肠上皮与肠道微生物相互作用研究进展

肠道不仅是消化和吸收的主要场所,也是机体重要的免疫器官。人类肠道中存在着超过百万亿的微生物,其在漫长的自然选择及共同进化中与宿主形成了紧密的共生关系。肠上皮是先天免疫的一个组成部分,通过各种黏膜保护屏障将肠腔内容物与机体内环境分隔开。各种肠上皮细胞相互协调维持肠道内稳态,并与肠道微生物、肠黏膜免疫系统共同形成抵御肠腔内有害抗原的第一道防线。肠上皮作为肠道微生物和肠黏膜免疫系统相互作用的枢纽,在黏膜免疫防御体系中具有重要作用,本文就肠上皮与肠道微生物之间的相互作用进行综述,旨在深入理解肠上皮,为探索肠道相关疾病的治疗提供新思路。     

肠道微生物群与药物相互作用的研究进展

药物的代谢是机体对药物处置过程的关键步骤,而肠道作为机体中重要的微生态系统,其在药物代谢方面的作用至关重要。肠道微生物群能够对各种药物等外源化合物进行生物转化、积累,并改变这些物质的活性和毒性,从而影响宿主机体对它们的反应。肠道微生物群与药物之间的相互作用相当复杂,亟待更多更加深入、全面的发掘和研究。近年来,随着人们对肠道微生物群代谢及其与药物互作关系,肠道菌-宿主共代谢认知的不断深化,越来越多的研究表明肠道微生物在药代动力学中扮演重要角色。本文通过调研、整理、归纳和总结国内外相关文献资料,对机体肠道微生物的分类、功能,几种常用药物对肠道微生物的影响以及肠道菌群对药物的代谢作用效果与几个主要的机制进行了梳理和综述,并讨论了微生物和药物之间的双向互作。有利于增进对微生物群影响药物疗效及其代谢途径和机制的了解,提高调控肠道微生物改善治疗的可能性,为指导临床合理用药、精准用药、个体化治疗、药物的评价和新药研发等提供科学参考。     

鱼类肠道微生物与宿主免疫系统相互作用研究进展

鱼类肠道中存在大量微生物,对于维持宿主健康具有重要作用。鱼类免疫系统能够监视并调控肠道微生物组成,维持肠道菌群稳态。同时,鱼类肠道共生微生物调节鱼类免疫系统,抑制病原微生物的过度增殖,保证宿主的健康。本文回顾了鱼类肠道微生物与宿主免疫系统相互作用的研究进展,重点介绍了宿主免疫系统识别肠道微生物、塑造肠道菌群以及益生菌对宿主免疫和肠道菌群的调控等,提出了理想的益生菌应该来自动物自身胃肠道,生产中应谨慎选用非宿主来源的益生菌,以期为推动鱼类肠道功能微生物开发和应用提供理论支撑。     

肠道微生物与慢性病

肠道微生物在长期进化过程中与人类形成了共生关系,对人类的生理代谢、生长发育、免疫应答和对疾病的抵抗力、衰老等,都起着不可忽视的作用,它们影响着每个人的健康.最新的研究进展表明,结构异常的肠道菌群很可能是肥胖、高血压、糖尿病等慢性病的直接诱因.     

寄生虫与肠道微生物群落的相互作用

近年来有关肠道菌群的研究不胜枚举,肠道菌群从人类出生开始一直到生命结束都一直伴随着宿主,并在宿主的身体中发挥着重要作用。肠道菌群不仅直接参与宿主肠道内大分子物质的消化、小分子物质的吸收、肠道机体正常代谢和肠道内的免疫系统的调节,还能抵抗某些病原体的侵袭,甚至被称为"另一人类机体系统"。寄生虫学作为一个古老而又重要的科目,人类对于它的探索亦从未停止。近年来国内外学者关于肠道菌群与寄生虫之间关系的研究逐渐增多,寄生虫对肠道菌群的正向反馈作用正成为研究热点。本文就近年来国内外学者有关寄生虫与肠道菌群相互关系和作用的研究进展作一综述。     

肠道微生物与人体健康研究进展

人类肠道中定居着许多对宿主有益的微生物,包括细菌、病毒、真核生物等,它们在肠道内能与其他微生物及免疫系统相互作用,对人体健康具有重要影响,被称为"被遗忘的器官",它们的基因组也被誉为人类的"第二基因组",与人体的能量代谢及物质代谢有关。本文总结了人体肠道中病毒、真核生物、细菌和宿主免疫系统的相互作用,微生物群的失衡可能导致的疾病如肥胖和克罗恩病等,以及微生物环境在人体内的成熟过程,期望有助于诊断和治疗与肠道微生物失衡相关的疾病。     

苯丙氨酸在宿主和肠道微生物中的代谢研究进展

肠道微生物是宿主生理活动的重要参与者,与宿主的健康和疾病密切相关。研究表明,肠道微生物代谢产物是饮食诱导宿主－微生物相互作用的关键介质,这些代谢产物由微生物直接产生或由环境和宿主中相关分子的代谢转化产生。宿主和肠道微生物之间的化学对话是影响宿主生理的重要环节,对这些代谢途径和信号通路的研究可以进一步揭示微生物代谢与宿主的相互作用机制。芳香族氨基酸包括苯丙氨酸、酪氨酸和色氨酸,是宿主－微生物相互作用的重要信号分子,在胃肠道和远隔器官中发挥着重要的调节作用。本文就苯丙氨酸与肠道微生物的最新研究进展进行综述,重点阐述苯丙氨酸在宿主和肠道微生物中的代谢情况。

     

肠道微生物菌群对脑及行为的影响

肠道微生物菌群组成的变化对正常生理的影响及其在疾病中的作用逐渐成为研究热点。肠道微生物菌群通过脑肠轴影响宿主生理学的各个方面,包括脑-肠交流、脑功能甚至行为。对无菌动物、被致病细菌感染的、使用益生菌或用抗生素药物的动物研究表明,肠道微生物菌群可以调节宿主焦虑样症状及行为。研究表明对肠道微生物菌群的调节可能是治疗复杂中枢神经系统失调症的新策略。     

单胃动物肠道微生物菌群与肠道免疫功能的相互作用

动物胃肠道栖息着大量的微生物,这些微生物及其代谢产物在营养、免疫等方面对宿主的健康有重要的意义。近年来研究发现肠道微生物与免疫系统间存在密切的交流和互作机制,尽管肠道共生菌具有定植抑制效应,但肠道微生物也可通过其特定组分刺激免疫细胞如Tregs细胞、Th17细胞的分化,肠道菌群的紊乱可能导致细菌移位、肠道屏障功能损伤,影响机体健康。宿主免疫系统可通过分泌多种免疫效应因子如MUC、sIgA、ITF、RegIIIγ、α-防御素等调节肠道微生物的分布和组成,调节肠道菌群的稳态。本文综述了单胃动物肠道微生物菌群的组成,深入探讨了肠道微生物菌群与动物肠道免疫功能之间的相互作用。     

肠道微生物群落与炎症性肠病关系研究进展

目的炎症性肠病（IBD）包括克罗恩病（CD）和溃疡性结肠炎（UC）,以持续性肠道非特异性炎症为特征,通常反复发作、迁延不愈,临床上仍无特效性的治疗手段。IBD确切的发病机制尚不清楚,涉及免疫、环境及遗传等因素,这些因素共同诱导肠道炎症、黏膜损伤和修复。肠道微生物群落及其代谢产物、宿主基因易感性及肠道黏膜免疫三方面共同参与了IBD的发病机制。本文从消化道微生态角度出发,对目前IBD相关的肠道微生物群落研究现状、宿主-微生物间免疫应答及益生菌治疗等内容进行探讨。     

Murine intestinal organoids resemble intestinal epithelium in their microRNA profiles

Intestinal organoids were established as an ex vivo model of the intestinal epithelium. We investigated whether organoids resemble the intestinal epithelium in their microRNA (miRNA) profiles. Total RNA samples were obtained from crypt and villus fractions in murine intestine and from cultured organoids. Microarray analysis showed that organoids largely resembled intestinal epithelial cells in their miRNA profiles. In silico prediction followed by qRT-PCR suggested that six genes are regulated by corresponding miRNAs along the crypt-villus axis, suggesting miRNA regulation of epithelial cell renewal in the intestine. However, such expression patterns of miRNAs and their target mRNAs were not reproduced during organoids maturation. This might be due to lack of luminal factors and endocrine, nervous, and immune systems in organoids and different cell populations between in vivo epithelium and organoids. Nevertheless, we propose that intestinal organoids provide a useful in vitro model to investigate miRNA expression in intestinal epithelial cells.     

Innate immune signalling at the intestinal epithelium in homeostasis and disease

The intestinal epithelium-which constitutes the interface between the enteric microbiota and host tissues-actively contributes to the maintenance of mucosal homeostasis and defends against pathogenic microbes. The recognition of conserved microbial products by cytosolic or transmembrane pattern recognition receptors in epithelial cells initiates signal transduction and influences effector cell function. However, the signalling pathways, effector molecules and regulatory mechanisms involved are not yet fully understood, and the functional outcome is poorly defined. This review analyses the complex and dynamic role of intestinal epithelial innate immune recognition and signalling, on the basis of results in intestinal epithelial cell-specific transgene or gene-deficient animals. This approach identifies specific epithelial cell functions within the diverse cellular composition of the mucosal tissue, in the presence of the complex and dynamic gut microbiota. These insights have thus provided a more comprehensive understanding of the role of the intestinal epithelium in innate immunity during homeostasis and disease.     

Alkaline phosphatase of basal lateral and brush border plasma membranes from intestinal epithelium

The alkaline phosphatases present on isolated brush border and basal lateral membranes of rat duodenal epitheilum were examined by means of a variety of biochemical assays and physical methods. The two alkaline phosphatases have similar pH optima of 9.6–9.8, similar substrate k_m's for p-nitrophenyl phosphate (PNPP) of 71 micromolar, similar responses to the inhibitors 2-mercaptoethanol, theophylline, phenylalanine, and ethylenediaminetetraacetic acid (EDTA), similar sensitivities to calcium, magnesium, zinc, sodium, and potassium, and similar insensitivities to digestion with trypsin or papain. The two enzymes also exhibit similar molecular weights on SDS-polyacrylamide gels in the range 124,000–150,000, and both enzymes show an R_f value of 0.092 on Triton X-100 polyacrylamide gels, indicating similar intrinsic charges. The V_max of the brush border enzyme is ten times greater than that of the basal lateral enzyme, 140 μmoles/mg-h as opposed to 14 μmoles/mg-h. The differences in V_max are a reflection of the known distribution of alkaline phosphatase in rat duodenum, there being more alkaline phosphatase activity present on the brush border than on the basal lateral surface. One other major difference was observed between the two enzymes, the stimulation of the basal lateral and not the brush border alkaline phosphatase by SDS, Triton X-100, or cholate. We conclude that the enzymes are very similar to one another and probably perform similar membrane functions.     

Gasdermin D (Gsdmd) is dispensable for mouse intestinal epithelium development

Members of the novel gene family Gasdermin (Gsdm) are exclusively expressed in a highly tissue-specific manner in the epithelium of skin and the gastrointestinal tract. Based on their expression patterns and the phenotype of the Gsdma3 spontaneous mutations, it is inferred that the Gsdm family genes are involved in epithelial cell growth and/or differentiations in different tissues. To investigate possible roles of the Gsdm gene family in the development of intestinal tracts, we generated a Gsdmd mutant mouse, which is a solitary member of the Gsdmd subfamily and which is predominantly expressed in the intestinal tract by means of targeted disruption. In the mutant homozygotes, we found no abnormality of intestinal tract morphology. Moreover, in mutant mice, there was normal differentiation of all constituent cell types of the intestinal epithelium. Thus, this study clearly shows that Gsdmd is not essential for development of mouse intestinal tract or epithelial cell differentiation.     

Canonical and noncanonical inflammasomes in intestinal epithelial cells

Inflammasomes are cytosolic, multimeric protein complexes capable of activating pro‐inflammatory cytokines such as IL‐1β and IL‐18, which play a key role in host defence. Inflammasome components are highly expressed in the intestinal epithelium. In recent years, studies have begun to demonstrate that epithelial‐intrinsic inflammasomes play a critical role in regulating epithelial homeostasis, both by defending the epithelium from pathogenic insult and through the regulation of the mucosal environment. However, the majority of research regarding inflammasome activation has focused on professional immune cells, such as macrophages. Here, we present an overview of the current understanding of inflammasome function in epithelial cells and at mucosal surfaces and, in particular, in the intestine.     

Stereological studies on the small intestinal epithelium of the rat

Summary Quantitative macroscopic, light-microscopic and electron-microscopic studies were performed on the small intestine of fasted and non-fasted adult, male Sprague-Dawley rats. In non-fasted rats the small intestine was longer than in fasted rats. Due to the presence of villi the surface area in the duodenum and the jejunum was enlarged about six times. The microvilli on the villous crests caused a surface enlargement by 13 times in the duodenum (value corrected for overestimation due to section thickness), and 19 times in the jejunum of the fasted rats. At the base of the villi these values were about 50% lower. It was calculated that, in the fasted rats, the total enlargement of the luminal surface area — due to villi and microvilli — was 63 times in the duodenum and 81 times in the jejunum (corrected for section thickness).Differences between the villous crest epithelium and the villous base epithelium were also found with regard to the mean cell height, and the volume densities of the absorptive cell nuclei, the mitochondria, and the paracellular channels.Supported by grants from the Swedish Medical Research Council (Project No. 12X-2298), from the Swedish Group-Insurance Co. Förenade Liv, from Tore Nilson's Fund for Medical Research and from the Medical Faculty, University of Umeå     

Uptake dynamics of scrapie agent in the intestinal villous epithelium of suckling and weanling Syrian hamsters

In mice, the number of intestinal villous columnar epithelium cells that incorporate abnormal prion protein (PrP(Sc) ) decreases significantly after weaning. In this study, the dynamics of PrP(Sc) uptake during the growth of hamsters were investigated by inoculating scrapie 263K agent orally into suckling and weanling Syrian hamsters and estimating the number of PrP(Sc) -positive villous epithelium cells immunohistochemically. The number of PrP(Sc) -positive cells declined significantly as the hamsters aged. The present results suggest that a tendency toward decline of PrP(Sc) -positive cells with increasing age might be a common phenomenon among the superfamily Muridae.     

Annual mitotic activity in the intestinal epithelium of the musselCrenomytilus grayanus

The seasonal dynamics of cell reproduction in the intestinal epithelium of the musselCrenomytilus grayanus are described in detail. Mitotic indices in the intestinal epithelium varied throughout the year from 0.005 to 0.26% (averaged data) and from 0.003 to 0.37% (individual data). Cyclic seasonal changes were found in the mussel’s intestinal epithelium. In general, the average values of mitotic activity in the intestinal epithelium were low (the mitotic index was 0.13%); there was a rise in activity in late April–June and September and a decline in July–August and especially in January–March. The winter-early spring period was characterized by a profound inhibition of cell reproduction and the transition of cells to the resting state. An outburst of proliferation occurred in the spring, due to a manifold increase in the number of cells in the mitotic cycle. The musselC. grayanus may be a good model for the study of the two extreme states of proliferation and their alternation in marine animals in nature. The diel dynamics of mitotic activity in the intestinal epithelium were followed during the most active growth period (May). The mitotic index (MI) varied during the day within a narrow range, deviating from the daily average value by no more than one third; no pronounced diel rhythm was found. Optimum water temperatures for cell reproduction ranged from 5 to 18°C.     

Interaction exists between matriptase inhibitors and intestinal epithelial cells

The type II trypsin-like transmembrane serine protease matriptase, is mainly expressed in epithelial cells and one of the key regulators in the formation and maintenance of epithelial barrier integrity. Therefore, we have studied the inhibition of matriptase in a non-transformed porcine intestinal IPEC-J2 cell monolayer cultured on polyester membrane inserts by the non-selective 4-(2-aminoethyl)-benzosulphonylfluoride (AEBSF) and four more selective 3-amidinophenylalanine-derived matriptase inhibitors. It was found that suppression of matriptase activity by MI-432 and MI-460 led to decreased transepithelial electrical resistance (TER) of the cell monolayer and to an enhanced transport of fluorescently labelled dextran, a marker for paracellular transport between apical and basolateral compartments. To this date this is the first report in which the inhibition of matriptase activity by synthetic inhibitors has been correlated to a reduced barrier integrity of a non-cancerous IPEC-J2 epithelial cell monolayer in order to describe interaction between matriptase activity and intestinal epithelium in vitro.