Targeting gut microbiota for precision medicine: Focusing on the efficacy and toxicity of drugs

Abstract

Intra- and interindividual variation in drug responses is one major reason for the failure of drug therapy, drug toxicity, and even the death of patients. Precision medicine, or personalized medicine, is a field of medicine that customizes an individual's medical diagnosis and treatment based on his/her genes, microbiomes, environments, etc. Over the past decade, a large number of studies have demonstrated that gut microbiota can modify the efficacy and toxicity of drugs, and the extent of the modification varies greatly from person to person because of the variability of the gut microbiota. Personalized manipulation of gut microbiota is an important approach to rectify the abnormal drug response. In this review, we aim to improve drug efficacy and reduce drug toxicity by combining precision medicine and gut microbiota. After describing the interactions between gut microbiota and xenobiotics, we discuss (1) the effects of gut microbiota on drug efficacy and toxicity and the corresponding mechanisms, (2) the variability of gut microbiota, which leads to variation in drug responses, (3) the biomarkers used for the patient stratification and treatment decisions before the use of drugs, and (4) the methods used for the personalized manipulation of gut microbiota to improve drug outcomes. Overall, we hope to improve the drug response by incorporating the knowledge of gut microbiota into clinical practice.

Keywords: drug efficacy; drug toxicity; gut bacteria engineering; gut microbiota; precision medicine.

Figure 1

Interactions between gut microbiota and xenobiotics. (A) The effects of xenobiotics on gut microbiota composition. Xenobiotics can directly and indirectly change the composition of gut microbiota, including inhibition, promotion, elimination, and colonization. (B) Metabolism-related activity of the gut microbiota. Gut microbiota can synthesize and release enzymes with the ability to transform xenobiotics (i), and transformed xenobiotics may undergo further enterohepatic cycling (ii). Gut microbiota can directly bind to xenobiotics, which reduces the final absorption of xenobiotics by hosts (iii). When the intestinal epithelium is breached by xenobiotics or for other reasons, gut microbiota can trigger the immune response of hosts (iv). Gut microbiota can synthesize and release metabolites with the capability to modulate immune response of hosts (iv), alter hepatic gene expression (v), compete for enzymes and drug transporters (vi), and act as intermediates (vii).

Figure 2

Direct and indirect modification of drug efficacy by gut microbiota. (A) Gut microbiota directly binds to drugs such as L-dopa. (B) Gut microbiota can inactivate, activate or change the potency and bioavailability of drugs via direct enzymatic metabolism. (C) Drugs modulate the composition and metabolism of gut microbiota to achieve efficacy. (D) Drugs modulate the spatial distribution of gut microbiota to achieve efficacy. (E) Gut microbiota synthesizes compounds with the ability to modulate and compete for drug transporters. Please see article text for the details on interactions and effects.

Figure 3

Direct and indirect modification of drug toxicity by gut microbiota. (A) Gut microbiota directly binds to drugs, especially heavy metal drugs. (B) Gut microbiota modulates the toxicity of drugs via direct enzymatic metabolism. (C) Drugs modulate the composition, metabolism and spatial distribution of gut microbiota to modulate toxicity. (D) Gut microbiota synthesizes compounds with the ability to compete for drug metabolism enzymes. Please see article text for the details on interactions and effects.

Figure 4

The factors influencing the composition and function of gut microbiota. Gut microbiota can modulate the efficacy and toxicity of drugs. However, the extent of modulation varies greatly from person to person and is highly dependent on the composition and function of gut microbiota of an individual. The composition and function of gut microbiota are influenced by multiple factors such as smoking, drug use, exercise, and emotional stress. The bioactivities of enzymes and metabolite contents are the direct scalable manifestations of the functional variability of gut microbiota.

Figure 5

The gut microbiota-based markers for the personalized use of drugs. (A) Possible gut microbiota-based biomarkers for the personalized use of drugs, including genes, enzymes, bacterial strains or species, and gut microbiota metabolites. (B) The fecal activity of nitroreductases is positively correlated with the bioavailability of berberine in treating hyperlipidemia. Thus, the fecal activity of nitroreductases can serve as a biomarker for choosing the dosage of berberine. (C) E. lenta carrying the cgr operon can inactivate digoxin. Thus, the copy number of cgr operon can serve as a biomarker for choosing the dosage of digoxin or guiding physicians to distinguish patients who are likely to respond favorably to digoxin. (D) F. prausnitzii can transform tacrolimus into compounds with reduced potency. The abundance of F. prausnitzii is positively correlated with the need for an increased dosage in patients. (E) Gut microbiota metabolite p-cresol can compete with acetaminophen for liver enzymes, leading to increased toxicity. Thus, fecal p-cresol is a biomarker of a reduced dosage of acetaminophen.

Figure 6

Integration of multiple factors to develop integrative biomarkers for patient stratification and treatment decisions. The parameters used for establishing integrative biomarkers can be derived from hosts, gut microbiota and other external factors. When an integrative biomarker has been preliminarily screened, a further validation step is needed to confirm the suitability. The major characteristic of integrative biomarkers in comparison with conventional biomarkers is that an integrative biomarker comprises multiple variables that act holistically to influence drug outcomes.

Figure 7

Conventional gut microbiota-oriented approaches for precision medicine. (A) Rational use of drugs, including the selection of a suitable dosage and drug administration time and the combinational use of (non-antibiotic) drugs. A dosage based on the levels of drug-metabolizing bacteria can ensure the consistency of the levels of active drugs between and within individuals. At different time points, gut microbiota release different levels of metabolites that can act synergically to enhance the toxicity of drugs such as acetaminophen. The combined use of drugs especially bacterial enzyme inhibitors can inhibit the metabolizing effects of gut microbiota on drugs. (B) Conventional methods for modulating gut microbiota. Gut microbiota can be modified by antibiotics, probiotics, diet, prebiotics and FMT. Notably, the extent of modification is not precise.

Figure 8

Typical strategies used in engineering gut bacteria for precision medicine. (A) An overview of engineered bacteria used for sensing and responding to surrounding signals. After sensing surrounding signals such as pH and temperature, engineered bacteria can synthesize and release a series of molecules that can modulate the immune system, control pathogens, alter xenobiotic metabolism, etc. (B) Engineering gut bacteria to report transient molecules that can be easily degraded, absorbed or modified in the gut as surrogate biomarkers. (C) Precise depletion of gut bacteria by engineered phages. The specific targets for depletion can be undesirable genes or polymorphisms encoding drug metabolism enzymes. (D) Bacteria can be conferred with the ability to release therapeutic molecules or other abilities such as the ability to modulate the metabolism of drugs. (E) Biocontainment of engineered bacteria exemplified by auxotrophy, in which the number of engineered bacteria can be regulated by the nutrients supplied. Using these strategies alone or in combination, the level of drug metabolized by gut microbiota can be precisely regulated and thus the final drug response can be controlled.