Pharmacology of gut microbiome Flashcards
what is the gut microbiome
the gut microbiome is the collective genome in the gut
give two possible reasons for reduced gut microbiota diversity
dietary fibre-deficient diet and antibiotic use
what is fecal microbial transplantation?
transfer o complex incompletely defined community of micro-organisms from a healthy donor (screened for the absence of pathogens) to a recipient.
the production of which metabolites can result from FMTT?
short-chain fatty acids and secondary bile acids
what clinical scenario is FMT currently used in?
clostridioides difficile colitis
what type of bacteria is c. diff?
an obligate anaerobic non-spore forming bacteria that produces a toxin.
what was the initial treatment of c. diff colitits?
antibiotic treatment; high failure rate.
what was the success rate of FMT from healthy donors to c. diff colitis patients?
90% success rate
what is acredited with FMT-related successful treatment of c. diff colitis?
the engraftment (establishment of replicating self-sustaining species) of donor symbiotic strains in the recipient
what is Rebyota?
FDA approved CDI treatment in patients aged 18+.
what were the most common symptoms associated with CDI?
abdominal pain, diarrhea, abdominal distension, flatulence and nausea
why was there more success with FMT in CDI than in UC?
In CDI, there is complete loss of microbiota, whereas in UC, would need bacteria already-present to adapt.
what obstacle has limited clinical use of FMT?
The inability to define donor samples’ exact composition
what are the five major phyla in gut?
bacteriodetes, firmicutes, verrucomicrobia, actinobacteria, and proteobacteria
plant-based diet increases the prevalence of which phylum in the gut?
plant based diet increases the prevalence of firmicutes in the gut
name two example species of firmicutes?
lactobacillales and clostridiales
give three functions of clostridiales?
resist pathogenic colonization, ameliorate IBD, and promote T cell differentiation
name two metabolites that clostridiales produce?
clostridiales produce butyrate and secondary bile acids.
how do lactobacillales impact the gut
lactobacillales interact with the gut epithelium to produce antimicrobial peptides, promote mucosal homeostasis and metabolise tryptophan to produce bioactive compounds
bacteriodetes comprise _ - _% of our colonic microbiota and this range is largely impacted by?
bacteriodetes comprise 5-60% of our colonic microbiota and this range is largely impacted by diet
which phyla can metabolise complex polysaccarides and how do they acheive this?
bacteriodetes can metabolise complex polysaccarides due to 25% of their genome encoding polysaccaride utilising loci
what is polysaccaride utilising loci
this loci is dedicated to polysaccaride import and degradation
what phylum is associated with enhanced response to immune checkpoint inhibitors?
verruccomicrobia
what is the predominant microbe in infant gut (ideally)?
bifidobacteria
what does bifidobacterium provide resistance to and how does it achieve this?
bifidobacterium strains expressing AC transporters which support acetate production which enhances resistance to enterohemorrhagic e coli
what immune cell does bifidobacterium breve stimulate?
bifidobacterium breve stmulates T regs in the colon
bifido strains and checkpoint inhibitors that have shown enhanced response to the checkpoint inhibitors?
b. breve and b. longum, PDL-1 inhibitor
what is a probiotic
live micro-organisms when administered in adequate amounts confer a health benefit to the host
what is a prebiotic?
a substrate that is selectively utilised by host micro-organisms conferring a health benefit
name the four categories of microbiome-based therapeutics? (besides FMT)
Diet and probiotics, symbiotic-microbial consertia, engineered symbiotic bacteria, and microbiota derived metabolites and proteins
name dietary and probiotic interventions
dietary fiber, complex polysaccharides, fermented foods
what needs to be present for prebiotics to be effective?
symbiotic bacterial strains need to be present for prebiotic efficacy as this is essentially ‘feeding’ already-present microbes
what is microbial consortia?
transfer of bacterial isolates (selected or defined) to promote specific-microbiota function
what is the aim of symbiotic microbia consortia?
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
what is the primary impact of a diverse microbiota?
resistance to colonistaion and inhibit enteric pathogenic bacteria growth.
consortia including which phylum inhibited colonisation with salmonella typhimurium?
consortia with propionate-producing bacteriodetes is assoicated with s. typhimurium resistance.
what loci can be engineered into bacterial strains to enhance colonisation resistance?
polysaccharide utilisation locus can be engineered into recombinant strains to provide a selective advantage over other bacterial populations as well as enhance colonisation resistance
genes derived from c. scindens are incoporated into c. sporagenes to enable what in the recombinant bacteria?
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
what genetic engineering tool can be used to eliminate pathogenic traits of a recombinant bacteria?
CRISPR-cass9
name two things often reduced or even completely depleted following antibiotic treatment?
SCFA and secondary bile acids
what receptor family can microbiota derived metabolites bind?
GPCRs can be activated by microbiota derived metabolites
in which population are microbiota derived proteins and metabolites ideal for?
in the immunocompromised
what are some problems associate with microbiota derived proteins and metabolites?
production, adequate drug delivery to intended GIT site, impact influenced by absorptive capacity and systemic dissemmination versus function in the gut lumen
name the three most abundant SCFA in the gut?
acetate, propionate, butyrate
what are SCFAs involved in the mediation of?
SCFAs are involved in the mediation of immunoregulation, colonisation resistance, and protection from LRT viral infection
describe the conversion of primary bile acids to secondary bile acids
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
what can varying BSH and 7alpha hydroxylase activity affcet?
T cell differentiation (Th17 and TRegs)
what are psychobiotics?
these are live micro-organisms that when ingested in adequate amounts they produce a health benefit in patients suffering with psychiatric illness
metabolism of which amino acid do psychobiotics typically target?
tryptophan metabolism - directly involved in supply for serotonin and kyneurenine production
where can propionate improve barrier integrity?
in the BBB
What two reactions are the primary chemical mechanisms of gut microbiota drug metabolism?
reductive and hydrolytic reactions are the primary reactions in gut microbiota metabolism of drugs
what is digoxin and what are its uses?
digoxin is a cardiac glycoside used to treat heart failure and atrial fibrillation
what happens in digoxin metabolism in 10% of patients?
in 10% patients, digoxin is converted to inactive metabolite as the result of reduction reaction
what prevents the metabolism of digoxin to an inactive metabolite?
arginine, hence high arginine diet reccomended for digoxin
what bacteria has an operon that is activated by digoxin and causes cardiac inactiivty
eggerthelia lenta has a cardiac glycoside reductase operon which is activated by digoxin
campothecan-11 metabolite?
SN-38 (by carboxylesterases)
what enzyme converts SN-38G to SN-38
bacterial beta-glucuronidase reactivates SN-38G to SN-38 (toxic)
what is meslamine - 5 Amino salicylic acid used to treat
IBD
how is up to 1/3 of 5-ASA metabolised?
acetylation by enzymes encoded by gut bacteria, specifically salmonella strains, convert 5-ASA to N-Acetyl 5-ASA
why is the formation of N-Acetyl 5-ASA unfavorable?
N-Acetyl 5-ASA lacks anti-inflammatory capacity and renders the treatment ineffective
