Investigation of Host–Gut Microbiota Modulation of Therapeutic Outcome

Abstract

A broader understanding of factors underlying interindividual variation in pharmacotherapy is important for our pursuit of "personalized medicine." Based on knowledge gleaned from the investigation of human genetics, drug-metabolizing enzymes, and transporters, clinicians and pharmacists are able to tailor pharmacotherapies according to the genotype of patients. However, human host factors only form part of the equation that accounts for heterogeneity in therapeutic outcome. Notably, the gut microbiota possesses wide-ranging metabolic activities that expand the metabolic functions of the human host beyond that encoded by the human genome. In this review, we first illustrate the mechanisms in which gut microbes modulate pharmacokinetics and therapeutic outcome. Second, we discuss the application of metabonomics in deciphering the complex host-gut microbiota interaction in pharmacotherapy. Third, we highlight an integrative approach with particular mention of the investigation of gut microbiota using culture-based and culture-independent techniques to complement the investigation of the host-gut microbiota axes in pharmaceutical research.

The liver–gut microbiota axis modulates hepatotoxicity of tacrine in the rat

“…Elucidating the mechanisms underlying interindividual responses to pharmacotherapy is paramount in personalized medicine research. The superorganismic nature of the human host means that not all variations in therapeutic outcome can be attributed to host genetics . Indeed, the gut microbiota possesses vast metabolic activities that can either complement or oppose the host's enzymatic actions, thereby modulating drug disposition and therapeutic outcomes .…”

“…The superorganismic nature of the human host means that not all variations in therapeutic outcome can be attributed to host genetics . Indeed, the gut microbiota possesses vast metabolic activities that can either complement or oppose the host's enzymatic actions, thereby modulating drug disposition and therapeutic outcomes . To date, only a small fraction of marketed drugs are known to be metabolically influenced by the microbiota, and the contribution of gut microbiota toward interindividual variation in pharmacology remains poorly understood.…”

Pharmacomicrobiomics: The Holy Grail to Variability in Drug Response?

“…The oral drug administration is the most complex path of delivery as the agent's efficacy and bioavailability depends on: (i) absorption in GI fluids, (ii) stability in the lumen, (iii) distribution through the epithelial membrane of the GI tract, and (iv) undergoing minimum first pass. The most important factor for efficient bioavailability is drug stability in the lumen . Drug stability is majorly influenced by luminal pH .…”

“…The most important factor for efficient bioavailability is drug stability in the lumen. 31,36,37 Drug stability is majorly influenced by luminal pH. 38 The pHinduced disintegration can be slowed using enteric coating Figure 1 The sites and enzymatic processes involved in drug metabolism by the gut microbiome.…”

Regulation of drug metabolism and toxicity by multiple factors of genetics, epigenetics, lncRNAs, gut microbiota, and diseases: a meeting report of the 21st International Symposium on Microsomes and Drug Oxidations (MDO)

“…Thirdly, genetic variations of ADME genes could lead to significant changes in DMET expression or activity in the metabolism and transport of drugs. In addition, recent studies have demonstrated that many other factors such as epigenetics, noncoding RNAs (ncRNAs), and gut microbiota4, 5, 6, 7, 8, 9 may modulate ADME gene expression and cause variations in drug metabolism and toxicity.…”