Pharmacology of gut microbiome

Question 1

what is the gut microbiome

Answer 1

the gut microbiome is the collective genome in the gut

Question 2

give two possible reasons for reduced gut microbiota diversity

Answer 2

dietary fibre-deficient diet and antibiotic use

Question 3

what is fecal microbial transplantation?

Answer 3

transfer o complex incompletely defined community of micro-organisms from a healthy donor (screened for the absence of pathogens) to a recipient.

Question 4

the production of which metabolites can result from FMTT?

Answer 4

short-chain fatty acids and secondary bile acids

Question 5

what clinical scenario is FMT currently used in?

Answer 5

clostridioides difficile colitis

Question 6

what type of bacteria is c. diff?

Answer 6

an obligate anaerobic non-spore forming bacteria that produces a toxin.

Question 7

what was the initial treatment of c. diff colitits?

Answer 7

antibiotic treatment; high failure rate.

Question 8

what was the success rate of FMT from healthy donors to c. diff colitis patients?

Answer 8

90% success rate

Question 9

what is acredited with FMT-related successful treatment of c. diff colitis?

Answer 9

the engraftment (establishment of replicating self-sustaining species) of donor symbiotic strains in the recipient

Question 10

what is Rebyota?

Answer 10

FDA approved CDI treatment in patients aged 18+.

Question 11

what were the most common symptoms associated with CDI?

Answer 11

abdominal pain, diarrhea, abdominal distension, flatulence and nausea

Question 12

why was there more success with FMT in CDI than in UC?

Answer 12

In CDI, there is complete loss of microbiota, whereas in UC, would need bacteria already-present to adapt.

Question 13

what obstacle has limited clinical use of FMT?

Answer 13

The inability to define donor samples’ exact composition

Question 14

what are the five major phyla in gut?

Answer 14

bacteriodetes, firmicutes, verrucomicrobia, actinobacteria, and proteobacteria

Question 15

plant-based diet increases the prevalence of which phylum in the gut?

Answer 15

plant based diet increases the prevalence of firmicutes in the gut

Question 16

name two example species of firmicutes?

Answer 16

lactobacillales and clostridiales

Question 17

give three functions of clostridiales?

Answer 17

resist pathogenic colonization, ameliorate IBD, and promote T cell differentiation

Question 18

name two metabolites that clostridiales produce?

Answer 18

clostridiales produce butyrate and secondary bile acids.

Question 19

how do lactobacillales impact the gut

Answer 19

lactobacillales interact with the gut epithelium to produce antimicrobial peptides, promote mucosal homeostasis and metabolise tryptophan to produce bioactive compounds

Question 20

bacteriodetes comprise _ - _% of our colonic microbiota and this range is largely impacted by?

Answer 20

bacteriodetes comprise 5-60% of our colonic microbiota and this range is largely impacted by diet

Question 21

which phyla can metabolise complex polysaccarides and how do they acheive this?

Answer 21

bacteriodetes can metabolise complex polysaccarides due to 25% of their genome encoding polysaccaride utilising loci

Question 22

what is polysaccaride utilising loci

Answer 22

this loci is dedicated to polysaccaride import and degradation

Question 23

what phylum is associated with enhanced response to immune checkpoint inhibitors?

Answer 23

verruccomicrobia

Question 24

what is the predominant microbe in infant gut (ideally)?

Answer 24

bifidobacteria

Question 25

what does bifidobacterium provide resistance to and how does it achieve this?

Answer 25

bifidobacterium strains expressing AC transporters which support acetate production which enhances resistance to enterohemorrhagic e coli

Question 26

what immune cell does bifidobacterium breve stimulate?

Answer 26

bifidobacterium breve stmulates T regs in the colon

Question 27

bifido strains and checkpoint inhibitors that have shown enhanced response to the checkpoint inhibitors?

Answer 27

b. breve and b. longum, PDL-1 inhibitor

Question 28

what is a probiotic

Answer 28

live micro-organisms when administered in adequate amounts confer a health benefit to the host

Question 29

what is a prebiotic?

Answer 29

a substrate that is selectively utilised by host micro-organisms conferring a health benefit

Question 30

name the four categories of microbiome-based therapeutics? (besides FMT)

Answer 30

Diet and probiotics, symbiotic-microbial consertia, engineered symbiotic bacteria, and microbiota derived metabolites and proteins

Question 31

name dietary and probiotic interventions

Answer 31

dietary fiber, complex polysaccharides, fermented foods

Question 32

what needs to be present for prebiotics to be effective?

Answer 32

symbiotic bacterial strains need to be present for prebiotic efficacy as this is essentially 'feeding' already-present microbes

Question 33

what is microbial consortia?

Answer 33

transfer of bacterial isolates (selected or defined) to promote specific-microbiota function

Question 34

what is the aim of symbiotic microbia consortia?

Answer 34

to establish well-characterised bacterial strains that behave in harmony and synergise functional responses that can re-establish microbiota compositions and may provide health benefits

Question 35

what is the primary impact of a diverse microbiota?

Answer 35

resistance to colonistaion and inhibit enteric pathogenic bacteria growth.

Question 36

consortia including which phylum inhibited colonisation with salmonella typhimurium?

Answer 36

consortia with propionate-producing bacteriodetes is assoicated with s. typhimurium resistance.

Question 37

what loci can be engineered into bacterial strains to enhance colonisation resistance?

Answer 37

polysaccharide utilisation locus can be engineered into recombinant strains to provide a selective advantage over other bacterial populations as well as enhance colonisation resistance

Question 38

genes derived from c. scindens are incoporated into c. sporagenes to enable what in the recombinant bacteria?

Answer 38

genes in c. scindens involved in the conversion of primary bile acids to secondary bile acids are engineered into c. sporogenes to enable recombinant bacteria to synthesise deoxycholic acid and lithocholic acid

Question 39

what genetic engineering tool can be used to eliminate pathogenic traits of a recombinant bacteria?

Answer 39

CRISPR-cass9

Question 40

name two things often reduced or even completely depleted following antibiotic treatment?

Answer 40

SCFA and secondary bile acids

Question 41

what receptor family can microbiota derived metabolites bind?

Answer 41

GPCRs can be activated by microbiota derived metabolites

Question 42

in which population are microbiota derived proteins and metabolites ideal for?

Answer 42

in the immunocompromised

Question 43

what are some problems associate with microbiota derived proteins and metabolites?

Answer 43

production, adequate drug delivery to intended GIT site, impact influenced by absorptive capacity and systemic dissemmination versus function in the gut lumen

Question 44

name the three most abundant SCFA in the gut?

Answer 44

acetate, propionate, butyrate

Question 45

what are SCFAs involved in the mediation of?

Answer 45

SCFAs are involved in the mediation of immunoregulation, colonisation resistance, and protection from LRT viral infection

Question 46

describe the conversion of primary bile acids to secondary bile acids

Answer 46

primary bile acids, 5% of which enter the LI. bile salt hydrolases (BSHs) remove a lycine or taurine to yield cholate or chenodeoxycholate. cholate and chenodeoxycholate are further metabolized by 7alpha-hydroxylation to produce secondary bile acids deoxycholic acid and lithocholic acid

Question 47

what can varying BSH and 7alpha hydroxylase activity affcet?

Answer 47

T cell differentiation (Th17 and TRegs)

Question 48

what are psychobiotics?

Answer 48

these are live micro-organisms that when ingested in adequate amounts they produce a health benefit in patients suffering with psychiatric illness

Question 49

metabolism of which amino acid do psychobiotics typically target?

Answer 49

tryptophan metabolism - directly involved in supply for serotonin and kyneurenine production

Question 50

where can propionate improve barrier integrity?

Answer 50

in the BBB

Question 51

What two reactions are the primary chemical mechanisms of gut microbiota drug metabolism?

Answer 51

reductive and hydrolytic reactions are the primary reactions in gut microbiota metabolism of drugs

Question 52

what is digoxin and what are its uses?

Answer 52

digoxin is a cardiac glycoside used to treat heart failure and atrial fibrillation

Question 53

what happens in digoxin metabolism in 10% of patients?

Answer 53

in 10% patients, digoxin is converted to inactive metabolite as the result of reduction reaction

Question 54

what prevents the metabolism of digoxin to an inactive metabolite?

Answer 54

arginine, hence high arginine diet reccomended for digoxin

Question 55

what bacteria has an operon that is activated by digoxin and causes cardiac inactiivty

Answer 55

eggerthelia lenta has a cardiac glycoside reductase operon which is activated by digoxin

Question 56

campothecan-11 metabolite?

Answer 56

SN-38 (by carboxylesterases)

Question 57

what enzyme converts SN-38G to SN-38

Answer 57

bacterial beta-glucuronidase reactivates SN-38G to SN-38 (toxic)

Question 58

what is meslamine - 5 Amino salicylic acid used to treat

Answer 58

IBD

Question 59

how is up to 1/3 of 5-ASA metabolised?

Answer 59

acetylation by enzymes encoded by gut bacteria, specifically salmonella strains, convert 5-ASA to N-Acetyl 5-ASA

Question 60

why is the formation of N-Acetyl 5-ASA unfavorable?

Answer 60

N-Acetyl 5-ASA lacks anti-inflammatory capacity and renders the treatment ineffective