scholarly journals Exploring drug metabolism by the gut microbiota: modes of metabolism and experimental approaches

2021 ◽  
pp. DMD-MR-2021-000669
Author(s):  
Pooja Dhurjad ◽  
Chinmayi Dhavaliker ◽  
Kajal Gupta ◽  
Rajesh Sonti
Keyword(s):  
Drug Metabolism ◽  
Gut Microbiota ◽  
Experimental Approaches

Abstract MP38: Identification Of A Gut Microbe That Attenuates The Blood Pressure Lowering Effect Of ACEi Quinapril

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Tao Yang ◽  
Xue Mei ◽  
Ethel Tackie-Yarboi ◽  
Jun Kyoung ◽  
Blair Mell ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Drug Resistance ◽  
Drug Metabolism ◽  
Gut Microbiota ◽  
Esterase Activity ◽  
Enzyme Inhibitor ◽  
Fecal Microbiota ◽  
Blood Pressure Lowering Effect ◽  
Spontaneously Hypertensive ◽  
Cecal Microbiota

Introduction: Treatment resistant hypertension (rHTN) is present in ~20% of all hypertensive patients. rHTN is critical in African American patients who experience early onset, severe outcomes, and weak responsiveness to angiotensin converting enzyme inhibitor (ACEi). The mechanism for drug resistance is unknown. Gut microbiota harbors biotransformative enzymes such as esterase, which may hydrolyze ACEis, reducing absorption. Our study was to identify microbe responsible for ACEi resistance. Methods: 16-week-old male Spontaneously Hypertensive Rats (SHR) were gavaged with (N=12) or without (N=6) Vancomycin, Meropenem, and Omeprazole (VMO) 50 mg/kg/day for five days to deplete the gut microbiota. A single 8mg/kg dose of quinapril was given to SHR and SHR+VMO before blood pressure (BP) recording via telemetry. Quinapril catabolism was quantified by liquid chromatography-mass spectrometry. Bacterial esterase activity was monitored by hydrolysis of p-nitro-phenylbutyrate. Cecal microbiota was analyzed by 16S rDNA. Fecal microbiota were analyzed by metagenomics in 29 (16 black, 13 white) HTN patients. Results: Quinapril lowered BP more in the SHR+VMO than SHR ( P <0.0001). With a 50% reduction in bacterial 16S copy numbers ( P <0.0001), the SHR+VMO group showed (1) reduced Coprococcus ( P <0.0001); (2) lower esterase activity per gram of cecal microbiota to hydrolyze quinapril ( P =0.0065); (3) a 50% lower reduction in quinapril quantity (nmol) after incubation with 1mg of cecal lysate for 3 hr ( P <0.0001); (4) decreased bacterial genes in KEGG drug metabolism pathway ( P <0.0001). The abundance of Coprococcus positively correlated with genes in drug metabolism ( P <0.0001). Importantly, co-administration of quinapril with C. comes, a species in Coprococcus genus, reduced the BP-lowering effects of quinapril in the SHR ( P <0.0001). Comparison of human microbiota demonstrated a higher abundance of C. comes in the black hypertensives (poor ACEi responder) than the white (ACEi responder) ( P =0.0167). Conclusion: We, for the first time, demonstrate a previously unrecognized role of gut microbes in reducing ACEi effectiveness. This serves a foundation for expanding clinical management of antihypertensive drug resistance via manipulation of gut microbiota.

I-screen: In vitro platform to study human gut microbiota induced drug metabolism and molecular transformations

2018 ◽  
Vol 33 (1) ◽  
pp. S81-S82
Author(s):  
Steven Erpelinck ◽  
Frank H.J. Schuren ◽  
Irene H.G. Nooijen ◽  
R. Scott Obach ◽  
Gregory S. Walker ◽  
...  
Keyword(s):  
Drug Metabolism ◽  
Gut Microbiota ◽  
Human Gut ◽  
Human Gut Microbiota

scholarly journals Gut Microbiome and Drug Metabolism

2021 ◽  
Vol 4 (1) ◽  
pp. e00146
Author(s):  
E.N. Ilina ◽  
E.M. Mayorova ◽  
A.I. Manolov ◽  
A.A. Korenkova ◽  
V.V. Bahmetjev ◽  
...  
Keyword(s):  
Microbial Community ◽  
Drug Metabolism ◽  
Gut Microbiota ◽  
Computational Models ◽  
Metabolic Reaction ◽  
Metabolic Potential ◽  
Adequate Model ◽  
Microbial Enzymes ◽  
Metabolic Reactions

The human physiology textbooks traditionally consider the intestine as a metabolically active organ, with its activity primarily associated with the production of numerous digestive enzymes. The development of molecular analysis technologies has significantly detailized this picture, primarily by decoding the metabolic potential of the intestinal microbiota. Data from numerous metagenomic studies indicate that the number of eukaryotic and bacterial cells in the human body is comparable - about 3.0×1013, while the number of genes in the intestinal metagenome is one hundred times greater than in the human genome. Obviously, the gut microbiota exhibits both direct and indirect effects on the metabolism of drugs and xenobiotics, that can affect their effectiveness and toxicity. Orally administrated xenobiotics have been found to be metabolized by intestinal microbial enzymes before being absorbed from the gastrointestinal tract into the blood flow. The metabolic reactions performed by the gut microbiota greatly differ from the metabolic reactions of the liver, providing modification of drugs by acetylation, deacetylation, decarboxylation, dehydroxylation, demethylation, dehalogenation, etc. Despite the metabolism of xenobiotics by microbial enzymes of the intestine is rather known, information about the specific microflora mediating each metabolic reaction is still limited, mainly by the lack of an adequate model of the intestinal microbial community to allow the accumulation of experimental data for the creation of computational models. Currently, studies of drug metabolism use microfluidic chips, reproducing functions of various organs and tissues, such as the liver, kidney, lungs and intestine, as in vitro models in the form of 2D and 3D cell cultures. Supplementation of such systems with the microbial community will allow to get as close as possible to in vitro modeling of complicated biological processes in the interests of pharmacological research and the accumulation of data for constructing computational models.

scholarly journals An Ex Vivo Fermentation Screening Platform to Study Drug Metabolism by Human Gut Microbiota

2018 ◽  
Vol 46 (11) ◽  
pp. 1596-1607 ◽  
Author(s):  
E. van de Steeg ◽  
F. H. J. Schuren ◽  
R. Scott Obach ◽  
C. van Woudenbergh ◽  
Gregory S. Walker ◽  
...  
Keyword(s):  
Drug Metabolism ◽  
Gut Microbiota ◽  
Ex Vivo ◽  
Study Drug ◽  
Human Gut ◽  
Human Gut Microbiota ◽  
Screening Platform

Impact of gut microbiota on drug metabolism: an update for safe and effective use of drugs

2017 ◽  
Vol 40 (12) ◽  
pp. 1345-1355 ◽  
Author(s):  
Keumhan Noh ◽  
You Ra Kang ◽  
Mahesh Raj Nepal ◽  
Rajina Shakya ◽  
Mi Jeong Kang ◽  
...  
Keyword(s):  
Drug Metabolism ◽  
Gut Microbiota ◽  
Effective Use

scholarly journals The influence of gut microbiota on drug metabolism and toxicity

2015 ◽  
Vol 12 (1) ◽  
pp. 31-40 ◽  
Author(s):  
Houkai Li ◽  
Jiaojiao He ◽  
Wei Jia
Keyword(s):  
Drug Metabolism ◽  
Gut Microbiota
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