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PT4024 > L11 Microbiome-based Therapeutics > Flashcards

L11 Microbiome-based Therapeutics Flashcards

1
Q

Possible reasons for reduced gut microbiota diversity

A
  • Fibre-deficient diets
  • Antibiotic use
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2
Q

What effect does FMT have on the microbiome?

A
  • Provides colonisation resistance
  • Production of beneficial metabolites (SCFAs & secondary bile acids)
  • Restoration of cross-talk with mucosal immune system
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3
Q

FMT clinical indication

A

C. diff colitis

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4
Q

First FDA approved FMT for recurrent CDI

A

Rebyota

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5
Q

5 major phyla that constitute the gut microbiota

A
  • Bacteroidetes
  • Firmicutes
  • Verrucomicrobia
  • Actinobacteria
  • Proteobacteria
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6
Q

What increases Firmicutes abundance in gut?

A

Plant-based diet

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7
Q

Examples of Firmicutes

A

Lactobacillales, Clostridiales

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8
Q

What are Bacteroidetes mainly known for?

A

Their ability to catabolise complex polysaccharides (25% of their genome encodes PUL)

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9
Q

Preclinical evidence suggests enhanced responses to immune checkpoint inhibitors when co-administered with __

A

A. muciniphila

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10
Q

__ stimulates Tregs in the colon

A

Bifidobacterium breve

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11
Q

Increase in __ is a sign of dysbiosis

A

Proteobacteria

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12
Q

Microbiome therapeutics

A
  • Probiotic
  • Prebiotic
  • Synbiotic
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13
Q

4 categories of microbiome-based therapeutics (alternatives to FMT)

A
  • Diet & prebiotics
  • Symbiotic-microbial consortia
  • Engineered symbiotic bacteria
  • Microbiota-derived proteins & metabolites
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14
Q

Examples of symbiotic-microbial consortia

A
  • 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
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15
Q

Examples of engineered symbiotic bacteria

A
  • 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
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16
Q

Which microbiome-based therapeutic category is most suited to immunocompromised individuals?

A

Microbiota-derived proteins and metabolites

17
Q

Variations in both __ and __ due to microbiota can impact T cell differentation (Treg & Th17)

A

bile salt hydrolase (BSH) activity and 7α-hydroxylation

18
Q

Most abundant SCFAs in gut

A
  • acetate
  • propionate
  • butyrate
19
Q

Propionate production could be stimulated by prebiotics to exert…

A

protective effects on BBB integrity

20
Q

Psychobiotics MOA and indication

A
  • Bacterial metabolism of tryptophan to indole compounds (source of 5-HT & kynurenine)
  • For stress-related disorders
21
Q

How do gut microbiota alter pharmacological drugs?

A
  • By degrading the drug (irinotecan)
  • By activating the drug (sulfasalazine)
  • By modulating host enzymes that metabolise the drug (digoxin)
22
Q

The primary chemical mechanisms of gut microbiota drug metabolism

A

Hydrolytic and reductive reactions

23
Q

How do gut microbiota affect digoxin?

A

Eggerthella lenta strains carry two-gene cardiac glycoside reductase operon, which is activated by digoxin and leads to cardiac inactivity

24
Q

How does arginine prevent digoxin inactivation?

A

by inhibiting cgr operon activation

25
Q

Irinotecan (CPT-11) is metabolised in the liver where its converted to its toxic metabolite __ by __

A

SN-38 by carboxylesterases

26
Q

SN-38G is inactivated by __

A

UDP-glucuronosyltransferase

27
Q

__ convert SN-38 back into its toxic form

A

Bacterial β-glucuronidases

28
Q

What are being investigated to minimise CPT-11 induced toxicity?

A

Probiotics

29
Q

How do gut microbiota affect 5-ASA?

A

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

30
Q

Clinical indication for 5-ASA

A

IBD

31
Q

Clinical indication for Irinotecan

A

Metastatic colorectal cancer

PT4024 (12 decks)

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