Antibiotics-Induced Changes to Gut Bacteria Influence Expression of Drug Side Effects

Antibiotic treatment disrupts the normal bacterial population of the gut resulting in changes in how the body deals with the breakdown and transport of drugs and other metabolites, which may increase the impact of deleterious side effects.

Dysbiosis (alteration of intestinal flora) is associated with various physiological changes including diseases. Investigators at Kumamoto University (Japan) sought to clarify the effect of dysbiosis on protein expression levels in mouse liver and kidney by quantitative proteomic analysis. They focused on particular drug-metabolizing enzymes and transporters in order to investigate the potential impact of dysbiosis on drug pharmacokinetics.

The investigators worked with three different mouse models: germ-free mice, which were free of intestinal bacteria since birth; mice that had received antibacterial drugs for five consecutive days; and a control group of mice with naturally occurring intestinal flora. Proteomic techniques were used to identify changes in the levels of proteins linked to drug metabolism and transport in the liver and kidneys of the mouse groups.

Results published in the August 1, 2016, issue of the journal Molecular Pharmaceutics revealed that expression levels of 825 and 357 proteins were significantly changed in the liver and kidney, respectively, of germ-free mice (versus specific-pathogen-free mice), while 306 and 178 proteins, respectively, were changed in antibiotics-treated mice (versus vehicle controls). Among them, 52 and 16 drug-metabolizing enzyme and transporter proteins were significantly changed in the liver and kidney, respectively, of germ-free mice, while 25 and 8, respectively were changed in antibiotics-treated mice. Expression of mitochondrial proteins was also changed in the liver and kidney of both germ-free and antibiotic treated mice.

"The most significant drug-metabolizing enzyme that decreased was cytochrome P450 2b10 (Cyp2b10)," said senior author Dr. Sumio Ohtsuki, professor of pharmaceutical sciences at Kumamoto University. "Not only was the amount of the enzyme reduced nearly 96%, but the metabolic capacity of the drug in the liver was also reduced by approximately 82%. Cyp3a11, a similar type of enzyme was also reduced by about 88%. The human enzymes corresponding to these two enzymes, CYP2B6 and CYP3A4 are reported to be related to the metabolism of more than half of the pharmaceuticals on the market. The results of this study show that many drugs may be affected by changes in the intestinal flora. In the future, if it is confirmed that similar mechanisms exist in humans, we expect our research to lead to optimal dosing and a reduction in drug side effects."

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