Gut Microbiome and Response to Cardiovascular Drugs
The importance of gut microbiome composition in health and disease is been well documented. There are recent researches found the gut microbiome as an important contributor for both cardiovascular disease risk and metabolism of xenobiotics. The microbiota can metabolize medications, which may change drug pharmacokinetics and pharmacodynamics or the formation of toxic metabolites which can interfere with drug outcome. The author Tuteja and Ferguson (2020) published a paper titled “Gut Microbiome and Response to Cardiovascular Drugs” in the “American Heart Association Journal”. Summary of the proposed paper is given below:
Objective:
To elaborate on the contribution of the gut microbiome to the development of CVD.
To specify how gut microbiome composition, affect drug metabolism, with specific evidence for cardiovascular drugs
To discuss mechanisms through which the microbiome affects CVD and variation in drug response.
Method:
The information specified is developed with the support of currently available evidence and scientific and medical knowledge.
Findings:
Contribution of the Gut Microbiome to CVD:
There have been many findings to associate the effect of the gut microbiome on CVD but the mechanism is still unclear. Atherosclerotic plaques from patients with coronary artery disease contain DNA from a wide range of bacterial species and this correlates with abundant bacteria in the oral cavity and intestine. Trimethylamine-N-oxide (TMAO) is proatherogenic, prothrombotic, and a causal contributor to CAD risk and it is derived from dietary choline and carnitine by the actions of the gut microbiome. The intestinal microbiota also regulates host lipid metabolism independent of body mass index and dependent on host genetics. In hypertensive animals and patients, alterations in the gut microbiome have been observed.
Due to the inference caused by drug pharmacokinetics or pharmacodynamics, gut microbiota can, directly and indirectly, influence drug response as follow:
Pharmacokinetic Interactions:
The process of drug absorption depends on many factors including stability of the drug in the pH of the GI lumen, drug solubility in gastrointestinal (GI) fluids, permeability across epithelial membranes, GI transit time, and presystemic metabolism by the host and microbial enzyme systems. The pH changes along the GI lumen affect not only drug stability but also provide distinct microenvironments that are compliant for the growth of certain microbiota. The intestine plays an important role in drug metabolism as it also expresses many drug-metabolizing enzymes and drug transporters and contributes to presystemic metabolism and drug transport from the intestinal lumen. The gut microbiota also controls the genetic machinery necessary to produce enzymes that metabolize orally administered drugs, through 2 main reaction types—hydrolysis and reduction. Hydrophilic drugs are converted to hydrophobic compounds through microbial metabolism, this enhances their absorption across the gut lumen. Microbial activity can hence lead to activation of prodrugs, altered drug pharmacokinetics, the unwanted formation of toxic metabolites, or inactivation of drugs.
Pharmacodynamic Interactions:
The mechanism through which the microbiome modifies the toxicity, as well as the efficacy of chemotherapeutic drugs, has been described using a mechanistic framework called TIMER—Translocation, Immunomodulation, Metabolism, Enzymatic degradation, and Reduced diversity. Although the mechanism by which gut microbiota might influence cardiovascular drug outcomes is not very clear there exist some known and proposed mechanisms. Known microbiome-drug interaction for Digoxin and proposed microbiome-drug interaction for some drugs are as follow:
Drug- Digoxin
Gut Bacteria – Eggerthella lenta
Mechanism(s) – Inactivation by reduction
Outcome – Bacterial reductase activity decreases the amount of active drug reaching target tissues.
Drug- Simvastatin
Gut Bacteria- Not known
Mechanism(s)- icrobial-derived bile acids competing for host uptake transporters. Alteration in bacterial communities with bile salt hydrolase (bsh) activity.
Outcome- Decreased amount of drug reaching target tissues, Variability in farnesoid X receptor (FXR) receptor signalling
Drug- Rosuvastatin
Gut Bacteria- Not known
Mechanism(s)- Alteration in host gene expression of bile acid metabolism pathways. Alteration in bacterial communities with bile salt hydrolase (bsh) activity
Outcome- Variability in FXR receptor signalling
Drug- Atorvastatin
Gut Bacteria- Not known
Mechanism(s)- Decreased amount of secondary bile acids
Outcome- Variability in FXR receptor signalling
Drug- Amlodipine
Gut Bacteria- Not known
Mechanism(s)- Presystemic metabolism by dehydrogenation
Outcome- Decreased amount of active drug reaching target tissues
Drug- Captopril
Gut Bacteria- Not known
Mechanism(s)- Not known
Outcome- Decreased intestinal permeability and improved villi length.
Anticoagulant, Antiplatelet, and Anti-inflammatory Drugs:
Warfarin is a commonly used anticoagulant. Antibiotics may increase the bleeding risk by interfering with warfarin metabolism through inhibition or induction of Cytochrome P450 (CYP) enzymes. On the other hand, disturbance to the intestinal flora can cause the elimination of vitamin K–producing bacteria, for example, Bacteroides, leading to an alteration in coagulation status.
Aspirin is a commonly used antiplatelet drug. Nonsteroidal anti-inflammatory drugs including aspirin are known to damage the mucosa of the upper GI tract while gut microbiome composition is a contributing factor.
Targeting of the Gut Microbiome and Implications for Drug Development:
Though there are ongoing researches for improved strategies, existing evidence suggests treatment that can modulate the microbiome for improving cardiovascular health would be of great potential. This strategy will have smaller chances of side effects as compared to drugs that target host metabolism. This knowledge of microbial reactions can be used for designing drugs in a way that will be beneficial in limiting drug toxicity. There has been the development of Inhibitors for known microbial enzymes.
Limitations:
There are fewer data to guide clinicians in utilizing knowledge of microbiome composition and function in clinical practice. The authors acknowledge that we need future studies to understand the potent nature of the microbiome over time, specifically during the development of the disease, and in response to lifestyle change, or pharmacological treatment of disease. There is a need to understand the role of the microbiome in drug efficacy and a consideration of the microbiome as a factor in drug nonresponse, and the variability of responses will help in a clear understanding. Intervention studies to test effective strategies to alter microbiome composition is required.
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