiotics known to precipitate CDI: 3rd gen cephalosporins, clindamycin, fluoroquinolones
