The metabolic effect of gut microbiota on drugs

Abstract

There are more than 1000 species of microbes reside in the human gut, umbering～10¹⁴ microbes. As the invisible organ of human beings, gut microbiota can usually participate in drug metabolism by producing specific enzymes, such as reductase and hydrolytic enzyme, thus affecting the efficacy, toxicity, and bioavailability of drugs. At least 30 commercially available drugs have been shown to be substrates of gut microbes-derived enzymes, and an increasing number of drugs may have the potential to contact with the distal gut with the help of improved release systems or poor solubility/permeability, more drugs are expected to be found to be metabolized through the gut flora. By collecting examples of intestinal flora participating in the metabolism of synthetic drugs and traditional Chinese medicine components, this article provides a comprehensive reference for future researchers to study drug metabolism by intestinal flora. Noticeably, the composition and quantity of intestinal flora varies among individuals, and can be affected by some drug administration (such as antibiotics) or environmental changes (acute plateau hypoxia). This seems to suggest that intestinal flora could have the potential to be a new drug target to affect the efficacy of drugs which can be metabolized by Intestinal flora. Accordingly, understanding the impact of intestinal flora on drug metabolism and clarifying the drug transformation process is of great significance for guiding rational clinical use, individualized use, toxicological evaluation, and promoting drug discovery and development.     

Gut microbiota modulates drug pharmacokinetics

Abstract

Gut microbiota, one of the determinants of pharmacokinetics, has long been underestimated. It is now generally accepted that the gut microbiota plays an important role in drug metabolism during enterohepatic circulation either before drug absorption or through various microbial enzymatic reactions in the gut. In addition, some drugs are metabolized by the intestinal microbiota to specific metabolites that cannot be formed in the liver. More importantly, metabolizing drugs through the gut microbiota prior to absorption can alter the systemic bioavailability of certain drugs. Therefore, understanding intestinal flora-mediated drug metabolism is critical to interpreting changes in drug pharmacokinetics. Here, we summarize the effects of gut microbiota on drug pharmacokinetics, and propose that the influence of intestinal flora on pharmacokinetics should be organically related to the therapeutic effects and side effects of drugs. More importantly, we could rationally perform the strategy of intestinal microflora-mediated metabolism to design drugs.     

药物基于“肠-脑”通路的研究进展

肠道菌群是由诸多共生及致病微生物组成的复杂而动态的群落,并与宿主紧密合作.近年来,越来越多的证据支持“肠-脑”轴理论,肠道菌群与神经精神疾病之间的联系逐步被发现.由于神经精神疾病治疗药物大多经口服后进入肠道,使得其与肠道菌群可能产生更广泛的相互作用.多项研究表明该类药物可改变肠道菌群的组成和功能,同时肠道菌群也会参与药...     

海洋硫酸多糖对糖脂代谢及肠道菌群调节作用的研究进展

肥胖已经成为人类首要健康问题,海洋硫酸多糖对糖脂代谢及肠道菌群具有调节作用,因此在肥胖预防和缓解中展现出良好的应用前景。本文综述了海洋硫酸多糖的种类,并从糖脂代谢和肠道微生物群的角度总结了海洋硫酸多糖在肥胖预防和缓解中的作用机制,提出了海洋硫酸多糖未来的研究和发展方向,以及为海洋硫酸多糖的进一步研究及市场化应用提供参考。     

Effects of gut microbiota on in vivo metabolism and tissue accumulation of cytochrome P450 3A metabolized drug: Midazolam

The link between drug-metabolizing enzymes and gut microbiota is well established. In particular, hepatic cytochrome P450 (CYP) 3A activities are presumed to be affected by gut microbiota. However, there is no direct evidence that the gut microbiota affects CYP3A metabolism or the clearance of clinically relevant drugs in vivo. Our purpose was to evaluate the effects of gut microbiota on in vitro and in vivo drug metabolism and on the clearance of midazolam, which is a standard CYP3A metabolized drug. Hepatic Cyp3a activity and in vitro midazolam hydroxylase activity were compared using specific pathogen-free (SPF) and germ-free (GF) mice. In a pharmacokinetics (PK) study, SPF and GF mice were intraperitoneally injected with 60 mg/kg of midazolam, and plasma and tissue concentrations were measured. Hepatic Cyp3a activity and midazolam hydroxylase activity were significantly lower in GF mice than in SPF mice. Notably, in the PK study, the area under the plasma concentration–time curve from time zero to infinity and the elimination half-life were approximately four-fold higher in GF mice compared with SPF mice. Furthermore, the concentration of midazolam in the brain 180 min after administration was about 14-fold higher in GF mice compared with SPF mice. Together, our results demonstrated that the gut microbiota altered the metabolic ability of Cyp3a and the tissue accumulation of midazolam.     

The role of gut microbiota in the modulation of drug action: a focus on some clinically significant issues

Introduction: A healthy gut microbiota is necessary for the normal operation of several body functions, including gastrointestinal sensitivity and motility, lipid and glucid metabolism, immune surveillance, and host behavior. In addition, intestinal bacteria contribute to determining the pharmacological properties of several drugs by producing different drug metabolizing enzymes.

Areas covered: Four enzymatic processes are discussed: prodrug activation; drug inactivation; drug deconjugation; and hydrolysis of natural glycosides with further metabolism of released aglycones. For each of these processes, a literature search has been undertaken on certain paradigmatic examples that have significant clinical implications: aminosalicylates and anthranoid laxatives; digoxin; irinotecan and non-steroidal anti-inflammatory drugs (NSAIDs); rutin, diosmin, and baicalin.

Expert commentary: The modulation of certain reactions catalyzed by gut bacterial enzymes may offer new opportunities to improve the clinical efficacy of drugs such as aminosalicylates, and natural glycosides by increasing their metabolic transformation, and of digoxin by reducing its inactivation, or to decrease the lower intestinal toxicity of irinotecan, and NSAIDs by inhibiting the hydrolytic cleavage of their conjugates. Randomized clinical trials are awaited to clarify whether new intervention strategies may modulate these processes and provide clinical benefits such as improved therapeutic outcomes and drug safety profiles.     

Cytochrome P450s and other enzymes in drug metabolism and toxicity

The cytochrome P450 (P450) enzymes are the major catalysts involved in the metabolism of drugs. Bioavailability and toxicity are 2 of the most common barriers in drug development today, and P450 and the conjugation enzymes can influence these effects. The toxicity of drugs can be considered in 5 contexts: on-target toxicity, hypersensitivity and immunological reactions, off-target pharmacology, bioactivation to reactive intermediates, and idiosyncratic drug reactions. The chemistry of bioactivation is reasonably well understood, but the mechanisms underlying biological responses are not. In the article we consider what fraction of drug toxicity actually involves metabolism, and we examine how species and human interindividual variations affect pharmacokinetics and toxicity.     

肠道菌群相关的抗抑郁治疗研究进展

目的 介绍肠道菌群与抑郁症的病理机制以及相关治疗的研究进展,为后续以肠道菌为靶点的抗抑郁药物的研发提供帮助。方法 查阅近年来肠道菌群与抑郁症方面的33篇中英文文献进行分类总结,从肠道菌群的门、科、属水平的角度探讨了抑郁状态下肠道菌群多样性的变化,从分子水平上阐述了肠道菌与抑郁症发病机制之间的关系,总结现有相关研究,进一步探索以肠道菌群为靶点进行药物研发治疗的可行性。结果 肠道菌紊乱与抑郁症之间相互作用,现有益生菌等生物制剂可通过改善肠道菌群病理状态下的紊乱对抑郁症治疗起到缓解作用。结论 肠道菌群失调与抑郁的发生密切相关,以肠道菌为靶点的相关药物研发治疗,可能成为治疗抑郁症的新途径。     

肠道菌群与2型糖尿病及益生菌关系的研究进展

糖尿病等代谢性疾病已经成为威胁人类社会和健康的重要问题之一。2型糖尿病患者肠道菌群与健康人不同,其中肠道菌群在其发生和发展过程中都发挥了巨大的作用。益生菌可以通过改善肠道通透性、增强机体免疫力等多种机制对2型糖尿病起到预防和改善作用。这一新兴的学术领域的飞速发展不但有助于阐明代谢性疾病的发病机制,而且将为探索新的治疗靶点和途径提供方向。     

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)

Variations in drug metabolism may alter drug efficacy and cause toxicity; better understanding of the mechanisms and risks shall help to practice precision medicine. At the 21^st International Symposium on Microsomes and Drug Oxidations held in Davis, California, USA, in October 2–6, 2016, a number of speakers reported some new findings and ongoing studies on the regulation mechanisms behind variable drug metabolism and toxicity, and discussed potential implications to personalized medications. A considerably insightful overview was provided on genetic and epigenetic regulation of gene expression involved in drug absorption, distribution, metabolism, and excretion (ADME) and drug response. Altered drug metabolism and disposition as well as molecular mechanisms among diseased and special populations were presented. In addition, the roles of gut microbiota in drug metabolism and toxicology as well as long non-coding RNAs in liver functions and diseases were discussed. These findings may offer new insights into improved understanding of ADME regulatory mechanisms and advance drug metabolism research.     

肠道菌群失衡与肠易激综合征

肠易激综合征（irritable bowel syndrome, IBS）是一种常见的功能性胃肠道疾病,其发病机制目前尚不完全清楚,但有越来越多的证据表明IBS可能与肠道菌群谱的改变有关。本文就IBS患者存在的结肠菌群失衡、小肠细菌过度生长及它们可能的致病机制,以及干预肠道菌群失衡等的治疗手段作一综述。     

Gut microbiota and lipid metabolism alterations in mice induced by oral cadmium telluride quantum dots

The potential toxicity of cadmium-containing quantum dots (QDs) has received much attention because of increasing biomedical applications. However, little has been known about how cadmium telluride (CdTe) QDs influence the gut microbiota and lipid metabolism. In this study, mice were exposed orally to CdTe QDs (200 μL of 0.2, 2, 20 or 200 μm ; twice per week) for 4 weeks. The oral experiments showed CdTe QD exposure led to a decrease of the Firmicutes/Bacteroidetes (F/B) ratio of gut microbiota, which highly negatively correlated with the low-density lipoprotein (LDL), triglyceride (TG) and total cholesterol (TC) levels in serum. In addition, the low-dose (0.2 and 2 μm ) CdTe QDs significantly increased the diversity of gut microbiota, and did not elevate the LDL, TG and TC levels in serum. The medium dose (20 μm ) of CdTe QDs caused the biggest decrease of the F/B ratio, so it significantly increased the LDL, TG and TC levels compared with the control. Furthermore, high-dose (200 μm ) CdTe QDs caused various toxicities in the histopathology of liver and intestine, liver function and intestinal immunity, but did not significantly lead to changes of the LDL, TG and TC levels in serum. This study demonstrates that high-dose oral CdTe QDs mainly lead to tissue damage of the liver and intestine, while the medium and low doses of oral CdTe QDs induce shifts of gut microbiota structure, which are associated with blood lipid levels.     

Variation in gut microbiota strongly influences individual rodent phenotypes.

Understanding genetic and phenotypic differences between experimentalanimals (both within a single population and between populationsheld at different sites) is potentially important in explainingvariability in responses to drugs and other stressors. Populationchanges in endogenous and exogenous metabolism in laboratoryanimal colonies have often been ascribed to genetic drift inthe experimental animals themselves. This undoubtedly occursin laboratory rodents; however, phenotypic drift in animal coloniescan have an immediate and potentially greater short term impacton normal physiological variation and mammalian metabolism,as exemplified by Robosky et al. in this issue of ToxicologicalSciences. They describe clear and stable metabolic differentiationof     

Gut microbiota: what is its place in pharmacology?

ABSTRACT

Introduction: In each section of the human gastrointestinal (GI) tract we may find bacteria that are adapted to local conditions and fulfill an important role in the proper functioning of the body. The gut microorganisms are crucial in human physiology in areas as diverse as the brain and the immune system functions. Therefore, there is a close relationship between the intestinal microbiota, its metabolic activity, and health of the host.

Areas covered: In this review, we explore the host–microbiome interactions and characterize the role they may play in drug metabolism and toxicity. The study is based on pertinent papers that were retrieved by a selective search using relevant keywords in PubMed and ScienceDirect databases.

Expert opinion: Increasing unhealthy eating habits, stress, antibiotic therapy, unfavorable environmental factors, and genetic predisposition contribute to imbalances in the composition and function of the GI tract microbes and the initiation and progression of disease processes. Restoration of the balanced gut microbiota composition is possible by oral administration of probiotics.     

靶向肠道菌群调控肠源尿毒素代谢通路干预慢性肾病进展的治疗策略分析

慢性肾病(chronic kidney disease, CKD)是一种发病率高、预后差、并发症复杂的重大慢性疾病,对人类健康造成极大危害。硫酸吲哚酚(indoxyl-sulfate, IS)和硫酸对甲酚(p-cresol sulfate, PCS)是两种典型的肠源尿毒素,由肠道菌群与宿主共代谢生成。随着慢性肾病的进展,慢性肾病患者体内的IS和PCS等肠源尿毒素不断蓄积,并进一步促进CKD进展。肠道菌群与CKD密切相关,靶向肠道菌群调控肠源尿毒素合成及代谢通路很可能是延缓CKD进展的新思路及新策略。本文通过对肠道菌群及肠源尿毒素与慢性肾病进展之间的关系进行分析,提出基于肠源尿毒素代谢调控干预慢性肾病进展的治疗策略。     

Review of mechanisms of deoxynivalenol‐induced anorexia: The role of gut microbiota

Deoxynivalenol (DON) is one of the most important mycotoxins in cereal‐based foods or other food productions, produced by Fusarium species . Because of the high occurrence of DON in food combined with vast consumption of cereals and grain worldwide, the DON‐contaminated food is a very harmful factor for human and animal health. DON has been reported to induce anorexia at lower or chronic doses in animal models. However, further researches for DON‐induced anorexia are limited. Previous publications demonstrated a close link between Bacteroidetes and Firmicutes , two kinds of gut microbiota, with weight loss and the effect of low administration of DON on neurotransmitters in the frontal cortex, cerebellum, hypothalamus, hippocampus and pons/medulla. These data are similar to other studies, which show selective 5HT_α receptor agonists apparently causing hyperphagia whereas 5HT_1β agonists appear to induce anorexia. Thus, the neurochemical effects of lower DON exposure can be as a result of peripheral toxicological events such as emesis, which overwhelmed its more subtle feed refusal activity. Besides, changes in the microbiota have an impact on stress‐related behaviors like anxiety and depression, which can lead to weight loss through decreased feed intake. Gut dysbiosis is also associated with brain dysfunction and with behavioral changes. These conclusions illustrate as well a potential explanation for DON‐induced anorexia.In this review, we summarize information about DON‐induced anorexia from previous studies and provide our opinion for future investigations that could establish a link between gut microbiota, neurotransmitters, anorexia and weight loss under the DON exposure. Copyright © 2017 John Wiley & Sons, Ltd.     

睡眠剥夺与肠道菌群紊乱的关系及改善睡眠药物研发的探讨

肠道菌群作为人体内一个复杂的微生态系统,在维持宿主生理功能上起非常重要的作用,也与许多代谢性疾病、免疫性疾病有着密切的关系。分析睡眠剥夺与肠道菌群紊乱相关性研究的提出和再提出,综合分析肠道菌群紊乱与睡眠障碍的关系,为以肠道菌群为靶点的改善睡眠药物开发及防治方法与思路提供参考。     

基于肠道菌群探讨甘草泻心汤对伊立替康致小鼠腹泻的影响

目的 研究甘草泻心汤对化疗相关腹泻小鼠肠道菌群的影响。方法 将小鼠随机分为对照组、模型组、洛哌丁胺（阳性药,0.4 mg·kg^-1）组和甘草泻心汤高、低剂量（16.4、4.1 g·kg^-1）组;采用连续4 d ip 55 mg·kg^-1伊立替康诱导小鼠化疗相关腹泻模型;记录小鼠首次排便时间、稀便级、稀便率和腹泻指数;采用试剂盒测定小鼠肠道消化酶活力及炎症因子水平;采用高通量测序技术分析结肠内容物肠道菌群变化。结果 与对照组比较,模型组小鼠首次排便时间显著缩短（P<0.01）,稀便级、稀便率和腹泻指数显著升高（P<0.01）;消化酶乳酸脱氢酶（LDH）、淀粉酶（AMS）和脂肪酶（LPS）活力显著降低（P<0.01）;炎症因子白细胞介素1β （IL-1β）、环氧化酶2 （COX-2）、细胞间黏附分子1 （ICAM-1）和肿瘤坏死因子α （TNF-α）水平显著升高（P<0.01）;肠道菌群α多样性Simpson指数显著升高（P<0.05）;肠道菌群β多样性差异较大;变形菌门、梭杆菌门、变形菌纲、梭杆菌纲、肠杆菌目、梭杆菌目、拟杆菌科、丹毒丝菌科、埃格特菌科和拟杆菌属丰度显著升高（P<0.01）,Muribaculaceae和norank_f__Muribaculaceae丰度显著降低（P<0.01）。与模型组比较,甘草泻心汤高、低剂量组小鼠首次排便时间显著延长（P<0.05、0.01）、稀便率和腹泻指数显著降低（P<0.05、0.01）,高剂量组稀便级显著降低（P<0.01）;高、低剂量组各消化酶活力显著回升（P<0.05、0.01）;高、低剂量组各炎症因子水平显著降低（P<0.05、0.01）;高剂量组Simpson指数显著降低（P<0.05）,β多样性更趋近对照组,显著回调各优势物种丰度的显著性变化（P<0.05、0.01）。结论 甘草泻心汤对于伊立替康诱导的腹泻小鼠具有明显的治疗作用,可能是其通过调整腹泻小鼠肠道菌群实现。     

琥珀酸曲格列汀对2型糖尿病小鼠肠道菌群的改变

目的:研究琥珀酸曲格列汀对2型糖尿病小鼠肠道菌群的影响。方法:16S rRNA高通量测序法对健康组、T2DM组、琥珀酸曲格列汀组、磷酸西格列汀组小鼠肠道菌群进行测序,利用QIME对数据进行过滤,对物种进行分类和注释。对样品的Alpha多样性指数和Beta多样性指数进行了分析,比较4组的样本菌群丰富度和多样性。结果:结果表明健康组、T2DM组、琥珀酸曲格列汀组、磷酸西格列汀组小鼠肠道菌群结构差异具有统计学意义。与健康组相比,T2DM组的厚壁菌门与拟杆菌门的比值降低,与琥珀酸曲格列汀组比较,T2DM组的Cyanobacteria、Verrucomicrobia、Tenericutes差异具有统计学意义(P<0.05);T2DM组候选生物标志物可能是:Bacilli、Lactobacillales、Lactococcus、Streptococcaceae;琥珀酸曲格列汀组候选生物标志物可能是:Bacteroidia、Bacteroidetes、Bacteroidales、Prevotella、Paraprevotellaceae、Parabacteroides、Porphyromonadaceae;磷酸西格列汀组候选生物标志物可能是:Lactobacillus、Lactobacillaceae、Helicobacter。结论:使用琥珀酸曲格列汀改善小鼠肠道菌落,可能通过改善肠道菌群而达到降糖效果。