- Please discuss both direct and indirect effects of the gut microbiota on drug
metabolism, both mechanistically and with specific examples.
Indirect impacts are impacts which are not directly mediated by bacterial enzymes.
Pharmacodynamics are altered for those indirect impacts.
Indirect effects of the gut microbiota on drug metabolism are seen for Simvastatin (ST). ST is a statin
(cholesterol↓) and used for the treatment of hyperlipidaemia. Plasmalevels of ST are positively
associated with microbially synthesized bile acid. Bile acid increases the bioavailabilty of the drug
itself. Furthermore bile acid needs cholesterol for it´s biosynthesis and therefore an increase in bile
acid decreases cholesterol levels
Direct impacts are impacts which are directly mediated by bacterial enzymes.
Direct impacts are seen for drugs like prontosil. This drug has azo-bonds which are cleaved by
bacterial enzymes. This bacterial metabolism leads to a sidespecific release of the pharmacologicalactive compound
- How does the gut microbiota contribute to certain types of drug-related toxicity?
Bacterial enzymes can increase the activation of drugs. This is seen for prodrugs which depend on
the activation by bacterial enzymes like prontosil.
Bacterial enzymes can prevent the excretion of glucuronidaded drugs. Bacterial beta-glucuronidases
can re-activate drugs and therefore prevent their elimination. A prominent example is CPT-11.
Also bacterial enzymes can produce more toxic compounds than the drug itself. NSAID´s are
metabolized by bacterial enzymes to aglycones which are taken up enterocytes and get metabolized
into reactive intermediates endoplasmatic reticulum stress↑ mitochondrial stress↑
- Please discuss the mechanisms of indirect gut microbiota effects on drug metabolism
and toxicity via e.g., the modulation of host drug metabolism and disposition and
competition of bacterial-derived metabolites.
- Please give examples for intended and unintended effects of therapeutic drugs on
the composition of the gut microbiota.
Unintended microbiota composition alteration: Antibiotics lead to an loss of bacteria in the gut. This
effect can be intended when the antibiotic is given for a GI-tract-infection, but for other Infections
the loss of bacteria in the gut is not intended.
Medication with metformin leads to an increased abundance of SCFA- and butyrate-producing
bacteria and to an increased abundance of mucin-degrading-bacteria. Those bacteria are associated
with an improved glucose tolerance.
- Please discuss in detail the (postulated) relationship between Akkermansia
muciniphilia abundance and the therapeutical effect of PD-1/PD-L1-blockers.
PD-1/PD-L1 blockers are drugs which inhibit the inactivation of t-cells. Cancer cells can bind to PD-1
and downregulate t-cell-response. A. Muciniphilia is able to alter specific immuncells, eg. Expression
of TCM-cells↑, Production of IL-12 by dendritic cells↑. This could lead to an increased recruitment
of immune-cells into the tumor and therefore a better pharmacological activity of PD-1 blockers.
A. Muciniphilia might also prevent leaky colon and systemic immunosuppression by
normal/homeostatic growth and composition of microbiota.
- What combined preclinical and clinical trial design would you choose to investigate
the relevance of Akkermansia muciniphilia in cancer patients treated with checkpoint
inhibitors?
Preclinical:
-Mice suffering from Colorectal cancer
-One germ free group, one “normal” group and one group with only A. Muciniphilia microbiom
-Placebo vs. Intervention group with A. Muciniphilia supplementation (total 6 different groups)
-Primary Outcomes: Time of survival, Tumor mass
-Secondary Outcomes: Plasma-Drug-Concentrations, ADR
Clinical:
-RCT with patients suffering from colorectal cancer (if preclinical trial was successful)
-Microbiom screening especially A. Muciniphilia
-Placebo vs. Intervention group with A. Muciniphilia supplementation (one group Supplementation
before and during treatment; one group while treatment)
-Primary Outcomes: Quality of life, Time of survival, ADR
-Secondary Outcomes: Tumor mass, Plasma-Drug-Concentrations
- What are current research questions regarding the clinical relevance of
pharmacomicrobiomics?
-How can we use the knowledge of pharmacomicrobiomics in clinical practise safely?
-Are there ways to investigate the effect of pharmacomicrobiomics studys in humans?
-Can we use probiotics to improve drug efficacy?
- Please make a realistic concept for an in-vitro-model to investigate the gut
microbiota effects on drug metabolism and toxicity.