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.     

Gut microbiome and the risk factors in central nervous system autoimmunity

Humans are colonized after birth by microbial organisms that form a heterogeneous community, collectively termed microbiota. The genomic pool of this macro-community is named microbiome. The gut microbiota is essential for the complete development of the immune system, representing a binary network in which the microbiota interact with the host providing important immune and physiologic function and conversely the bacteria protect themselves from host immune defense. Alterations in the balance of the gut microbiome due to a combination of environmental and genetic factors can now be associated with detrimental or protective effects in experimental autoimmune diseases. These gut microbiome alterations can unbalance the gastrointestinal immune responses and influence distal effector sites leading to CNS disease including both demyelination and affective disorders. The current range of risk factors for MS includes genetic makeup and environmental elements. Of interest to this review is the consistency between this range of MS risk factors and the gut microbiome. We postulate that the gut microbiome serves as the niche where different MS risk factors merge, thereby influencing the disease process.     

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.     

Mesenteric lymph system constitutes the second route in gut–liver axis and transports metabolism-modulating gut microbial metabolites

The gut–liver axis denotes the intricate connection and interaction between gut microbiome and liver, in which compositional and functional shifts in gut microbiome affect host metabolism. Hepatic portal vein of the blood circulation system has been thought to be the major route for metabolite transportation in the gut–liver axis, but the existence and importance of other routes remain elusive. Here, we perform metabolome comparison in blood circulation and mesenteric lymph systems and identify significantly shifted metabolites in serum and mesentery. Using cellular assays, we find that the majority of decreased metabolites in lymph system under high-fat diet are effective in alleviating metabolic disorders, indicating a high potential of lymph system in regulating liver metabolism. Among those, a representative metabolite, L-carnitine, reduces diet-induced obesity in mice. Metabolic tracing analysis identifies that L-carnitine is independently transported by the mesenteric lymph system, serving as an example that lymph circulation comprises a second route in the gut–liver axis to modulate liver metabolism. Our study provides new insights into metabolite transportation via mesenteric lymph system in the gut–liver axis, offers an extended scope for the investigations in host-gut microbiota metabolic interactions and potentially new targets in the treatment of metabolic disorders.     

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.     

Microbiota-immune-brain interactions: A lifespan perspective

There is growing appreciation of key roles of the gut microbiota in maintaining homeostasis and influencing brain and behaviour at critical windows across the lifespan. Mounting evidence suggests that communication between the gut and the brain could be the key to understanding multiple neuropsychiatric disorders, with the immune system coming to the forefront as an important mechanistic mediator. Throughout the lifespan, the immune system exchanges continuous reciprocal signals with the central nervous system. Intestinal microbial cues alter immune mediators with consequences for host neurophysiology and behaviour. Several factors challenge the gut microbiota composition, which in response release molecules with neuro- and immuno-active potential that are crucial for adequate neuro–immune interactions. In this review, multiple factors contributing to the upkeep of the fine balance between health and disease of these systems are discussed, and we elucidate the potential mechanistic implications for the gut microbiota inputs on host brain and behaviour across the lifespan.     

5-Fluorouracil induced dysregulation of the microbiome-gut-brain axis manifesting as depressive like behaviors in rats

Disturbances of the gut microbiome have been widely suggested to be associated with 5-fluorouracil (5-Fu) induced digestive pathologies. Furthermore, it has been elucidated that the gut microbiome may play a key role in the pathogenesis of depressive disorders via the microbiota-gut-brain axis. Despite the speculation, there exists no direct evidence proving the causality between disturbances in the gut microbiome induced by 5-Fu and depressive mood dysregulation. Herein, behavioral testing was used to evaluate depressive-like behaviors in 5-Fu treated rats. Subsequently, the gut microbiota and prefrontal cortex (PFC) metabolic were analyzed by 16S rRNA sequencing and ¹H nuclear magnetic resonance (¹H NMR). To clarify the association between the gut microbiota and their role on depressive-like behaviors caused by 5-Fu, a fecal microbiota transplantation (FMT) experiment was carried out. The results suggested that 5-Fu could significantly alter the diversity and abundance of the gut microbiome, and induce PFC metabolic disorders, as well as depressive behaviors in rats. Transplantation of fecal microbiota from healthy control into 5-Fu treated rats significantly alleviated the PFC metabolic disorder and depressive-like behaviors. In conclusion, this study demonstrated that the gut microbiome was actively involved in the occurrence of 5-Fu induced depressive-like behaviors, and manipulation of specific gut microbiome parameters may serve as a promising novel target for side effects of 5-Fu treatment.     

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。     

Gut microbiome in cancer immunotherapy: Current trends,translational challenges and future possibilities

Gut microbiota is regarded as a crucial regulator of the immune system. Healthy gut microbiota plays a specialized role in host xenobiotics, nutrition, drug metabolism, regulation of the structural integrity of the gut mucosal barrier, defense against infections, and immunomodulation. It is now understood that any imbalance in gut microbiota composition from that present in a healthy state is linked to genetic susceptibility to a number of metabolic disorders, including diabetes, autoimmunity, and cancer. Recent research has suggested that immunotherapy can treat many different cancer types with fewer side effects and better ability to eradicate tumors than conventional chemotherapy or radiotherapy. However, a significant number of patients eventually develop immunotherapy resistance. A strong correlation was observed between the composition of the gut microbiome and the effectiveness of treatment by examining the variations between populations that responded to immunotherapy and those that did not. Therefore, we suggest that modulating the microbiome could be a potential adjuvant therapy for cancer immunotherapy and that the architecture of the gut microbiota may be helpful in explaining the variation in treatment response. Herein, we focus on recent research on the interactions among the gut microbiome, host immunity, and cancer immunotherapy. In addition, we highlighted the clinical manifestations, future opportunities, and limitations of microbiome manipulation in cancer immunotherapy.     

Review: Microbial endocrinology: intersection of microbiology and neurobiology matters to swine health from infection to behavior

From birth to slaughter, pigs are in constant interaction with microorganisms. Exposure of the skin, gastrointestinal and respiratory tracts, and other systems allows microorganisms to affect the developmental trajectory and function of porcine physiology as well as impact behavior. These routes of communication are bi-directional, allowing the swine host to likewise influence microbial survival, function and community composition. Microbial endocrinology is the study of the bi-directional dialogue between host and microbe. Indeed, the landmark discovery of host neuroendocrine systems as hubs of host–microbe communication revealed neurochemicals act as an inter-kingdom evolutionary-based language between microorganism and host. Several such neurochemicals are stress catecholamines, which have been shown to drastically increase host susceptibility to infection and augment virulence of important swine pathogens, including Clostridium perfringens. Catecholamines, the production of which increase in response to stress, reach the epithelium of multiple tissues, including the gastrointestinal tract and lung, where they initiate diverse responses by members of the microbiome as well as transient microorganisms, including pathogens and opportunistic pathogens. Multiple laboratories have confirmed the evolutionary role of microbial endocrinology in infectious disease pathogenesis extending from animals to even plants. More recent investigations have now shown that microbial endocrinology also plays a role in animal behavior through the microbiota–gut–brain axis. As stress and disease are ever-present, intersecting concerns during each stage of swine production, novel strategies utilizing a microbial endocrinology-based approach will likely prove invaluable to the swine industry.     

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.     

"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。     

Mind-altering with the gut: Modulation of the gut-brain axis with probiotics

It is increasingly evident that bidirectional interactions exist among the gastrointestinal tract, the enteric nervous system, and the central nervous system. Recent preclinical and clinical trials have shown that gut microbiota plays an important role in these gut-brain interactions. Furthermore, alterations in gut microbiota composition may be associated with pathogenesis of various neurological disorders, including stress, autism, depression, Parkinson’s disease, and Alzheimer’s disease. Therefore, the concepts of the microbiota-gut-brain axis is emerging. Here, we review the role of gut microbiota in bidirectional interactions between the gut and the brain, including neural, immune-mediated, and metabolic mechanisms. We highlight recent advances in the understanding of probiotic modulation of neurological and neuropsychiatric disorders via the gut-brain axis.     

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.     

Alterations of brain endocannabinoidome signaling in germ-free mice

We investigated the hypothesis that the endocannabinoidome (eCBome), an extension of the endocannabinoid (eCB) signaling system with important functions in the CNS, may play a role in the microbiota-gut-brain axis. Using LC-MS/MS and qPCR arrays we profiled the brain eCBome of juvenile (4 weeks) and adult (13 weeks) male and female germ-free (GF) mice, which are raised in sterile conditions and virtually devoid of microbiota, present neurophysiological deficits, and were found recently to exhibit a strongly altered gut eCBome in comparison to conventionally raised age/sex-matched controls. The causal effect of the gut microbiome on the eCBome was investigated through the re-introduction into adult male GF mice of a functional gut microbiota by fecal microbiota transfer (FMT). The concentrations of the eCB, 2-arachidonoylglycerol (2-AG), and its 2-monoacylglycerol congeners, were significantly reduced in the brain, but not in the hypothalamus, of both juvenile and adult male and adult female GF mice. FMT rendered these decreases non-statistically significant. The eCB, anandamide (AEA), and its congener N-acylethanolamines (NAEs), were instead increased in the brain of adult female GF mice. Saturated fatty acid-containing NAEs were decreased in adult male GF mouse hypothalamus in a manner not reversed by FMT. Only few changes were observed in the expression of eCBome enzymes and receptors. Our data open the possibility that altered eCBome signaling may underlie some of the brain dysfunctions typical of GF mice.     

肠道菌群与大脑相互作用的研究进展

定植于宿主肠道中的微生物参与了宿主多种生理功能以及相关疾病的发生。一个新的医学研究热点在近年内逐渐被关注,肠道菌群可通过主要由神经—内分泌介导的肠—脑轴(gut-brain axis,GBA)与大脑进行双向式交流。GBA不仅实现了肠道菌群对大脑发育和功能的影响,也促使大脑对肠道菌群结构和多样性的改变成为可能。本文旨在对肠道菌群与大脑相互作用的研究进展作一综述,以期为肠道和大脑功能领域的研究以及重要相关疾病的治疗策略提供理论依据。     

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。     

肠道、肺部菌群直接或通过肠—肺轴对 呼吸系统慢性疾病的影响

人体寄生的微生物与人体为共生关系,数量庞大,并形成不同的微生态系统,影响人体免疫、代谢、内分泌等生理过程。菌群失衡导致微生态紊乱,从而导致相关疾病的发生发展。呼吸系统慢性疾病患者常有肠道菌群和肺部菌群的改变,肠道菌群通过肠-肺轴影响呼吸系统免疫及呼吸系统慢性疾病,肺部菌群的改变导致肺部疾病的同时亦会通过血流引起肠道菌群的变化。近年来随着高通量测序及生物信息学技术的发展,相关研究也越发被重视,本文着重对肠道菌群、肺部菌群通过肠-肺轴或直接在肺部免疫及呼吸系统慢性疾病中所起的作用进行综述。     

Roles of the gut microbiota in severe SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. The pathophysiological mechanisms linking gut dysbiosis and severe SARS-CoV-2 infection are poorly understood, although gut microbiota disorders are related to severe SARS-CoV-2 infections. The roles of the gut microbiota in severe SARS-CoV-2 infection were compared with those in respiratory viral infection, which is an easily understood and enlightening analogy. Secondary bacterial infections caused by immune disorders and antibiotic abuse can lead to dysregulation of the gut microbiota in patients with respiratory viral infections. The gut microbiota can influence the progression of respiratory viral infections through metabolites and the immune response, which is known as the gut–lung axis. Angiotensin-converting enzyme 2 is expressed in both the lungs and the small intestine, which may be a bridge between the lung and the gut. Similarly, SARS-CoV-2 infection has been shown to disturb the gut microbiota, which may be the cause of cytokine storms. Bacteria in the gut, lung, and other tissues and respiratory viruses can be considered microecosystems and may exert overall effects on the host. By referencing respiratory viral infections, this review focused on the mechanisms involved in the interaction between SARS-CoV-2 infections and the gut microbiota and provides new strategies for the treatment or prevention of severe SARS-CoV-2 infections by improving gut microbial homeostasis.