L11 Microbiome-based Therapeutics Flashcards
Possible reasons for reduced gut microbiota diversity
- Fibre-deficient diets
- Antibiotic use
What effect does FMT have on the microbiome?
- Provides colonisation resistance
- Production of beneficial metabolites (SCFAs & secondary bile acids)
- Restoration of cross-talk with mucosal immune system
FMT clinical indication
C. diff colitis
First FDA approved FMT for recurrent CDI
Rebyota
5 major phyla that constitute the gut microbiota
- Bacteroidetes
- Firmicutes
- Verrucomicrobia
- Actinobacteria
- Proteobacteria
What increases Firmicutes abundance in gut?
Plant-based diet
Examples of Firmicutes
Lactobacillales, Clostridiales
What are Bacteroidetes mainly known for?
Their ability to catabolise complex polysaccharides (25% of their genome encodes PUL)
Preclinical evidence suggests enhanced responses to immune checkpoint inhibitors when co-administered with __
A. muciniphila
__ stimulates Tregs in the colon
Bifidobacterium breve
Increase in __ is a sign of dysbiosis
Proteobacteria
Microbiome therapeutics
- Probiotic
- Prebiotic
- Synbiotic
4 categories of microbiome-based therapeutics (alternatives to FMT)
- Diet & prebiotics
- Symbiotic-microbial consortia
- Engineered symbiotic bacteria
- Microbiota-derived proteins & metabolites
Examples of symbiotic-microbial consortia
- Consortium of 4 bacterial strains, incl. Clostridium scindens (can convert 1º bile acids to 2º bile acids) - enhanced resistance to C. diff colitis in mice
- Consortia that include propionate-producing Bacteroides species provide colonisation resistance against S. typhimurium
Examples of engineered symbiotic bacteria
- Engineered to express PUL (provides a selective advantage over other resident bacteria)
- Genes derived from C. scindens have been heterologously expressed in C. sporogenes, enabling the recombinant bacteria to synthesise deoxycholic acid & lithocholic acid
- CRISPR-Cas9 can be used to delete pathogenic metabolites from bacterial species
Which microbiome-based therapeutic category is most suited to immunocompromised individuals?
Microbiota-derived proteins and metabolites
Variations in both __ and __ due to microbiota can impact T cell differentation (Treg & Th17)
bile salt hydrolase (BSH) activity and 7α-hydroxylation
Most abundant SCFAs in gut
- acetate
- propionate
- butyrate
Propionate production could be stimulated by prebiotics to exert…
protective effects on BBB integrity
Psychobiotics MOA and indication
- Bacterial metabolism of tryptophan to indole compounds (source of 5-HT & kynurenine)
- For stress-related disorders
How do gut microbiota alter pharmacological drugs?
- By degrading the drug (irinotecan)
- By activating the drug (sulfasalazine)
- By modulating host enzymes that metabolise the drug (digoxin)
The primary chemical mechanisms of gut microbiota drug metabolism
Hydrolytic and reductive reactions
How do gut microbiota affect digoxin?
Eggerthella lenta strains carry two-gene cardiac glycoside reductase operon, which is activated by digoxin and leads to cardiac inactivity
How does arginine prevent digoxin inactivation?
by inhibiting cgr operon activation
Irinotecan (CPT-11) is metabolised in the liver where its converted to its toxic metabolite __ by __
SN-38 by carboxylesterases
SN-38G is inactivated by __
UDP-glucuronosyltransferase
__ convert SN-38 back into its toxic form
Bacterial β-glucuronidases
What are being investigated to minimise CPT-11 induced toxicity?
Probiotics
How do gut microbiota affect 5-ASA?
Up to 1/3rd of 5-ASA can be metabolised via microbial acetyltransferase genes (e.g. Salmonella strains) into N-acetyl 5-ASA, which lacks anti-inflammatory activity
Clinical indication for 5-ASA
IBD
Clinical indication for Irinotecan
Metastatic colorectal cancer
