Microbes and the mind: emerging hallmarks of the gut microbiota–brain axis

The concept of a gut microbiota–brain axis has emerged to describe the complex and continuous signalling between the gut microbiota and host nervous system. This review examines key microbial‐derived neuromodulators and structural components that comprise the gut microbiota–brain axis. To conclude, we briefly identify current challenges in gut microbiota–brain research and suggest a framework to characterize these interactions. Here, we propose five emerging hallmarks of the gut microbiota–brain axis: (i) Indistinguishability, (ii) Emergence, (iii) Bidirectional Signalling, (iv) Critical Window Fluidity and (5) Neural Homeostasis.     

微生物-肠-脑轴的研究进展

肠道微生物群能够调节宿主肠道稳态,同时参与调节宿主神经系统功能和行为。肠道菌群失调可能导致宿主神经系统功能障碍,从而引发神经退行性疾病。因此,研究微生物在肠?脑轴中发挥的作用及其机制,靶向调控肠道微生物菌群结构和功能,将为神经系统疾病的诊断与治疗提供新的手段。近年来,有关肠道微生物与机体神经系统间的互作研究受到了广泛关注,然而其具体的调控机制还未明晰。因此,本文综述了肠道微生物对宿主神经健康的调节作用,以及肠道微生物与宿主间的互作在调节神经功能、行为的潜力等研究进展,为更好地了解肠道微生物在调控宿主神经系统功能和行为的作用机制提供参考。     

Nutritional modulation of the intestinal microbiota; future opportunities for the prevention and treatment of neuroimmune and neuroinflammatory disease

The gut–brain axis refers to the bidirectional communication between the enteric nervous system and the central nervous system. Mounting evidence supports the premise that the intestinal microbiota plays a pivotal role in its function and has led to the more common and perhaps more accurate term gut–microbiota–brain axis. Numerous studies have identified associations between an altered microbiome and neuroimmune and neuroinflammatory diseases. In most cases, it is unknown if these associations are cause or effect; notwithstanding, maintaining or restoring homeostasis of the microbiota may represent future opportunities when treating or preventing these diseases. In recent years, several studies have identified the diet as a primary contributing factor in shaping the composition of the gut microbiota and, in turn, the mucosal and systemic immune systems. In this review, we will discuss the potential opportunities and challenges with respect to modifying and shaping the microbiota through diet and nutrition in order to treat or prevent neuroimmune and neuroinflammatory disease.     

Living the high life: Could gut microbiota matter for adaptation to high altitude?

At high altitude, the reduced availability of thermal energy and oxygen poses major challenges to organisms. Different species or populations have evolved similar solutions to these challenges, such as blood flow regulation in animals (Bouverot, 1985). Previous studies investigating such convergent adaptations have primarily looked at changes in host genomes (e.g., see Scheinfeldt & Tishkoff, 2010), but have rarely considered the potential role of the gut microbiome in mediating host adaptation. As gut microbes can indirectly regulate host blood pressure (Pluznick, 2014) and energy intake efficiency, it has been hypothesized that they could help maintain normal energy production and/or optimize nutritional assimilation in high‐altitude hypoxic environments (e.g., Li & Zhao, 2015). However, it has been hard to (a) show that there is a direct effect of altitude on the gut microbiota, because of the many potential confounding effects of altitude (e.g., diet is correlated to altitude, as well as to the microbiome) and to (b) understand the mechanisms by which the microbiota could mediate host hypoxic and thermoregulatory stresses. In this issue of Molecular Ecology, Suzuki, Martins, and Nachman (2018) show that, independently of diet, taxonomic composition and functions of mouse gut microbiota converge in independent high‐altitude environments and propose the intriguing hypothesis that some of these functional convergences might be beneficial to their host.     

Gut Microbes and Health: A Focus on the Mechanisms Linking Microbes,Obesity, and Related Disorders

The past decade has been characterized by tremendous progress in the field of the gut microbiota and its impact on host metabolism. Although numerous studies show a strong relationship between the composition of gut microbiota and specific metabolic disorders associated with obesity, the key mechanisms are still being studied. The present review focuses on specific complex pathways as well as key interactions. For instance, the nervous routes are explored by examining the enteric nervous system, the vagus nerve, and the brain, as well as the endocrine routes (i.e., glucagon‐like peptide‐1, peptide YY, endocannabinoids) by which gut microbes communicate with the host. Moreover, the key metabolites involved in such specific interactions (e.g., short chain fatty acids, bile acids, neurotransmitters) as well as their targets (i.e., receptors, cell types, and organs) are briefly discussed. Finally, the review highlights the role of metabolic endotoxemia in the onset of metabolic disorders and the implications for alterations in gut microbiota‐host interactions and ultimately the onset of diseases.     

肠道微生物群在人类健康衰老中的作用机制研究进展北大核心

衰老的特征是组织器官的功能衰退以及衰老相关疾病风险的增加,这给维护和促进健康长寿带来一系列新的挑战。尽管进行了广泛的衰老相关研究,但进展有限。人们越来越意识到肠道微生物群的结构和功能积极参与了衰老过程。肠道微生物群紊乱表现为许多与年龄相关的肠外器官轴的衰老。肠道微生物群可以被调节,这暗示了通过肠道微生物群抗衰老是一个可以实现的重要目标。本综述总结了肠道微生物群在不同年龄段中的动态演替,这种动态的肠道微生物群从胎儿到出生和婴儿期开始迅速发展,从断奶期到幼儿期迅速变化,然后建立稳定的成年人菌群,直到随着年龄增长最后发生衰退;肠道微生物群与肠外器官轴(大脑、心脏、肝脏、胰腺、肌肉、皮肤和骨骼)衰老相关疾病,以及通过饮食、粪菌移植和微生态制剂调节肠道微生物群靶向抗衰老的研究进展,以期为调控肠道微生物群抗衰老研究提供参考。     

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。     

Microbial Metabolites and Intestinal Stem Cells Tune Intestinal Homeostasis

Microorganisms that colonize the gastrointestinal tract, collectively known as the gut microbiota, are known to produce small molecules and metabolites that significantly contribute to host intestinal development, functions, and homeostasis. Emerging insights from microbiome research reveal that gut microbiota‐derived signals and molecules influence another key player maintaining intestinal homeostasis—the intestinal stem cell niche, which regulates epithelial self‐renewal. In this review, the literature on gut microbiota‐host crosstalk is surveyed, highlighting the effects of gut microbial metabolites on intestinal stem cells. The production of various classes of metabolites, their actions on intestinal stem cells are discussed and, finally, how the production and function of metabolites are modulated by aging and dietary intake is commented upon.     

The role of gut microbiota in the gut-brain axis: current challenges and perspectives

Brain and the gastrointestinal (GI) tract are intimately connected to form a bidirectional neurohumoral communication system. The communication between gut and brain, knows as the gut-brain axis, is so well established that the functional status of gut is always related to the condition of brain. The researches on the gut-brain axis were traditionally focused on the psychological status affecting the function of the GI tract. However, recent evidences showed that gut microbiota communicates with the brain via the gut-brain axis to modulate brain development and behavioral phenotypes. These recent fi ndings on the new role of gut microbiota in the gut-brain axis implicate that gut microbiota could associate with brain functions as well as neurological diseases via the gut-brain axis. To elucidate the role of gut microbiota in the gut-brain axis, precise identification of the composition of microbes constituting gut microbiota is an essential step. However, identifi cation of microbes constituting gut microbiota has been the main technological challenge currently due to massive amount of intestinal microbes and the diffi culties in culture of gut microbes. Current methods for identifi cation of microbes constituting gut microbiota are dependent on omics analysis methods by using advanced high tech equipment. Here, we review the association of gut microbiota with the gut-brain axis, including the pros and cons of the current high throughput methods for identifi cation of microbes constituting gut microbiota to elucidate the role of gut microbiota in the gut-brain axis.     

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。     

A future perspective on neurodegenerative diseases: nasopharyngeal and gut microbiota

Neurodegenerative diseases are considered a serious life‐threatening issue regardless of age. Resulting nerve damage progressively affects important activities, such as movement, coordination, balance, breathing, speech and the functioning of vital organs. Reports on the subject have concluded that neurodegenerative disease can be caused by mutations of susceptible genes, alcohol consumption, toxins, chemicals and other unknown environmental factors. Although several diagnostic techniques can be used to determine aetiologies, the process is difficult and often fails. Research shows that nasopharyngeal and gut microbiota play important roles in brain to spinal cord coordination. However, no conclusive epidemiologic evidence is available on the roles played by respiratory and gut microbiota in the development of neurodegenerative diseases. Thus, understanding the connection between respiratory and gut microbiota and the nervous system could provide information on causal links. The present review describes future perspectives on the role played by nasopharyngeal and gut microbiota in the development of neurodegenerative diseases.     

The microbiome: stress,health and disease

Bacterial colonisation of the gut plays a major role in postnatal development and maturation of key systems that have the capacity to influence central nervous system (CNS) programming and signaling, including the immune and endocrine systems. Individually, these systems have been implicated in the neuropathology of many CNS disorders and collectively they form an important bidirectional pathway of communication between the microbiota and the brain in health and disease. Regulation of the microbiome–brain–gut axis is essential for maintaining homeostasis, including that of the CNS. Moreover, there is now expanding evidence for the view that commensal organisms within the gut play a role in early programming and later responsivity of the stress system. Research has focused on how the microbiota communicates with the CNS and thereby influences brain function. The routes of this communication are not fully elucidated but include neural, humoral, immune and metabolic pathways. This view is underpinned by studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic agents or antibiotics which indicate a role for the gut microbiota in the regulation of mood, cognition, pain and obesity. Thus, the concept of a microbiome–brain–gut axis is emerging which suggests that modulation of the gut microflora may be a tractable strategy for developing novel therapeutics for complex stress-related CNS disorders where there is a huge unmet medical need.     

The role of gut microbiota in pathogenesis of Alzheimer's disease

This paper describes the effects of the gut microbiota on the pathogenesis of Alzheimer's pathology by evaluating the current original key findings and identifying gaps in the knowledge required for validation. The diversity of the gut microbiota declines in the elderly and in patients with Alzheimer's disease (AD). Restoring the diversity with probiotic treatment alleviates the psychiatric and histopathological findings. This presents a problem: How does gut microbiota interact with the pathogenesis of AD? The starting point of this comprehensive review is addressing the role of bacterial metabolites and neurotransmitters in the brain under various conditions, ranging from a healthy state to ageing and disease. In the light of current literature, we describe three different linkages between the present gut microbiome hypothesis and the other major theories for the pathogenesis of AD as follows: bacterial metabolites and amyloids can trigger central nervous system inflammation and cerebrovascular degeneration; impaired gut microbiome flora inhibits the autophagy-mediated protein clearance process; and gut microbiomes can change the neurotransmitter levels in the brain through the vagal afferent fibres.     

Microbiota-gut-brain axis in autism spectrum disorder

Extensive studies, largely during the past decade, identify the dynamic and bidirectional interaction between the bacteria resident in the intestines and their host brain along the "microbiota-gut-brain axis". This interaction modulates the development and function of the central nervous system and is implicated in neurological disorders. As a neurodevelopmental disorder, autism spectrum disorder (ASD) is considered a historically defect in the brain. With accumulating evidence showing how the microorganisms modulate neural activities, more and more research is focusing on the role of the gut microbiota in mitigating ASD symptoms and the underlying mechanisms. In this review, we describe the intricate and crucial pathways via which the gut microbiota communicates with the brain, the microbiota-gut-brain axis, and summarize the specific pathways that mediate the crosstalk of the gut microbiota to the brain in ASD.     

Gutsy Moves: The Amygdala as a Critical Node in Microbiota to Brain Signaling

The amygdala is a key brain area regulating responses to stress and emotional stimuli, so improving our understanding of how it is regulated could offer novel strategies for treating disturbances in emotion regulation. As we review here, a growing body of evidence indicates that the gut microbiota may contribute to a range of amygdala‐dependent brain functions from pain sensitivity to social behavior, emotion regulation, and therefore, psychiatric health. In addition, it appears that the microbiota is necessary for normal development of the amygdala at both the structural and functional levels. While further investigations are needed to elucidate the exact mechanisms of microbiota‐to‐amygdala communication, ultimately, this work raises the intriguing possibility that the gut microbiota may become a viable treatment target in disorders associated with amygdala dysregulation, including visceral pain, post‐traumatic stress disorder, and beyond. Also see the video abstract here: https://youtu.be/O5gvxVJjX18     

Proteomics at the interface of psychology,gut physiology and dysfunction: an underexploited approach that deserves expansion

Gut functions such as digestion and absorption are essential to life and the emerging insights into the gut–brain axis – that is, the cross talk between the enteric and CNS – point towards critical links between (eating) behavior, psychology, whole body and gut physiology, and digestive and overall health. While proteomics is ideally positioned to shed more light on these interactions, be it applied to the periphery (e.g., blood) or the locus of action (i.e., the gut), it is to date largely underexploited, mainly because of challenging sampling and tissue complexity. In view of the contrast between potential and current delivery of proteomics in the context of intestinal health, this article briefs the reader on the state-of-the-art of molecular intestinal research, reviews current proteomic studies (explicitly focusing on the most recent ones that target inflammatory bowel disease patient samples) and argues for an expansion of this research field.     

Gut microbial diversity across a contact zone for California voles: Implications for lineage divergence of hosts and mitonuclear mismatch in the assembly of the mammalian gut microbiome

Gut microbial diversity is thought to reflect the co‐evolution of microbes and their hosts as well as current host‐specific attributes such as genetic background and environmental setting. To explore interactions among these parameters, we characterized variation in gut microbiome composition of California voles (Microtus californicus) across a contact zone between two recently diverged lineages of this species. Because this contact zone contains individuals with mismatched mitochondrial‐nuclear genomes (cybrids), it provides an important opportunity to explore how different components of the genotype contribute to gut microbial diversity. Analyses of bacterial 16S rRNA sequences and joint species distribution modelling revealed that host genotypes and genetic differentiation among host populations together explained more than 50% of microbial community variation across our sampling transect. The ranked importance (most to least) of factors contributing to gut microbial diversity in our study populations were: genome‐wide population differentiation, local environmental conditions, and host genotypes. However, differences in microbial communities among vole populations (β‐diversity) did not follow patterns of lineage divergence (i.e., phylosymbiosis). Instead, among‐population variation was best explained by the spatial distribution of hosts, as expected if the environment is a primary source of gut microbial diversity (i.e., dispersal limitation hypothesis). Across the contact zone, several bacterial taxa differed in relative abundance between the two parental lineages as well as among individuals with mismatched mitochondrial and nuclear genomes. Thus, genetic divergence among host lineages and mitonuclear genomic mismatches may also contribute to microbial diversity by altering interactions between host genomes and gut microbiota (i.e., hologenome speciation hypothesis).     

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。     

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.