Functional effects of gut microbiota-derived metabolites in Alzheimer's disease

The precise causation of Alzheimer's disease (AD) is unknown, and the factors that contribute to its etiology are highly complicated. Numerous research has been conducted to investigate the potential impact of various factors to the risk of AD development or prevention against it. A growing body of evidence suggests to the importance of the gut microbiota-brain axis in the modulation of AD, which is characterized by altered gut microbiota composition. These changes can alter the production of microbial-derived metabolites, which may play a detrimental role in disease progression by being involved in cognitive decline, neurodegeneration, neuroinflammation, and accumulation of Aβ and tau. The focus of this review is on the relationship between the key metabolic products of the gut microbiota and AD pathogenesis in the brain. Understanding the action of microbial metabolites can open up new avenues for the development of AD treatment targets.     

Gut microbiota composition of Japanese macaques associates with extent of human encroachment

In recent decades, human–wildlife interaction and associated anthropogenic food provisioning has been increasing and becoming more severe due to fast population growth and urban development. Noting the role of the gut microbiome in host physiology like nutrition and health, it is thus essential to understand how human–wildlife interactions and availability of anthropogenic food in habitats can affect an animal's gut microbiome. This study, therefore, set out to examine the gut microbiota of Japanese macaques (Macaca fuscata) with varying accessibility to anthropogenic food and the possibility of using gut microbiota as indicator for macaques’ reliance on anthropogenic food. Using 16S ribosomal RNA gene sequencing, we described the microbial composition of Japanese macaques experiencing different types of human disturbance and anthropogenic food availability—captive, provisioned, crop‐raiding, and wild. In terms of alpha diversity, our results showed that observed richness of gut microbiota did not differ significantly between disturbance types but among collection sites, whereas Shannon diversity index differed by both disturbance types and sites. In terms of beta diversity, captive populations harbored the most distinctive gut microbial composition, and had the greatest difference compared with wild populations. Whereas for provisioned and crop‐raiding groups, the macaques exhibited intermediate microbiota between wild and captive. We identified several potential bacterial taxa at different taxonomic ranks whose abundance potentially could help in assessing macaques’ accessibility to anthropogenic food. This study revealed the flexibility of the gut microbiome of Japanese macaques and provided possible indices based on the gut microbiome profile in assessing macaques’ accessibility to/reliance on anthropogenic foods.     

"肠道微生物-肠道-脑轴"机制--肠道微生物干预神经退行性病变研究进展

肠道微生物是人体中最为庞大和复杂的微生物群落,其对机体的健康,尤其是中枢神经退行性病变具有重要调节作用。其中,"肠道微生物-肠道-脑轴"机制是肠道微生物干预中枢神经退行性病变的重要途径。该机制主要通过以下三种方式来调节大脑功能:一是肠道微生物直接产生神经递质通过肠神经细胞上行至中枢神经系统;二是肠道微生物代谢产物刺激肠内分泌细胞产生神经肽类和胃肠激素类物质,影响大脑功能;三是肠道微生物或其代谢产物直接刺激肠道免疫系统,产生干扰素类物质干扰大脑免疫反应。本文对"肠道微生物-肠道-脑轴"机制的概念及研究进展进行了详细的介绍,同时总结了有关肠道微生物与阿尔兹海默症、帕金森症和多发性硬化症等神经退行性疾病相互作用的相关文献。依据"肠道微生物-肠道-脑轴"机制,利用肠道微生物预防和治疗神经退行性病变,或将成为解决中枢神经系统疾病的新措施。     

肠道菌群-肠-脑-肌轴信号交流的研究进展

肠道菌群及其代谢产物在老年神经退行性疾病、胃肠道疾病以及肌肉骨骼系统性疾病的发病与康复中的作用越来越受到关注。肠道菌群及其代谢产物可通过免疫、内分泌和神经系统等多种途径调节大脑神经或肌肉骨骼系统功能;反之,肠道、大脑或肌肉骨骼系统也可通过炎症、代谢或线粒体通路作用于肠道系统,调节肠道菌群微生态,形成肠道菌群与肠-脑、肠-肌、 肠-脑-肌之间的双向信号交流机制,从而影响机体健康。因此,本综述总结了肠道菌群如何通过代谢产物、肠道通透性和免疫-神经通路建立起肠-脑-肌之间的相互联系,为促进大脑神经的可塑性和改善肌肉健康提供新思路。     

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。     

Are you what you eat? A highly transient and prey‐influenced gut microbiome in the grey house spider Badumna longinqua

Stable core microbial communities have been described in numerous animal species and are commonly associated with fitness benefits for their hosts. Recent research, however, highlights examples of species whose microbiota are transient and environmentally derived. Here, we test the effect of diet on gut microbial community assembly in the spider Badumna longinqua. Using 16S rRNA gene amplicon sequencing combined with quantitative PCR, we analyzed diversity and abundance of the spider's gut microbes, and simultaneously characterized its prey communities using nuclear rRNA markers. We found a clear correlation between community similarity of the spider's insect prey and gut microbial DNA, suggesting that microbiome assembly is primarily diet‐driven. This assumption is supported by a feeding experiment, in which two types of prey—crickets and fruit flies—both substantially altered microbial diversity and community similarity between spiders, but did so in different ways. After cricket consumption, numerous cricket‐derived microbes appeared in the spider's gut, resulting in a rapid homogenization of microbial communities among spiders. In contrast, few prey‐associated bacteria were detected after consumption of fruit flies; instead, the microbial community was remodelled by environmentally sourced microbes, or abundance shifts of rare taxa in the spider's gut. The reshaping of the microbiota by both prey taxa mimicked a stable core microbiome in the spiders for several weeks post feeding. Our results suggest that the spider's gut microbiome undergoes pronounced temporal fluctuations, that its assembly is dictated by the consumed prey, and that different prey taxa may remodel the microbiota in drastically different ways.     

益生菌对特应性皮炎的防治及机制研究进展

特应性皮炎(atopic dermatitis, AD)是一种以反复发作和严重瘙痒为特征、发病率最高的过敏性皮肤病。AD的致病机制涉及遗传易感性、表皮屏障功能障碍、微生物组失调、免疫反应失衡以及环境等多个因素,而现有治疗用药副作用大、疗效欠佳。目前研究已发现肠道菌群尤其是益生菌在AD中起着重要作用。益生菌能够通过抑制病原菌、增强屏障功能、改善肠道环境和平衡Th1/Th2免疫应答等机制改善AD症状。本文综述了AD患者皮肤及肠道微生态特征,基于AD发病的致病机制和影响因素,系统阐明益生菌缓解AD的机制,以期为益生菌治疗AD及相关皮肤过敏性疾病提供理论支持。     

Patients with Infections of The Central Nervous System Have Lowered Gut Microbiota Alpha Diversity

There are multiple lines of evidence for the existence of communication between the central nervous system (CNS), gut, and intestinal microbiome. Despite extensive analysis conducted on various neurological disorders, the gut microbiome was not yet analyzed in neuroinfections. In the current study, we analyzed the gut microbiome in 47 consecutive patients hospitalized with neuroinfection (26 patients had viral encephalitis/meningitis; 8 patients had bacterial meningitis) and in 20 matched for age and gender health controls. Using the QIIME pipeline, 16S rRNA sequencing and classification into operational taxonomic units (OTUs) were performed on the earliest stool sample available. Bacterial taxa such as Clostridium, Anaerostipes, Lachnobacterium, Lachnospira, and Roseburia were decreased in patients with neuroinfection when compared to controls. Alpha diversity metrics showed lower within-sample diversity in patients with neuroinfections, though there were no differences in beta diversity. Furthermore, there was no significant change by short-term (1–3 days) antibiotic treatment on the gut microbiota, although alpha diversity metrics, such as Chao1 and Shannon’s index, were close to being statistically significant. The cause of differences between patients with neuroinfections and controls is unclear and could be due to inflammation accompanying the disease; however, the effect of diet modification and/or hospitalization cannot be excluded.     

肠道菌群及其代谢产物对心肌纤维化影响与治疗的研究进展

心肌纤维化是多种心血管疾病,如冠心病、心肌梗死和心力衰竭等的终末期表现和主要致病因素。研究发现,免疫和炎症过程在心肌纤维化的发病机制中起决定性作用。近年来,人们发现肠道微生物在心肌纤维化的发病机制和发展中起着至关重要的作用。肠道菌群的失调可导致微生物的代谢产物转移到血液循环中,如短链脂肪酸、脂多糖和氧化三甲胺等。这些代谢物直接或间接地诱导组织损伤免疫和激活全身炎症反应,进而影响心肌纤维化。如何改变肠道菌群来改善心肌纤维化已成为当前的研究重点,包括饮食干预、使用抗生素、补充益生菌和益生元,以及粪便微生物群移植等。本综述旨在回顾肠道菌群及其代谢产物与心肌纤维化的相互作用,介绍通过干预肠道菌群改善心肌纤维化的研究进展,为心肌纤维化的治疗提供新思路。     

Interrelationship between the 5-lipoxygenase pathway and microbial dysbiosis in the progression of Alzheimer's disease

Alzheimer's disease (AD) is an age-related neurodegenerative disorder involving neurofibrillary tangles and amyloid plaques. The tau phosphorylation responsible for neurofibrillary tangles and amyloid deposition which causes plaques are both accelerated through the activity of 5-lipoxygenase (5-LO). In addition to these pathological pathways, 5-LO has also been linked to the neuro-inflammation associated with disease progression as well as to dysbiosis in the gut. Interestingly, gut dysbiosis itself has been correlated to AD development. Not only do gut metabolites have direct effects on the brain, but pro-inflammatory mediators such as LPS, BMAA and bacterial amyloids produced in the gut due to dysbiosis reach the brain causing increased neuro-inflammation. While microbial dysbiosis and 5-LO exert detrimental effects in the brain, the cause/effect relationship between these factors remain unknown. These issues may be addressed using mouse models of AD in the context of different knockout mice in the 5-LO pathway in specific pathogen-free, germ-free as well as gnotobiotic conditions.     

Fecal metabolite of a gnotobiotic mouse transplanted with gut microbiota from a patient with Alzheimer’s disease

ABSTRACT

Studies of Alzheimer’s disease are based on model mice that have been altered by transgenesis and other techniques to elicit pathogenesis. However, changes in the gut microbiota were recently suggested to diminish cognitive function in patients, as well as in model mice. Accordingly, we have created model mice of the human gut microbiota by transplanting germ-free C57BL/6N mice with fecal samples from a healthy volunteer and from an affected patient. These humanized mice were stably colonized and reproduced the bacterial diversity in donors. Remarkably, performance on Object Location Test and Object Recognition Test was significantly reduced in the latter than in the former at 55 weeks of age, suggesting that gut microbiota transplanted from an affected patient affects mouse behavior. In addition, metabolites related to the nervous system, including γ-aminobutyrate, taurine, and valine, were significantly less abundant in the feces of mice transplanted with microbiota from the affected patient.     

The Effects and Mechanisms of Flavonoids on Cancer Prevention and Therapy: Focus on Gut Microbiota

Flavonoids are a group of polyphenolic compounds which are ubiquitously found in plants and are consumed as part of the human diet in substantial amounts. The verification of flavonoids'' cancer chemopreventive benefits has led to a significant interest in this field. Gut microbiota includes a diverse community of microorganisms and has a close relationship with cancer development. Increasing evidence has indicated that flavonoids exert anticarcinogenic effects by reshaping gut microbiota. Gut microbiota can convert flavonoids into bioactive metabolites that possess anticancer activity. Here, we present a brief introduction to gut microbiota and provide an overview of the interplay between gut microbiota and cancer pathogenesis. We also highlight the crucial roles of flavonoids in preventing cancer based on their regulation of gut microbiota. This review would encourage research on the flavonoid-intestinal microbiota interactions and clinical trials to validate the chemotherapeutic potentials of targeting gut microbiota by dietary bioactive compounds.     

Exploring the bovine rumen bacterial community from birth to adulthood

The mammalian gut microbiota is essential in shaping many of its host''s functional attributes. One such microbiota resides in the bovine digestive tract in a compartment termed as the rumen. The rumen microbiota is necessary for the proper physiological development of the rumen and for the animal''s ability to digest and convert plant mass into food products, making it highly significant to humans. The establishment of this microbial population and the changes occurring with the host''s age are important for understanding this key microbial community. Despite its importance, little information about colonization of the microbial populations in newborn animals, and the gradual changes occurring thereafter, exists. Here, we characterized the overall bovine ruminal bacterial populations of five age groups, from 1-day-old calves to 2-year-old cows. We describe the changes occurring in the rumen ecosystem after birth, reflected by a decline in aerobic and facultative anaerobic taxa and an increase in anaerobic ones. Some rumen bacteria that are essential for mature rumen function could be detected as early as 1 day after birth, long before the rumen is active or even before ingestion of plant material occurs. The diversity and within-group similarity increased with age, suggesting a more diverse but homogeneous and specific mature community, compared with the more heterogeneous and less diverse primary community. In addition, a convergence toward a mature bacterial arrangement with age was observed. These findings have also been reported for human gut microbiota, suggesting that similar forces drive the establishment of gut microbiotas in these two distinct mammalian digestive systems.     

The role of the gut microbiome and its metabolites in metabolic diseases

It is well known that an unhealthy lifestyle is a major risk factor for metabolic diseases,while in recent years,accumulating evidence has demonstrated that the gut microbiome and its metabolites also play a crucial role in the onset and development of many metabolic dis-eases,including obesity,type 2 diabetes,nonalcoholic fatty liver disease,cardiovascular disease and so on.Numerous microorganisms dwell in the gastrointestinal tract,which is a key interface for energy acquisition and can metabolize dietary nutrients into many bioactive substances,thus acting as a link between the gut microbiome and its host.The gut microbiome is shaped by host genetics,immune responses and dietary fac-tors.The metabolic and immune potential of the gut microbiome determines its significance in host health and diseases.Therefore,targeting the gut microbiome and relevant metabolic pathways would be effective therapeutic treatments for many metabolic diseases in the near future.This review will summarize information about the role of the gut microbiome in organism metabolism and the relationship between gut micro-biome-derived metabolites and the pathogenesis of many metabolic diseases.Furthermore,recent advan-ces in improving metabolic diseases by regulating the gut microbiome will be discussed.     

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.     

Gut dysbacteriosis and intestinal disease: mechanism and treatment

The gut microbiome functions like an endocrine organ, generating bioactive metabolites, enzymes or small molecules that can impact host physiology. Gut dysbacteriosis is associated with many intestinal diseases including (but not limited to) inflammatory bowel disease, primary sclerosing cholangitis-IBD, irritable bowel syndrome, chronic constipation, osmotic diarrhoea and colorectal cancer. The potential pathogenic mechanism of gut dysbacteriosis associated with intestinal diseases includes the alteration of composition of gut microbiota as well as the gut microbiota–derived signalling molecules. The many correlations between the latter and the susceptibility for intestinal diseases has placed a spotlight on the gut microbiome as a potential novel target for therapeutics. Currently, faecal microbial transplantation, dietary interventions, use of probiotics, prebiotics and drugs are the major therapeutic tools utilized to impact dysbacteriosis and associated intestinal diseases. In this review, we systematically summarized the role of intestinal microbiome in the occurrence and development of intestinal diseases. The potential mechanism of the complex interplay between gut dysbacteriosis and intestinal diseases, and the treatment methods are also highlighted.     

Alzheimer’s disease and gut microbiota

Alzheimer’s disease (AD) is a most common neurodegenerative disorder, which associates with impaired cognition. Gut microbiota can modulate host brain function and behavior via microbiota-gut-brain axis, including cognitive behavior. Germ-free animals, antibiotics, probiotics intervention and diet can induce alterations of gut microbiota and gut physiology and also host cognitive behavior, increasing or decreasing risks of AD. The increased permeability of intestine and blood-brain barrier induced by gut microbiota disturbance will increase the incidence of neurodegeneration disorders. Gut microbial metabolites and their effects on host neurochemical changes may increase or decrease the risk of AD. Pathogenic microbes infection will also increase the risk of AD, and meanwhile, the onset of AD support the “hygiene hypothesis”. All the results suggest that AD may begin in the gut, and is closely related to the imbalance of gut microbiota. Modulation of gut microbiota through personalized diet or beneficial microbiota intervention will probably become a new treatment for AD.     

Metabolically similar cohorts of bacteria exhibit strong cooccurrence patterns with diet items and eukaryotic microbes in lizard guts

Gut microbiomes perform essential services for their hosts, including helping them to digest food and manage pathogens and parasites. Performing these services requires a diverse and constantly changing set of metabolic functions from the bacteria in the microbiome. The metabolic repertoire of the microbiome is ultimately dependent on the outcomes of the ecological interactions of its member microbes, as these interactions in part determine the taxonomic composition of the microbiome. The ecological processes that underpin the microbiome's ability to handle a variety of metabolic challenges might involve rapid turnover of the gut microbiome in response to new metabolic challenges, or it might entail maintaining sufficient diversity in the microbiome that any new metabolic demands can be met from an existing set of bacteria. To differentiate between these scenarios, we examine the gut bacteria and resident eukaryotes of two generalist‐insectivore lizards, while simultaneously identifying the arthropod prey each lizard was digesting at the time of sampling. We find that the cohorts of bacteria that occur significantly more or less often than expected with arthropod diet items or eukaryotes include bacterial species that are highly similar to each other metabolically. This pattern in the bacterial microbiome could represent an early step in the taxonomic shifts in bacterial microbiome that occur when host lineages change their diet niche over evolutionary timescales.     

Rapidly expanding knowledge on the role of the gut microbiome in health and disease

The human gut is colonized by a wide diversity of micro-organisms, which are now known to play a key role in the human host by regulating metabolic functions and immune homeostasis. Many studies have indicated that the genomes of our gut microbiota, known as the gut microbiome or our “other genome” could play an important role in immune-related, complex diseases, and growing evidence supports a causal role for gut microbiota in regulating predisposition to diseases. A comprehensive analysis of the human gut microbiome is thus important to unravel the exact mechanisms by which the gut microbiota are involved in health and disease. Recent advances in next-generation sequencing technology, along with the development of metagenomics and bioinformatics tools, have provided opportunities to characterize the microbial communities. Furthermore, studies using germ-free animals have shed light on how the gut microbiota are involved in autoimmunity. In this review we describe the different approaches used to characterize the human microbiome, review current knowledge about the gut microbiome, and discuss the role of gut microbiota in immune homeostasis and autoimmunity. Finally, we indicate how this knowledge could be used to improve human health by manipulating the gut microbiota. This article is part of a Special Issue entitled: From Genome to Function.     

On the origin of species: Factors shaping the establishment of infant's gut microbiota

The human gut microbiota is a complex and dynamic ecosystem, which naturally lives in a symbiotic relationship with the host. Perturbations of the microbial composition (dysbiosis) and reduced diversity may promote disease susceptibility and recurrence. In contrast to the mature intestinal microbiota of healthy adults, which appears relatively stable over time, the infant's microbiome only establishes and matures during the first years of life. In this respect, early childhood seems to represent a crucial age‐window in disease prevention, since microbial diversification and maturation of the microbiome primarily occurs during this period of life. A better understanding of ecological processes and pioneer consortia in microbial development is crucial, in order to support the development of a beneficial microbiota. Various deterministic and stochastic aspects seem to shape the microbiome in early life, including maternal, environmental, and host factors. Here, we review the current understanding of the origin of pioneer bacteria and the evolutionary factors that influence the development of the gut microbiota in infants. In addition, future perspectives, including manipulating and promoting the succession of initial bacteria during infancy, will be highlighted. Birth Defects Research (Part C) 105:240–251, 2015. © 2015 Wiley Periodicals, Inc.