Microbiome

Question 1

What the microbiome is and what it is affected by

Answer 1

• microflora comprised of ‘good’ and ‘bad’ bacteria
• weighs around 2kg
• composition changes throughout our lives and also changes depending on site i.e gut vs oral
• can be affected by diet, stress, environment, ABX use (this can cause ABX resistant bacteria to proliferate and out-compete good bacteria, this can cause worse vaccine efficacy)
• 75% of immune cells held here

Question 2

Examples of good bacteria

Answer 2

• aids in digestion and antitumor activity: bifidobacterium, lactobacillus
• production of SCFA: eubacterium, fusobacterium

Question 3

Examples of pathogenic bacteria

Answer 3

• production of enterotoxins: clostridia

- production of toxins: staphlococcus, proteus, pseudomonas aeruginosa

Question 4

Composition of the gut (+ consequences of gastrointestinal perforation)

Answer 4

• the gut epithelium contains microfold cells which secrete mucus to act as a barrier to the gut contents and microbiome to the epithelium (in diseases such as UC this is disrupted)
• mucus contains IgA (which can be produced from B cells in lamina propia upon activation from dendritic cells which are activated by acetate) which can opsonise and kill bacteria
• gastrointestinal perforation (stabbing, shooting) can disrupt this barrier and lead to systemic inflammation and bacteria movement. 30% mortality rate. Treatment is surgery and ABX delivery

Question 5

Interaction between SCFA and the gut

Answer 5

SCFA: acetate, butyrate and propionate are produced by bacteria following fermentation of NSPs

• can interact with gut via GPCR (FFA2 and FFA3 bind to all SCFA) (GPR109a is found on dendritic cells and binds to butyrate)
• SCFA bind to GPR109a on dendritic cells which releases retinoic acid and IL10 which inhibits Th17 (inflammatory) and activate Treg cells which inhibit Th1 (inflammatory)
• butyrate is also a key substrate for oxidative phosphorylation in enterocytes
• influx of butyrate into enterocytes also activates K+ influx which activates the inflammasome to produce IL18 and IL1b which strengthens the intestinal barrier
• butyrate can also accumulate in tumour cells during colon cancer due to the warburg effect which inactivates HDAC dampening proliferation

Question 6

The gut- brain axis

Answer 6

• communicates via the vagus (brainstem) and enteric nerve
• also communicate via soluble mediators, such as SCFA and tryptophan metabolites (which can be converted to 5-HT via gut or brain hydrolases)
• neuroendocrine cells release hormones which affect hunger perception (ghrelin)
• microbiome implicated in PD due to changes in dopamine and FMT into germ free mice causing movement disorders

Question 7

The microbiome and obesity and T2DM

Answer 7

• no causal link
• genetic predisposition found to cause microbiome development in obesity
• FMT into germ free mice causes obese phenotype and onset of T2DM

Question 8

The microbiome and immunotherapy

Answer 8

• found that microbiome composition affects efficacy of immunotherapy
• if supplement with probiotics this could improve outcome