IF40.8！国际顶刊重磅综述：理解人类健康和疾病中的微生物组

IF40.8！国际顶刊重磅综述：理解人类健康和疾病中的微生物组

近日，德国研究人员在国际顶刊《signal transduction and targeted therapy》(IF:40.8)发表了题为“A systematic framework for understanding the microbiome in human health and disease: from basic principles to clinical translation"的综述论文。

人体微生物组是一个复杂且动态的系统，在人类健康和疾病中发挥着重要作用。然而，我们目前对微生物与人类之间复杂关系的理解仍存在局限性和理论空白。在这篇叙述性综述中，我们整合了来自解剖学、生理学、免疫学、组织学、遗传学和进化等各个领域的知识和见解，以提出一个系统框架。它引入了诸如 “先天和适应性基因组” 等关键概念，增强了对人类基因组的遗传和进化理解。“无菌综合征” 挑战了传统的 “微生物即病原体” 观点，主张微生物对健康的必要性。“从属组织” 概念强调了人体组织与其微生物对应物之间的共生复杂性，突出了微生物相互作用对健康的动态影响。“获得性微生物免疫” 将微生物组定位为人类免疫系统的辅助，为益生菌疗法和谨慎使用抗生素提供了理论依据。“稳态重编程假说” 将微生物组纳入内环境理论，有可能解释工业化后稳态指标的变化。“细胞 - 微生物共生态模型” 阐明了影响细胞平衡的共生调节机制，而 “元宿主模型” 将宿主的定义拓宽至包括共生微生物。“健康 - 疾病转化模型” 涵盖了先天和适应性基因组的相互作用以及生态失调模式。其目的在于提供对微生物组更集中且连贯的理解，并强调未来的研究方向，这些研究方向可能会促成一个更有效、更高效的医疗保健系统。

结论

人类精子和卵子的融合创造了我们的先天基因组，而微生物组具有随机性和非遗传性，它作为一种适应性基因组不断进化。这种适应性基因组是动态的且具有个性化特征，不断适应我们的生理、病理、环境、饮食和微生物相互作用。先天基因组和适应性微生物组相互交织，导致生物体的稳态重新编程。与适应性基因组失去相互作用可能会导致无菌综合征（基于无菌动物的假设）。从组织学的角度来看，人类微生物群可以被视为由从先天基因组进化而来的上皮组织、结缔组织、肌肉组织和神经组织管理的 “从属组织”。从属组织的纳入扩展了身体的免疫能力，提供了一种额外的防御和免疫调节形式。在与外部环境相互作用时，将宿主及其微生物组视为一个统一的实体，即 “元宿主”，这可能部分解释了疾病易感性、致病性、严重程度以及器官移植成功率的差异。在考察人体与其微生物组的内部关系时，我们知道人体组织从微生物组获得潜在益处，同时使用各种机制来调节并最小化与之相关的潜在危害或成本。微生物与人体神经、代谢和免疫系统的稳态和生态失调是健康和疾病结果的因果驱动力。

在如图 8 所示理论框架内，“无菌综合征” 强调需要从传统的 “微生物即病原体” 的观点转变为 “缺乏微生物也可能对健康有害” 的认识。“先天和适应性基因组” 在完整人类基因组的遗传和进化层面上增进了我们的理解，详细阐述了适应性基因组的基本特征。“从属组织” 的概念整合了生态学和人体组织的观点，说明了多细胞生物与其相关微生物组之间的复杂关系。它阐明了人类主体组织如何因微生物的存在而既受益又承受不利。这个概念将重点转向疾病进展过程中 “从属组织” 的变化，强调了宿主与微生物在健康和疾病中的动态相互作用。“获得性微生物免疫” 统一了定植抗性和免疫调节的作用，将微生物组视为人类防御的补充力量来源。这个概念为对抗抗生素滥用以及在治疗过敏性和炎症性疾病中利用微生态疗法提供了理论基础。“稳态重编程假说” 通过弥补因忽视微生物组作用而留下的概念空白，补充了以 “内环境理论” 为代表的现代医学基础。这可能在一定程度上解释了自工业化以来观察到的一些身体稳态指标下降的趋势，例如基础体温和血糖水平的变化与身体微生物多样性相关。“细胞 - 微生物共生态模型” 展示了 “微生物调节” 与 “细胞稳态” 之间的密切关联，提供了对微生物失调为何会影响人体稳态平衡的必要理解。“元宿主模型” 扩展了宿主的定义。它表明共生微生物在人类生态环境中充当共同宿主。“健康 - 疾病转化模型” 阐明了先天和适应性基因组作为一个整体的双重关系及其内部竞争。它总结了人体内部微生物失调的四种模式。

图文赏析

Fig. 1 Human microbial-related characteristics. The distribution data of the microbiome were obtained from the Human Microbiome Project, supplemented by modified data from Ron Sender et al.

Fig. 2 Acquired microbial immunity. The human immune consists of innate and acquired immunity, which is mainly carried out by T and B cells. The main strategies of adaptive immunity are active and passive immunization. In active immunity, natural immunity can be acquired by direct infection with the pathogen, while vaccination with the antigen is the artificial way. Passive immunization is mainly achieved by natural means, such as breastfeeding, or artificial means, such as immunoglobulin injections. Commensal microbiota described here can provide another form of acquired defence and regulating power against pathogens (commensal microbiota immunity). Correspondingly, maternal human milk oligosaccharides (HMOs), acquired through maternal reproductive transmission and exposure, can enhance the colonization of beneficial microbes under natural conditions. Under artificial conditions, fecal microbiota transplantation (FMT),660,661,662,663,664 probiotics,665,666,667,668,669 prebiotics,670 synbiotics671,672 and postbiotics673,674,675,676 can be used to acquire this immunity. Commensal microbiota immunity strengthens cellular barriers and regulates immune cells through metabolites such as short-chain fatty acids. They train and educate the immune system as a competitor while providing colonization resistance against foreign and established pathogenic microbes. The decline of commensal microbiota immunity increases the risk of skin and food allergies,677 asthma,548 type 1 diabetes (T1D),678 pathogenic overgrowth (such as Clostridium difficile),667,679,680,681,682,683,684,685,686,687 and susceptibility to inflammatory bowel disease (IBD)555,688,689,690,691,692,693,694,695 and other potential diseases696,697

 

Fig. 3 The meaning of adaptive genome. Human sperm and egg form the innate human genome. Microbes, through various selections, become the adaptive genome. Adaptive genomes may adapt to host selection and regulation, the dynamics of established microbial communities (which may promote, inhibit or remain neutral),698,699,700 exposure to different diets and drugs, and fluctuations in the external environment. DASH: Dietary Approaches to Stop Hypertension

Fig. 4 Original host (conventional host model) and Meta-host (ecological host model). The meta-host is used to describe conventional host that exhibit marked differences in colonization, susceptibility and pathogenicity to microorganisms following microbial accession. This phenomenon is the result of the dynamic integration of the adaptive genome with the innate genome and corresponds to the human ecological perspective

Fig. 5 Slave tissue hypothesis. Microbial tissue is the additional fundamental tissue of the human body, a slave tissue alongside nervous, epithelial, connective and muscular tissues.701,702 The maternal microbiota exerts a regulatory influence on fetal growth and development and can partially transfer seed microbiota to the newborn through microbial exposure. Microbes that colonize in body site (including but not limited to the gastrointestinal tract, respiratory tract, reproductive tract, skin and urinary tract) play a vital role in digestion, immunity, neural regulation and metabolic crosstalk throughout human growth and ageing, and ultimately participate in the degradation of the body upon death.37,415,703,704 The human microbiota has undergone co-speciation, co-evolution, co-adaptation, and co-diversification with humans over a long period of time.53 Throughout the life cycle, factors such as mode of delivery, genetics, gender, diet, medication, environment and behavior (e.g. exercise) can potentially contribute to differential microbial tissue formation705,706,707

Fig. 6 The conceptual model of homeostatic reprogramming mediated by commensal microbes. a The concept of ‘Homeostatic reprogramming’ is used to describe a phenomenon in which the adaptive genome (commensal microbiota) coordinates with the innate genome (human cell/tissues) to deviate the scope and regulation outcome from the original trajectory including body temperature, uric acid levels, glucose level, blood pressure, etc. The interplay between human life stages - from youth to old age - and microbial development - from increasing to decreasing diversity - overall results in different regulatory forces. b The conceptual model of cell-microbe co-ecology and co-homeostasis. Plasma, tissue fluid and lymphatic fluid form the internal environment of the human body’s cell life. This internal environment is regulated by the neural, immune, and metabolic systems to maintain a dynamic homeostasis of physical and chemical properties such as temperature, pH, and osmotic pressure. The internal factors of cell differentiation, proliferation, ageing, damage, and apoptosis can affect this homeostasis. Human tissues are involved in shaping a physico-chemical and nutritional environment where external microorganisms can colonize, replicate, experience loss and die. On the one hand, human cells, and microorganisms in the digestive tract work together to metabolize nutrients from food. Microbes not only affect nutrient absorption, but also produce metabolites, vitamins, and potential “dark matter”, which can enter the internal environment and affect its homeostasis. The imbalance of the internal environment also leads directly to the disruption of the microenvironment they form. The diversity, relative abundance, and products of beneficial, harmful, and neutral microorganisms (composition) are important indicators for assessing the environmental balance. On the other hand, microorganisms also participate in shaping the microenvironment by providing a barrier to respond to external environmental changes. This overall change regulates the susceptibility of the internal environment to external perturbations, acting another regulatory force for homeostasis

Fig. 7 The model of the interplay between the human innate and adaptive genome in health and disease transformation. The human innate and adaptive genomes form a holistic functional phenotype but are also in constant competition. The regulation of the nervous, immune, metabolic, and commensal microbiota constitutes the four major features and regulatory forces of human health and disease states. These forces interact with each other, and microbial dysbiosis can lead to the disruption of other forces and vice versa. The innate genome requires (a) the necessary exposure to commensal microbiota and a controllable microbial community, (b) an intact microbial barrier, (c) the ability to resist damage from microbial genetic mutations, and (d) the ability to utilize beneficial products of the adaptive genome and metabolize harmful ones to maintain a healthy steady state (with the innate genome in the dominant position). Conversely, (e) inadequate exposure to appropriate microbiota (which can lead to germ-free syndrome in extreme cases) or microbial overgrowth, (f) microbes or their components (e.g. LPS) entering the circulation through an incomplete barrier and causing harm to other tissues and organs, (g) microbial genetic mutations causing additional damage, and (h) a decrease in beneficial microbial products and an increase in harmful ones can lead humans towards disease progression (with the adaptive genome dominant). LPS Lipopolysaccharides, TMA Trimethylamine, TMAO Trimethylamine N-oxide, PAGln Phenylacetylglutamine, ClpB a melanocyte-stimulating hormone (α-MSH) analogue, BCAAs Branched-chain amino acids, SCFAs Short-chain fatty acids, RKH Arginyl-lysyl-histidine

Fig. 8 A systematic framework for understanding human microbes and the history of the development of some of these concepts. The systematic framework consists of eight fundamental concepts/models: “innate genome and adaptive genome”, “slave tissue”, “acquired microbial immunity”, “cell-microbe co-ecology and co-homeostasis model”, “meta-host model”, “health and illness transformation model” and “germ-free syndrome”

原文链接

https://doi.org/10.1038/s41392-024-01946-6