17 - gastrointestinal & urinary tracts Flashcards
the gut
is home to many microbes
becomes more alkaline along the tract and the number of microbes increases
host-gut microbiota interactions
imbalance in the intestinal bacteria (dysbiosis) leads to disease
symbiosis –> dysbiosis can be due to:
• medicines and hygiene
• lifestyle - diet, stress
• genetics
inflammatory bowel disease
e.g.. crohns disease
chronic inflammatory disease of gut intestinal mucosa
can affect any area of the GI tract but most commonly affects the distal ileum
associated with gut pain and diarrhoea
debilitating
impact on the healthcare system is enormous
where is the majority of inflammation found in crohns disease?
at the junction of the ileum and the cecum
genetic susceptibility for crohns disease
intracellular pathogen-recognition receptor NOD2
• nucleotide binding oligomerisation domain 2 receptor
• acts as a sensor looking for bacteria/microbes
• binds morally dipeptide (peptidoglycan component of bacteria)
autophagy genes ATG16L1 and IRGM
• self-destructing genes
transcription factor XBP1
• stress response - protein folding
what are defensins?
antimicrobial peptides
- natural antibiotics of the body
- gut epithelium produces alpha and beta defensins
- is an innate response
- cationic - attracted to the negative membrane of microbes
- hydrophobic - can be inserted into the membrane
- blebbing - peptides inserted into bacterial membrane , making a hole
NOD2 and defence of the gut epithelium
- villi are located on the apical membrane
- you have intracellular NOD2 receptors in the epithelia
- granules in the cell are full on antimicrobial peptides
- gut bacteria are dividing all the time
- muramyl dipeptide released by gut bacteria
- also have gut proteases and digestive enzymes that break down bacteria to release the dipeptide
- this is a form of homeostasis
bacterial overgrowth at the gut epithelium
controlled inflammation
- bacteria start to overgrow
- increased amounts of muramyl dipeptide
- cells start to endocytose the dipeptide - take it up in vesicles and show it to NOD2 receptors
- sets off signalling response to release antimicrobials into the gut lumen to destroy the bacteria - also attracts macrophages to the bacteria
- macrophages release cytokines and engulf bacteria
- returns body back to homeostasis
NOD2R receptor mutations
a group of crohns patents carry mutations in the gene encoding NOD2 receptors
leads to a non functional receptor
can be identified by PCR and sequencing
treatment: steroids and immunosuppressants
what happens in the gut if you have a NOD2R receptor mutation?
1) dipeptide is endocytosed
2) receptor doesn’t bind to it or can’t signal - no defensins are released - no innate response
3) bacteria overgrow and breakdown the epithelial barrier
4) macrophages are released - uncontrolled cytokine response
5) leads to the inflammatory disease, the redness and the wateriness of the gut
its a dysbiosis
whats rheumatoid arthritis?
an autoimmune disease
characterised by synovitis, inflammation and auto-antibodies
protein deposits in the joints - creates inflammation and redness
suggestion that the gut microbiota plays a role in the cause of RA
what is SFB?
segmented filamentous bacteria
causes rheumatoid arthritis
how does SFB cause rheumatoid arthritis?
1) SFB starts to overgrow in the gut lumen
2) causes a signalling cascade in the gut epithelial cells
3) causes differentiation and proliferation of TH17 cells in the lamina propria which are part of the immune system
4) released into blood and circulate body
5) this increases the IL17 synthesis - pro-inflammatory cytokine
6) IL17 synthesis activates auto reactive B cells - production of auto-antibodies - protein deposition in the joints
7) autoimmune artritis
the urinary tract
sterile environment
Lactobacillus is the predominant genus
UTIs
most common bacterial infection in women - in the shorter urethra
long term antibiotic treatment is of limited benefit and selects for resistance
UPEC (uropathogenic E.coli) is cause of 80-90% of all UTIs
• flagellated
