肠道菌介导的药物毒性及机制研究进展

药物毒性及机制研究是药物在临床安全使用的重要内容,备受关注。肠道菌群对药物的代谢转化、药效及作用机制具有重大意义,可作为代谢器官在物质信息传递、生物转化等方面发挥重要作用。然而,越来越多的研究发现,肠道菌与某些药物毒性密切相关。一方面,药物会在肠道菌的作用下转化成毒性代谢产物诱发药物的直接毒性;另一方面,肠道菌群会在药物的作用下改变组成和功能,导致内源性代谢通路的紊乱,进而使肠屏障受损而影响其他器官产生药物的间接毒性。本文总结了近年来由肠道菌引发的药物毒性的相关实例,探讨了肠道菌特征代谢酶可能是口服药物毒性产生的重要原因,并对未来肠道菌与药物毒性及机制研究进行了展望,为药物在临床的合理使用及新药的安全性评价提供了新见解。     

肠道菌群代谢药物研究进展

长期以来,由于肠道菌群本身的复杂性以及培养方法和分析技术的限制,肠道菌群在药物代谢和体内处置中的作用未得到应有的重视。近年来,随着技术的快速发展,围绕肠道菌群的大量研究将对肠道菌代谢和肠道菌-宿主共代谢的认识提高到前所未有的深度。肠道菌群不仅能够直接代谢许多药物,还通过宿主、菌群、药物之间复杂多维的相互作用间接改变药物代谢,从而影响个体对药物治疗的响应(效应、毒性、耐药性等)。肠道菌群结构及代谢功能受多种因素的影响。综述近期肠道菌群代谢药物研究领域的重要进展及研究趋势,以期推进精准治疗,促进药物发现及新的治疗策略的出现。     

肠道菌群与放疗敏感性及放射性黏膜炎关系的研究进展

肠道菌群在肿瘤治疗中的作用在近几年受到广泛关注，包括化疗及免疫治疗在内的抗肿瘤治疗疗效均受到肠道菌群的调节。放疗是抗肿瘤中的重要组成部分，其疗效及不良反应发生风险受到多种因素的影响。近期研究表明，肠道菌群通过调节机体免疫系统影响放疗敏感性以及放射性黏膜炎的严重程度。该文系统地回顾了描述肠道菌群调节放疗疗效及其黏膜毒性的研究，希望通过调节肠道菌群以提高放疗疗效并减轻放疗副反应。     

肠道菌群与健康、疾病和药物作用的影响

肠道菌群作为人体内一个复杂的微生态系统,在维持人体微生态的稳态中,肠道菌群在维持宿主生理功能具有上非常重要的作用,也对许多代谢性疾病、免疫性疾病以及肿瘤都有着密切的关系,且对于药物治疗合理安全有效具有重要意义。本文从正视存在人体的细菌的有益性和有害性、肠道菌群与健康和寿命、肠道菌群与疾病以及药物作用的影响等4方面分析和讨论。肠道菌群与不同类型药物的关系已经成为近些年的热点研究领域,本文分别讨论免疫治疗、化学药物、抗生素和中药的相关问题,希望为认识药物治疗过程、科学合理用药、认识药物作用机制、新药研究开发等研究有所参考。     

肠道菌群研究的转化潜能

肠道菌群研究是一个热门话题。随着高通量测序技术的进步,肠道菌群为疾病的发病机理、药物的作用机制、治疗的选择策略提供了突破口,揭示了肠道菌群研究的转化潜能。该文关注肠道菌群研究,突出我国在该领域的贡献,提出对菌群研究的粗浅看法。     

肠道菌群对某些疾病及药物疗效与毒性的影响

经过长期的协同进化,肠道菌群与宿主间形成了密切的共生关系,并对宿主的多种生理功能起着重要作用。在相关疾病的治疗过程中,药物对肠道菌群的影响以及肠道菌群对药物和疾病的影响相互交织,并有可能改变药物在体内的药动学过程及药效。综述药物、肠道菌群以及疾病三者间的相互作用与联系,提出利用药物调节肠道菌群以治疗相关疾病的思路,为现有药物的新药理作用的发现和以肠道菌群为作用靶点的新型药物的研发提供有益信息。     

肠道菌群与药物成瘾及相关神经精神疾病关系的研究进展

药物成瘾不仅严重损害成瘾者自身健康,还造成了巨大的社会经济负担。吸毒人数不断攀升,复吸率居高不下,严重威胁公共安全。药物成瘾是一种慢性脑病,替代药物治疗如美沙酮,非药物治疗如手术治疗、正念疗法、重复经颅磁刺激等,均不能有效降低成瘾者的心理渴求。目前药物成瘾的治疗方法存在很大局限性,治愈后复吸率高。寻找新的治疗药物和方法仍是药物成瘾的重要课题。近年来,肠道菌群与神经精神疾病相关的研究被大量报道,逐渐揭示了肠道菌群与中枢神经系统之间的联系,随着"微生物-肠-脑轴"的发现,肠道菌群在药物成瘾相关方面的研究也逐渐受到关注,通过查阅国内外文献,该文对肠道菌群与药物成瘾、肠道菌群与神经精神疾病的关系研究进展进行综述。     

肠道菌群对药物代谢影响的研究进展

肠道菌群是寄居在肠道的种类繁多、数量庞大的微生物群落,对药物等外来化合物的代谢至关重要,近年来肠道菌群作为机体"隐形器官"被广泛关注。通过查阅国内外相关文献,该文对机体中肠道菌群的分类、功能及其对中药化学成分和化学药物代谢的影响进行了分析、归纳和总结。了解肠道菌群对药物代谢的影响,明确药物转化过程,对于指导临床合理用药、个体化用药、毒理学评估及推动药物发现和研发具有重要意义,为后期研究高原环境下肠道菌群对药物代谢的影响提供理论指导。     

肠道菌群与降糖药物的关系

肠道菌群是寄生于人体肠道内微生物群落的总称,肠道菌群目前已成为医学界热门的课题。近年来全球2型糖尿病患病率逐年攀升,口服降糖药物是常用的治疗方法。有证据表明,口服降糖药物可能会改变肠道微生物组,从而改变胃肠道代谢物以改善宿主健康。尽管肠道菌群、菌群代谢物和2型糖尿病之间的联系很复杂,但了解降糖药物与肠道菌群的关系,对于优化治疗至关重要,对2型糖尿病中益生菌治疗和肠道菌群移植具有指导意义,现就肠道菌群与降糖药物之间的关系做一综述。     

抗菌药物致肠道菌群失调的机制及防治

抗菌药物对人体肠道微生态确有影响。本文综述了肠道菌群的生态学、抗菌药物对肠道菌群的影响、肠道菌群失调的机理与表现．以及微生态制剂在防治肠道菌群失调中的作用。合理应用微生态制剂可减少抗菌药物所致肠道菌群失调。     

Evaluation of pharmacokinetic differences of acetaminophen in pseudo germ-free rats

To evaluate the metabolic interaction between host and gut microflora on drug metabolism, pseudo germ‐free rats were prepared with an antibiotics cocktail to change their gut conditions. The usefulness of the pseudo germ‐free model was evaluated for observing the DMPK of acetaminophen (APAP). Pseudo germ‐free rats were prepared by orally administering antibiotic cocktails consisting of bacitracin, streptomycin and neomycin, and then APAP was orally administered to control and pseudo germ‐free rats. The plasma concentration of APAP and its six metabolites were quantified using a validated LC‐MS/MS method. A non‐compartment model estimated the pharmacokinetic parameters of APAP and its metabolites, and the ratios of the area under curve (AUC; AUC_metabolite/AUC_APAP) were also observed to evaluate the change of APAP metabolism. The AUCs of APAP and APAP‐Glth (glutathione) were higher and the AUC_APAP‐Sul/AUC_APAP (metabolic efficiency of sulfate conjugation) was lower in pseudo germ‐free rats than those in the control rats. The decrease in metabolic efficiency of sulphate conjugation could result from the reduction of the sulphate supply, causing an increase of the AUC of APAP and APAP‐Glth. The activities of gut microflora can affect the state of hepatic sulphate for drug conjugation, indirectly leading to characteristic APAP metabolism. These results indicate that gut microflora may play an important role in the pharmacokinetics and metabolism of APAP. Thus, the metabolic interaction between host and gut microflora should be considered upon drug administration and pseudo germ‐free rats prepared in the present study can be competent for investigating the metabolic interaction between host and gut microflora on drug metabolism. Copyright © 2012 John Wiley & Sons, Ltd.     

The influence of gut microbiota on drug metabolism and toxicity

Introduction: Gut microbiota plays critical roles in drug metabolism. The variation of gut microbiota contributes to the interindividual differences toward drug therapy including drug-induced toxicity and efficacy. Accordingly, the investigation and elucidation of gut microbial impacts on drug metabolism and toxicity will not only facilitate the way of personalized medicine, but also improve rational drug design.

Areas covered: This review provides an overview of the microbiota–host co-metabolism on drug metabolism and summarizes 30 clinical drugs that are co-metabolized by host and gut microbiota. Moreover, this review is specifically focused on elucidating the gut microbial modulation of some clinical drugs, in which the gut microbial influences on drug metabolism, drug-induced toxicity and efficacy are discussed.

Expert opinion: The gut microbial contribution to drug metabolism and toxicity is increasingly recognized, but remains largely unexplored due to the extremely complex relationship between gut microbiota and host. The mechanistic elucidation of gut microbiota in drug metabolism is critical before any practical progress in drug design or personalized medicine could be made by modulating human gut microbiota. Analytical technique innovation is urgently required to strengthen our capability in recognizing microbial functions, including metagenomics, metabolomics and the integration of multidisciplinary knowledge.     

Potential Implications of Gut Microbiota in Drug Pharmacokinetics and Bioavailability

Gut microbial communities are capable of enzymatically transforming pharmaceutical compounds into active, inactive, and toxic metabolites, thus potentially affecting the pharmacokinetics and bioavailability of orally administered medications. Our understanding of the impact and clinical relevance of how gut microbial communities can directly and indirectly affect drug metabolism and, ultimately, clinical outcomes, is limited. Interindividual variability of gut microbial composition may partially explain differences observed in drug efficacy and toxicity in certain patient populations. This review provides an overview of how gut microbial communities can potentially contribute to individual drug response. This review focuses on the current landscape of clinical and preclinical research that defines the microbiome contribution on medication response with the goal of improving medication efficacy and decreasing medication toxicity.     

Modulation of the human gut microflora towards improved health using prebiotics--assessment of efficacy

There is increasing awareness that the human gut microflora plays a critical role in maintaining host health, both within the gastrointestinal tract and, through the absorption of metabolites, systemically. An "optimal" gut microflora establishes an efficient barrier to the invasion and colonisation of the gut by pathogenic bacteria, produces a range of metabolic substrates which in turn are utilized by the host (e.g. vitamins and short chain fatty acids) and stimulates the immune system in a non-inflammatory manner. Although little is known about the individual species of bacteria responsible for these beneficial activities, it is generally accepted that the bifidobacteria and lactobacilli constitute important components of the beneficial gut microflora. A number of diet-based microflora management tools have been developed and refined over recent decades including probiotic, prebiotic and synbiotic approaches. Each aims to stimulate numbers and/or activities of the bifidobacteria and lactobacilli within the gut microflora. The aim of this article is to examine how prebiotics are being applied to the improvement of human health and to review the scientific evidence supporting their use.     

新生儿肺炎疗效及肠道微生态变化的研究

目的观察新生儿感染性肺炎常用的抗生素的疗效以及抗生素对肠道微生态的影响。方法以新生儿感染性肺炎患者为研究对象,按抗生素的使用不同而分组,以各项观察项目全部正常的时间作为肺炎病程终止时间,比较各观察组的治愈率并进行时间一效应分析。分析使用抗生素3、7d时肠道茵群中细菌的含量,以了解抗生素对肠道菌群影响情况。结果①青霉素组、头孢组、联合用药组的治愈率以及时间一效应分析的结果差异无显著性;②使用抗生素对新生儿肠道菌群有影响,其影响随着抗生素使用时间的增加而增大;③3个观察组对肠道微生态的影响以青霉素与头孢菌素联合使用组最为明显,头孢菌素组次之,青霉素组最小。结论治疗新生儿感染性肺炎,青霉素类抗生素的疗效不差于头孢类,仍值得推广应用。联合用药并不优于单用青霉素,抗生素使用种类越多,用药时间越长,对肠道微生态的影响越大,且以头孢类影响大于青霉素类。     

Metabolism of isoflavones and lignans by the gut microflora: a study in germ-free and human flora associated rats.

We have investigated the metabolism of isoflavones and lignans in germ-free (GF) rats and rats associated with human faecal bacteria (human flora associated [HFA] rats), in order to provide unequivocal evidence for the role of the gut microflora in the absorption and metabolism of these phytoestrogens. Furthermore, we have investigated whether certain metabolic characteristics (high equol-producing and low equol-producing status) of human intestinal floras can be transferred to GF rats. Germ-free rats fed a soy-isoflavone containing diet excreted large quantities of daidzein and genistein in urine indicating that the gut microflora is not required for the absorption of isoflavones. The isoflavone metabolites equol, O-desmethylangolensin and the lignan enterolactone were not detectable in urine from the GF rats, but were present in HFA rat urine, indicating that they were products of gut microflora activity. Colonization of GF rats with a faecal flora from a human subject with the capacity to convert daidzein to equol, resulted in the rats excreting substantial amounts of the metabolite. In contrast, equol was undetectable in urine of HFA rats associated with a faecal flora from a low equol-producing subject. The results therefore show that the inability of some subjects to produce equol is a consequence of the lack of specific components of the gut microflora.     

Theoretical relationships between area under the curve and route of administration of drugs and their precursors for evaluating sites and pathways of metabolism

The bioavailability of a drug administered extrasystemically is a measure of the initial extraction of a compound by a series of eliminating events involving the intestinal mucosal enzymes, the gut bacterial microflora, the liver, and the lung. A theoretical analysis is presented to differentiate the process of gut wall elimination and hepatic removal of a drug during this first-pass effect. The area under the blood concentration--time curve (AUC) for a drug and its metabolite is shown to be useful in determining the presence of these processes when a drug and its metabolite are administered concomitantly by different routes of administration. Furthermore, the fraction of a precursor transformed to its metabolite also can be determined by pharmacokinetic analysis of the AUC of a drug and its metabolite after administration of both substances.     

The pathogenic role of intestinal flora in IBD and colon cancer

The intestine is populated by a large variety of microorganisms that colonize the host soon after birth. The gut microflora contributes to several intestinal functions, including the development of the mucosal immune system, the absorption of complex macromolecules, the synthesis of amino acids and vitamins and the protection against pathogenic microorganisms. Its composition varies along the different segments of the gut, with a gradient from the stomach to the colon where it is more abundant. Given the vital relationship between the microflora and the intestinal function, it is important that the microflora is kept continuously under control so to preserve gut homeostasis. When this is not achieved or perturbed, several immune disorders can arise, like allergies or inflammation. Protracted immune deregulations can also lead to severe disorders including diabetes, cancer and inflammatory bowel disease (IBD). It is therefore crucial that the immune system learns both to tolerate and to control the growth of beneficial microorganisms so to preserve the intestinal homeostasis. The mechanisms that are in place to achieve this control are not yet understood but recent work has started to unravel the complex relationship between several players including the microflora, intestinal barriers and immune cells. In this review we will analyze how the microflora interacts with the host and how deregulation of this interaction can lead to inflammatory disorders and eventually also to cancer.