Paneth cells in intestinal homeostasis and tissue injury

Adult stem cell niches are often co-inhabited by cycling and quiescent stem cells. In the intestine, lineage tracing has identified Lgr5(+) cells as frequently cycling stem cells, whereas Bmi1(+), mTert(+), Hopx(+) and Lrig1(+) cells appear to be more quiescent. Here, we have applied a non-mutagenic and cell cycle independent approach to isolate and characterize small intestinal label-retaining cells (LRCs) persisting in the lower third of the crypt of Lieberkühn for up to 100 days. LRCs do not express markers of proliferation and of enterocyte, goblet or enteroendocrine differentiation, but are positive for Paneth cell markers. While during homeostasis, LR/Paneth cells appear to play a supportive role for Lgr5(+) stem cells as previously shown, upon tissue injury they switch to a proliferating state and in the process activate Bmi1 expression while silencing Paneth-specific genes. Hence, they are likely to contribute to the regenerative process following tissue insults such as chronic inflammation.     

肠道菌群与疾病发生及中草药调节和治疗作用的研究概述

肠道正常菌群及微生态稳定对人体极具重要性,中草药对肠道菌群具有调节作用.本文综述了人体的肠道正常菌群与疾病产生和发展的关系,结合中草药对肠道菌群调节作用的研究,探讨中药调节肠道菌群与其发挥疾病防治效果之间的相关性,以期为中草药的临床应用及药理学研究提供一定的参考依据.     

Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis

Building and maintaining a homeostatic relationship between a host and its colonizing microbiota entails ongoing complex interactions between the host and the microorganisms. The mucosal immune system, including epithelial cells, plays an essential part in negotiating this equilibrium. Paneth cells (specialized cells in the epithelium of the small intestine) are an important source of antimicrobial peptides in the intestine. These cells have become the focus of investigations that explore the mechanisms of host-microorganism homeostasis in the small intestine and its collapse in the processes of infection and chronic inflammation. In this Review, we provide an overview of the intestinal microbiota and describe the cell biology of Paneth cells, emphasizing the composition of their secretions and the roles of these cells in intestinal host defence and homeostasis. We also highlight the implications of Paneth cell dysfunction in susceptibility to chronic inflammatory bowel disease.     

Wnt signalling induces maturation of Paneth cells in intestinal crypts

Wnt signalling, which is transduced through beta-catenin/TCF4, maintains the undifferentiated state of intestinal crypt progenitor cells. Mutational activation of the pathway initiates the adenomacarcinoma sequence. Whereas all other differentiated epithelial cells migrate from the crypt onto the villus, Paneth cells home towards the source of Wnt signals--that is, the crypt bottom. Here, we show that expression of a Paneth gene programme is critically dependent on TCF4 in embryonic intestine. Moreover, conditional deletion of the Wnt receptor Frizzled-5 abrogates expression of these genes in Paneth cells in the adult intestine. Conversely, adenomas in Apc-mutant mice and colorectal cancers in humans inappropriately express these Paneth-cell genes. These observations imply that Wnt signals in the crypt can separately drive a stem-cell/progenitor gene programme and a Paneth-cell maturation programme. In intestinal cancer, both gene programmes are activated simultaneously.     

MicroRNA通过肠道菌群对绝经后骨质疏松症影响的机制探讨

胃肠道是营养和矿物质高效吸收的重要部位。研究显示胃肠道微生物群通过肠-骨轴对骨质量具有调节作用,其作用机制十分复杂,主要通过矿物质吸收、激素控制和免疫调节来实现。中药可以调节肠道菌群,起到治疗绝经后骨质疏松症的作用。近期研究发现,microRNA通过调节肠道微生物基因,改变肠道微生物的生理功能,从而调节骨代谢,影响绝经后骨质疏松症的发生与发展。本文就microRNA调节肠道菌群的研究现状作一综述,探讨绝经后骨质疏松症的调节机制,为绝经后骨质疏松症的肠道微生态研究提供一定的理论依据。     

中药"神曲"对肠道菌群失调小鼠调整和保护作用的观察

目的研究中药"神曲"在肠道微生态失调中的调整和保护作用.方法使用中药大黄煎剂给小鼠灌胃8 d,造成肠道菌群失调病理模型,将菌群失调小鼠分为5组模型组、自然恢复组、丽珠肠乐组、同仁堂神曲组和复方神曲组.实验动物经不同因素处理后,取结肠内容物、粪便进行菌群培养;取回肠组织进行各项病理指标的测定;取各组小鼠肝脏和结肠标本进行光镜观察.结果治疗组肠道菌群与正常对照组相比无明显变化,与自然恢复组相比差异有显著性(P＜0.05);各治疗组超氧化物歧化酶(superoxide dismutase,SOD)、丙二醛(methyl-di-alde-hyde,MDA)、黄嘌吟氧化酶(xanthine oxidase,XOD)和一氧化氮(NO)水平与正常组相比差异无显著性,与自然恢复组相比差异有显著性(P＜0.05);治疗组肝脏和结肠与正常对照组相比无明显变化,其与自然恢复组相比差异有显著性.结论中药"神曲"对肠道菌群失调动物具有调整和保护作用.     

Lgr4 is required for Paneth cell differentiation and maintenance of intestinal stem cells ex vivo

Gene inactivation of the orphan G protein-coupled receptor LGR4, a paralogue of the epithelial-stem-cell marker LGR5, results in a 50% decrease in epithelial cell proliferation and an 80% reduction in terminal differentiation of Paneth cells in postnatal mouse intestinal crypts. When cultured ex vivo, LGR4-deficient crypts or progenitors, but not LGR5-deficient progenitors, die rapidly with marked downregulation of stem-cell markers and Wnt target genes, including Lgr5. Partial rescue of this phenotype is achieved by addition of LiCl to the culture medium, but not Wnt agonists. Our results identify LGR4 as a permissive factor in the Wnt pathway in the intestine and, as such, as a potential target for intestinal cancer therapy.     

Paneth cells drive intestinal stem cell competition and clonality in aging and calorie restriction

Calorie restriction has been recently shown to increase intestinal stem cell competition and to reduce mutation fixation in young mice. However, the impact of aging on this process is unknown. By employing Confetti reporter mice, here we show that, unexpectedly, old mice have more intestinal stem cell (ISC) competition than young mice. Moreover, differently from what observed in young mice, calorie restriction, when applied at late-life, decreases this process. Importantly, we also observed a strong correlation between the ISC competition and Paneth cell number. In vivo analysis and in vitro organoid experiments indicated that Paneth cells play a major role in driving intestinal stem cell competition and crypt clonality. Taken together, our results provide evidence that increasing the number of Paneth cells can increase the number of competitive ISCs, representing a valuable therapeutic target to delay fixation of mutated intestinal stem cells.     

马齿苋多糖对衰老小鼠肠道微生态调节作用的研究

目的探讨中药马齿苋多糖对衰老小鼠微生态调节作用。方法皮下注射D-半乳糖建立衰老小鼠模型,用马齿苋多糖进行治疗,同时设正常对照组、阳性对照组和阴性对照组,用药30d后处死小鼠,进行肠道微生态指标检测。结果用D-半乳糖造模以后,小鼠肠道双歧杆菌及乳酸杆菌数量降低（P〈0．05）,而肠杆菌及肠球菌数量增加说明模型建立,血内毒素含量也升高（P〈0．05）。用马齿苋治疗后,益生菌数量升高而肠杆菌和肠球菌数量减少,血内毒素含量也降低（P〈0．05）。结论马齿苋多糖对衰老小鼠的肠道菌群和血内毒素具有调节作用。     

中药调节肠道菌群防治高血压的研究进展

肠道菌群是人体内环境的重要组成部分,可影响机体的代谢、免疫和炎症反应,与原发性高血压的发生发展密切相关,已成为防治高血压的研究热点。中药在临床用于原发性高血压的治疗且疗效显著。研究表明中药可被肠道菌群分解代谢为易于吸收的活性物质,而这些活性物质又可通过调节肠道菌群结构及其代谢产物防治高血压。本文以肠道菌群作为切入点,通过分析肠道菌群与原发性高血压发生发展的关系和中药在调节原发性高血压肠道菌群方面的研究,总结中药通过调节肠道菌群防治原发性高血压的作用和机制,以期为中药防治高血压及药物研发提供新的研究思路。     

A key role for E-cadherin in intestinal homeostasis and Paneth cell maturation

Background

E-cadherin is a major component of adherens junctions. Impaired expression of E-cadherin in the small intestine and colon has been linked to a disturbed intestinal homeostasis and barrier function. Down-regulation of E-cadherin is associated with the pathogenesis of infections with enteropathogenic bacteria and Crohn''s disease.

Methods and Findings

To genetically clarify the function of E-cadherin in intestinal homeostasis and maintenance of the epithelial defense line, the Cdh1 gene was conditionally inactivated in the mouse intestinal epithelium. Inactivation of the Cdh1 gene in the small intestine and colon resulted in bloody diarrhea associated with enhanced apoptosis and cell shedding, causing life-threatening disease within 6 days. Loss of E-cadherin led cells migrate faster along the crypt-villus axis and perturbed cellular differentiation. Maturation and positioning of goblet cells and Paneth cells, the main cell lineage of the intestinal innate immune system, was severely disturbed. The expression of anti-bacterial cryptidins was reduced and mice showed a deficiency in clearing enteropathogenic bacteria from the intestinal lumen.

Conclusion

These results highlight the central function of E-cadherin in the maintenance of two components of the intestinal epithelial defense: E-cadherin is required for the proper function of the intestinal epithelial lining by providing mechanical integrity and is a prerequisite for the proper maturation of Paneth and goblet cells.     

The intestinal flora: the scales without the sword

The intestine is colonised by a vast population of resident bacteria which have established mutualistic relationships with their host throughout evolution, progressing from commensalism to symbiotic interactions. Intestinal bacteria benefit from resources available in their host, but reciprocally provide advantages to their host, by supplying enzymatic activities not encoded in the host genome, by promoting maturation of the intestine and of the gut associated immune system as well as by modifying the host metabolism. The commensal bacteria, although deprived of pathogenic attributes, might however become a danger for the host in case of translocation, acquisition of pathogenic features or via the inappropriate activation of intestinal inflammation. Remarkably, the commensal flora promotes the onset of innate and adaptive immune defences which, in turn, allow to set up a subtle balance between the host and the flora that promotes the symbiosis.     

人体肠道菌群与高血压的研究进展

高血压是一种以血压升高为特征的疾病。除少数继发性高血压外,大多数高血压发生的病因至今尚未明确。近年来,越来越多的研究表明高血压的发生机制与肠道菌群有关。通过对最新的研究进行分析,发现膳食纤维、高盐摄入等因素可刺激肠道菌群,进而对高血压产生不同的影响。短链脂肪酸作为肠道菌群的发酵产物,是膳食纤维具有降血压作用的主要原因。高盐摄入导致高血压,是因为肠道菌群引起了免疫系统的改变。另外,高血压的形成也与肠道致病微生物的异质性炎症反应有关。此综述希望能为高血压的控制与防治提供新的科学依据与研究思路。     

肠道菌群与肠黏膜免疫及相关肠道疾病的研究进展

肠道菌群与肠黏膜免疫之间存在密切的关系,二者相互促进、相互影响,共同维持肠道微生态的平衡,二者失衡可造成肠道器质性及功能性的病变。对肠道菌群、肠黏膜免疫及相关肠道疾病的研究进展作一综述。     

Starving for more: Nutrient sensing by LIN-28 in adult intestinal progenitor cells

ABSTRACT

In this Extra View, we extend our recent work on the protein LIN-28 and its role in adult stem cell divisions. LIN-28 is an mRNA- and microRNA-binding protein that is conserved from worms to humans. When expressed ectopically, it promotes the reprogramming of differentiated vertebrate cells into pluripotent stem cells as well as the regeneration of vertebrate tissues after injury. However, its endogenous function in stem cell populations is less clear. We recently reported that LIN-28 is specifically expressed in progenitor cells in the adult Drosophila intestine and enhances insulin signaling within this population. Loss of lin-28 alters the division patterns of these progenitor cells, limiting the growth of the intestinal epithelium that is ordinarily caused by feeding. Thus, LIN-28 is part of an uncharacterized circuit used to remodel a tissue in response to environmental cues like nutrition. Here, we extend this analysis by reporting that the levels of LIN-28 in progenitor cells are sensitive to nutrient availability. In addition, we speculate about the role of LIN-28 in the translational control of target mRNAs such as Insulin Receptor (InR) and how such translational control may be an important mechanism that underlies the stem cell dynamics needed for tissue homeostasis and growth.