从肠道菌群角度认识阿尔茨海默病的潜在发病机制

过去10年中,人们逐渐认识到肠道微生物群的多样性及菌群平衡在维护宿主健康中发挥的作用。肠道微生物及其代谢产物通过一系列的生化、免疫和生理功能环节与宿主进行交流,从而影响宿主的稳态和健康。阿尔茨海默病(Alzheimer’s disease,AD)是一种复杂的神经退行性疾病,其易感性和发展过程受年龄、遗传和表观遗传等因素的影响。研究发现,肠道微生物群的紊乱(组成改变和易位)与神经系统疾病(AD)有关,胃肠道通过肠脑轴与中枢神经系统进行沟通,包括对神经的直接作用、内分泌途径和免疫调控方式。动物模型、粪便菌群移植及益生菌干预为肠道菌群与AD的相关性提供了证据。外漏的细菌代谢产物可能直接损害神经元功能,也可能诱发神经炎症,促进AD的发病。本文主要综述了肠道微生物群与AD的关联和作用机制,以期为通过改善肠道菌群结构预防AD的可能干预措施提供依据。     

Salmonella enterica Serovar Typhimurium Exploits Inflammation to Compete with the Intestinal Microbiota

Most mucosal surfaces of the mammalian body are colonized by microbial communities (“microbiota”). A high density of commensal microbiota inhabits the intestine and shields from infection (“colonization resistance”). The virulence strategies allowing enteropathogenic bacteria to successfully compete with the microbiota and overcome colonization resistance are poorly understood. Here, we investigated manipulation of the intestinal microbiota by the enteropathogenic bacterium Salmonella enterica subspecies 1 serovar Typhimurium (S. Tm) in a mouse colitis model: we found that inflammatory host responses induced by S. Tm changed microbiota composition and suppressed its growth. In contrast to wild-type S. Tm, an avirulent invGsseD mutant failing to trigger colitis was outcompeted by the microbiota. This competitive defect was reverted if inflammation was provided concomitantly by mixed infection with wild-type S. Tm or in mice (IL10^−/−, VILLIN-HA^CL4-CD8) with inflammatory bowel disease. Thus, inflammation is necessary and sufficient for overcoming colonization resistance. This reveals a new concept in infectious disease: in contrast to current thinking, inflammation is not always detrimental for the pathogen. Triggering the host's immune defence can shift the balance between the protective microbiota and the pathogen in favour of the pathogen.     

The gut microbiota and its interactions with cardiovascular disease

The intestine is colonized by a considerable community of microorganisms that cohabits within the host and plays a critical role in maintaining host homeostasis. Recently, accumulating evidence has revealed that the gut microbial ecology plays a pivotal role in the occurrence and development of cardiovascular disease (CVD). Moreover, the effects of imbalances in microbe–host interactions on homeostasis can lead to the progression of CVD. Alterations in the composition of gut flora and disruptions in gut microbial metabolism are implicated in the pathogenesis of CVD. Furthermore, the gut microbiota functions like an endocrine organ that produces bioactive metabolites, including trimethylamine/trimethylamine N-oxide, short-chain fatty acids and bile acids, which are also involved in host health and disease via numerous pathways. Thus, the gut microbiota and its metabolic pathways have attracted growing attention as a therapeutic target for CVD treatment. The fundamental purpose of this review was to summarize recent studies that have illustrated the complex interactions between the gut microbiota, their metabolites and the development of common CVD, as well as the effects of gut dysbiosis on CVD risk factors. Moreover, we systematically discuss the normal physiology of gut microbiota and potential therapeutic strategies targeting gut microbiota to prevent and treat CVD.     

Interactions between multiple helminths and the gut microbiota in wild rodents

The gut microbiota is vital to host health and, as such, it is important to elucidate the mechanisms altering its composition and diversity. Intestinal helminths are host immunomodulators and have evolved both temporally and spatially in close association with the gut microbiota, resulting in potential mechanistic interplay. Host–helminth and host–microbiota interactions are comparatively well-examined, unlike microbiota–helminth relationships, which typically focus on experimental infection with a single helminth species in laboratory animals. Here, in addition to a review of the literature on helminth–microbiota interactions, we examined empirically the association between microbiota diversity and composition and natural infection of multiple helminth species in wild mice (Apodemus flavicollis), using 16S rRNA gene catalogues (metataxonomics). In general, helminth presence is linked with high microbiota diversity, which may confer health benefits to the host. Within our wild rodent system variation in the composition and abundance of gut microbial taxa associated with helminths was specific to each helminth species and occurred both up- and downstream of a given helminth''s niche (gut position). The most pronounced helminth–microbiota association was between the presence of tapeworms in the small intestine and increased S24–7 (Bacteroidetes) family in the stomach. Helminths clearly have the potential to alter gut homeostasis. Free-living rodents with a diverse helminth community offer a useful model system that enables both correlative (this study) and manipulative inference to elucidate helminth–microbiota interactions.     

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。     

蜜蜂肠道菌群结构功能研究进展

在长期的共同进化中,肠道菌群与其宿主形成了紧密的联系,为宿主提供了许多有益的作用。作为一种社会性昆虫,蜜蜂的生活习性为其肠道菌群提供了良好而稳定的传播途径,因此,蜜蜂与其肠道菌群形成了一种紧密的互惠互利共生关系。近年来,随着对蜜蜂肠道菌群了解的不断加深,对蜜蜂肠道菌群功能的研究也不断深入,大量研究表明蜜蜂的肠道菌群在宿主食物的消化代谢、宿主免疫的激活和抵抗致病菌、调节宿主生理等方面都有着重要的作用,同时破坏肠道菌群的稳定对蜜蜂的健康有着明显的负面影响。本文对近年来西方蜜蜂肠道菌群功能研究进行了总结,旨在为进一步深入探索蜜蜂肠道菌群与其宿主的相互作用及在养蜂生产上应用肠道菌群防控疾病提供参考。     

Diet drives convergent evolution of gut microbiomes in bamboo-eating species

Gut microbiota plays a critical role in host physiology and health. The coevolution between the host and its gut microbes facilitates animal adaptation to its specific ecological niche. Multiple factors such as host diet and phylogeny modulate the structure and function of gut microbiota. However, the relative contribution of each factor in shaping the structure of gut microbiota remains unclear. The giant(Ailuropoda melanoleuca) and red(Ailurus styani) pandas belong to different families of order Carnivora. They have evolved as obligate bamboo-feeders and can be used as a model system for studying the gut microbiome convergent evolution. Here, we compare the structure and function of gut microbiota of the two pandas with their carnivorous relatives using 16S rRNA and metagenome sequencing. We found that both panda species share more similarities in their gut microbiota structure with each other than each species shares with its carnivorous relatives. This indicates that the specialized herbivorous diet rather than host phylogeny is the dominant driver of gut microbiome convergence within Arctoidea.Metagenomic analysis revealed that the symbiotic gut microbiota of both pandas possesses a high level of starch and sucrose metabolism and vitamin B12 biosynthesis. These findings suggest a diet-driven convergence of gut microbiomes and provide new insight into host-microbiota coevolution of these endangered species.     

A metabolomic view of how the human gut microbiota impacts the host metabolome using humanized and gnotobiotic mice

Defining the functional status of host-associated microbial ecosystems has proven challenging owing to the vast number of predicted genes within the microbiome and relatively poor understanding of community dynamics and community–host interaction. Metabolomic approaches, in which a large number of small molecule metabolites can be defined in a biological sample, offer a promising avenue to ‘fingerprint'' microbiota functional status. Here, we examined the effects of the human gut microbiota on the fecal and urinary metabolome of a humanized (HUM) mouse using an optimized ultra performance liquid chromatography–mass spectrometry-based method. Differences between HUM and conventional mouse urine and fecal metabolomic profiles support host-specific aspects of the microbiota''s metabolomic contribution, consistent with distinct microbial compositions. Comparison of microbiota composition and metabolome of mice humanized with different human donors revealed that the vast majority of metabolomic features observed in donor samples are produced in the corresponding HUM mice, and individual-specific features suggest ‘personalized'' aspects of functionality can be reconstituted in mice. Feeding the mice a defined, custom diet resulted in modification of the metabolite signatures, illustrating that host diet provides an avenue for altering gut microbiota functionality, which in turn can be monitored via metabolomics. Using a defined model microbiota consisting of one or two species, we show that simplified communities can drive major changes in the host metabolomic profile. Our results demonstrate that metabolomics constitutes a powerful avenue for functional characterization of the intestinal microbiota and its interaction with the host.     

番茄红素调控肠道菌群对健康影响的研究进展北大核心

番茄红素(lycopene)在番茄中含量丰富,具有多种功能活性和营养价值,探讨番茄红素调控肠道菌群对健康的影响有助于深入理解番茄红素的健康效应和作用机制。本文综述了番茄红素的理化性质及其消化、吸收、代谢,重点阐述了番茄红素对宿主肠道菌群种类、数量和代谢产物的影响,以及在番茄红素调控作用下肠道菌群对宿主炎症、心血管疾病、非酒精性脂肪肝和癌症发展的干预作用。该综述为未来番茄营养探索及产品开发提供了思路和方向。     

Environmental filtering increases with elevation for the assembly of gut microbiota in wild pikas

Despite their important roles in host nutrition, metabolism and adaptability, the knowledge on how the mammalian gut microbial community assemble is relatively scanty, especially regarding the ecological mechanisms that govern microbiota along environmental gradients. To address this, we surveyed the diversity, function and ecological processes of gut microbiota in the wild plateau pika, Ochotona curzoniae, along the elevational gradient from 3106 to 4331 m on ‘the Roof of the World’—Qinghai-Tibet Plateau. The results indicated that the alpha, beta and functional diversity of gut microbiota significantly increased with elevation, and elevation significantly explained the variations in the gut microbial communities, even after controlling for geographical distance, host sex and body weight. Some gene functions (e.g. nitrogen metabolism and protein kinases) associated with metabolism were enriched in the high-altitude pikas. Null model and phylogenetic analysis suggest that the relative contributions of environmental filtering responsible for local gut communities increased with elevation. In addition, deterministic processes dominated gut microbial communities in the high-altitude (more than 3694 m) pikas, while the percentages of stochastic and deterministic processes were very close in the low-altitude (3106 and 3580 m) pikas. The observed mechanisms that influence pika gut microbiota assembly and function seemed to be mainly mediated by the internal gut environment and by the external environmental pressure (i.e. lower temperature) in the harsh high-altitude environment. These findings enhance our understanding of gut microbiota assembly patterns and function in wild mammals from extreme harsh environments.     

蜜蜂肠道菌群定殖研究进展

肠道菌群在其宿主健康中发挥着各种各样的重要功能。蜜蜂是高度社会化的昆虫,其肠道菌群与大多数昆虫明显不同,由兼性厌氧和微好氧的细菌组成,具有高度保守性和专门的核心肠道微生物群。近年来的研究表明,蜜蜂肠道微生物群在代谢、免疫功能、生长发育以及保护机体免受病原体侵袭等方面起着重要作用,并已证实肠道微生物在蜜蜂健康和疾病中起着重要作用,肠道微生物群的破坏对蜜蜂健康会产生不利影响。本文综述了蜜蜂肠道菌群的特征及菌群定殖研究进展,介绍了蜜蜂的日龄、群体、季节等对蜜蜂肠道菌群定殖的影响,探讨了宿主的功能和新陈代谢对肠道菌群的影响。     

Comparison of the Distal Gut Microbiota from People and Animals in Africa

The gut microbiota plays a key role in the maintenance of healthy gut function as well as many other aspects of health. High-throughput sequence analyses have revealed the composition of the gut microbiota, showing that there is a core signature to the human gut microbiota, as well as variation in its composition between people. The gut microbiota of animals is also being investigated. We are interested in the relationship between bacterial taxa of the human gut microbiota and those in the gut microbiota of domestic and semi-wild animals. While it is clear that some human gut bacterial pathogens come from animals (showing that human – animal transmission occurs), the extent to which the usually non-pathogenic commensal taxa are shared between humans and animals has not been explored. To investigate this we compared the distal gut microbiota of humans, cattle and semi-captive chimpanzees in communities that are geographically sympatric in Uganda. The gut microbiotas of these three host species could be distinguished by the different proportions of bacterial taxa present. We defined multiple operational taxonomic units (OTUs) by sequence similarity and found evidence that some OTUs were common between human, cattle and chimpanzees, with the largest number of shared OTUs occurring between chimpanzees and humans, as might be expected with their close physiological similarity. These results show the potential for the sharing of usually commensal bacterial taxa between humans and other animals. This suggests that further investigation of this phenomenon is needed to fully understand how it drives the composition of human and animal gut microbiotas.     

Transient adult microbiota,gut homeostasis and longevity: Novel insights from the Drosophila model

In the last decade, Drosophila has emerged as a useful model to study host–microbiota interactions, creating an active research field with prolific publications. In the last 2 years, several studies contributed to a better understanding of the dynamic nature of microbiota composition and its impact on gut immunity and intestinal tissue homeostasis. These studies depicted the mechanisms by which microbiota regulates gut homeostasis to modulate host fitness and lifespan. Moreover, the latest findings demonstrating that the gut is a physiologically and histologically compartmentalized organ brought fresh perspectives to study the region-specific nature of the interactions between the commensal microbes and the intestinal tissue, and consequences of these interactions on overall host biology.     

Gut microbiota,inflammation, and molecular signatures of host response to infection

Gut microbial dysbiosis has been linked to many noncommunicable diseases. However, little is known about specific gut microbiota composition and its correlated metabolites associated with molecular signatures underlying host response to infection. Here, we describe the construction of a proteomic risk score based on 20 blood proteomic biomarkers, which have recently been identified as molecular signatures predicting the progression of the COVID-19. We demonstrate that in our cohort of 990 healthy individuals without infection, this proteomic risk score is positively associated with proinflammatory cytokines mainly among older, but not younger, individuals. We further discover that a core set of gut microbiota can accurately predict the above proteomic biomarkers among 301 individuals using a machine learning model and that these gut microbiota features are highly correlated with proinflammatory cytokines in another independent set of 366 individuals. Fecal metabolomics analysis suggests potential amino acid-related pathways linking gut microbiota to host metabolism and inflammation. Overall, our multi-omics analyses suggest that gut microbiota composition and function are closely related to inflammation and molecular signatures of host response to infection among healthy individuals. These results may provide novel insights into the cross-talk between gut microbiota and host immune system.     

Current understanding of microbiota- and dietary-therapies for treating inflammatory bowel disease

Inflammatory bowel disease (IBD) is a result of chronic inflammation caused, in some part, by dysbiosis of intestinal microbiota, mainly commensal bacteria. Gut dysbiosis can be caused by multiple factors, including abnormal immune responses which might be related to genetic susceptibility, infection, western dietary habits, and administration of antibiotics. Consequently, the disease itself is characterized as having multiple causes, etiologies, and severities. Recent studies have identified >200 IBD risk loci in the host. It has been postulated that gut microbiota interact with these risk loci resulting in dysbiosis, and this subsequently leads to the development of IBD. Typical gut microbiota in IBD patients are characterized with decrease in species richness and many of the commensal, and beneficial, fecal bacteria such as Firmicutes and Bacteroidetes and an increase or bloom of Proteobacteria. However, at this time, cause and effect relationships have not been rigorously established. While treatments of IBD usually includes medications such as corticosteroids, 5-aminosalicylates, antibiotics, immunomodulators, and anti-TNF agents, restoration of gut dysbiosis seems to be a safer and more sustainable approach. Bacteriotherapies (now called microbiota therapies) and dietary interventions are effective way to modulate gut microbiota. In this review, we summarize factors involved in IBD and studies attempted to treat IBD with probiotics. We also discuss the potential use of microbiota therapies as one promising approach in treating IBD. As therapies based on the modulation of gut microbiota becomes more common, future studies should include individual gut microbiota differences to develop personalized therapy for IBD.     

土壤动物肠道微生物多样性研究进展

随着分子生物学技术方法的快速发展,动物肠道微生物已成为医学、动物生理学与微生物生态学等研究领域热点。土壤动物种类繁多,分布广泛,其作为陆地生态系统重要组分,是驱动生态系统功能的关键因子。土壤动物体内的微生物由于与宿主长期共存,在与宿主协同进化中形成了丰富多样的群落结构,能够影响土壤动物本身的健康,进而介导土壤动物生态功能的实现。近些年,土壤动物肠道微生物工作方兴未艾,日渐得到重视。总结了四个部分内容：1)首先总结了土壤动物肠道微生物多样性领域的研究现状,该领域年发文量逐年增长,且近十年增长快速。土壤模式生物肠道微生物多样性研究较多且更为深入。土壤动物肠道微生物多样性组成与驱动机制、共存机制及群落构建的理论研究是该领域前沿;2)进而展示了土壤动物肠道微生物多样性组成和研究方法,土壤动物肠道菌群组成以变形菌门、厚壁菌门、放线菌门和拟杆菌门为主。早期工作基于传统分离培养,近年来新一代测序技术推动了该领域发展;3)接着关注了土壤动物肠道微生物的生态学功能,总体上体现在肠道微生物能帮助宿主分解食物基质、参与营养利用、影响寿命和繁殖及提高宿主免疫能力,且其能够影响土壤动物的气体排放及介导其对生态系...     

Host adaptive immunity alters gut microbiota

It has long been recognized that the mammalian gut microbiota has a role in the development and activation of the host immune system. Much less is known on how host immunity regulates the gut microbiota. Here we investigated the role of adaptive immunity on the mouse distal gut microbial composition by sequencing 16 S rRNA genes from microbiota of immunodeficient Rag1^−/− mice, versus wild-type mice, under the same housing environment. To detect possible interactions among immunological status, age and variability from anatomical sites, we analyzed samples from the cecum, colon, colonic mucus and feces before and after weaning. High-throughput sequencing showed that Firmicutes, Bacteroidetes and Verrucomicrobia dominated mouse gut bacterial communities. Rag1⁻ mice had a distinct microbiota that was phylogenetically different from wild-type mice. In particular, the bacterium Akkermansia muciniphila was highly enriched in Rag1^−/− mice compared with the wild type. This enrichment was suppressed when Rag1^−/− mice received bone marrows from wild-type mice. The microbial community diversity increased with age, albeit the magnitude depended on Rag1 status. In addition, Rag1^−/− mice had a higher gain in microbiota richness and evenness with increase in age compared with wild-type mice, possibly due to the lack of pressure from the adaptive immune system. Our results suggest that adaptive immunity has a pervasive role in regulating gut microbiota''s composition and diversity.     

Major shifts in gut microbiota during development and its relationship to growth in ostriches

The development of gut microbiota during ontogeny is emerging as an important process influencing physiology, immunity and fitness in vertebrates. However, knowledge of how bacteria colonize the juvenile gut, how this is influenced by changes in the diversity of gut bacteria and to what extent this influences host fitness, particularly in nonmodel organisms, is lacking. Here we used 16S rRNA gene sequencing to describe the successional development of the faecal microbiome in ostriches (Struthio camelus, n = 66, repeatedly sampled) over the first 3 months of life and its relationship to growth. We found a gradual increase in microbial diversity with age that involved multiple colonization and extinction events and a major taxonomic shift in bacteria that coincided with the cessation of yolk absorption. Comparisons with the microbiota of adults (n = 5) revealed that the chicks became more similar in their microbial diversity and composition to adults as they aged. There was a five‐fold difference in juvenile growth during development, and growth during the first week of age was strongly positively correlated with the abundance of the genus Bacteroides and negatively correlated with Akkermansia. After the first week, the abundances of six phylogenetically diverse families (Peptococcaceae, S24‐7, Verrucomicrobiae, Anaeroplasmataceae, Streptococcaceae, Methanobacteriaceae) were associated with subsequent reductions in chick growth in an age‐specific and transient manner. These results have broad implications for our understanding of the development of gut microbiota and its associations with animal growth.