Paper reading (二十一)：Human gut microbiome: hopes, threats and promises

论文题目：Human gut microbiome: hopes, threats and promises

scholar 引用：120

页数：10

发表时间：2018.04

发表刊物：Gut

作者：Patrice D Cani

摘要：

The microbiome has revieved increasing attention over the last 15 years. Although gut microes have been explored for several decades, investigations of the role of microorganisms that reside in the human gut has attracted much attention beyond classical infectious diseases. For example, numerous studies have reported changes in the gut microbiota during not only obsesity, diabetes, and liver diseases but also cancer and even neurodegeneratives(神经性病变) diseases. The human gut microbiota is viewed as a potential source of novel therapeutics. Between 2013 and 2017, the number of publications focusing on the gut microbiota was, remarkably, 12900, which represents four-fifths of the total number of publications over the last 40 years that investigated this topic. This review discusses recent evidence of the impact of the gut microbiota on metabolic disorders and focus on selected key mechanisms. This review also aims to provide a critical analysis of the current knowledge in this field, identify putative key issues or problems and discuss misinterpretations. The abundance of metagenomic data generated on comparing diseased and healthy subjects can lead to the erroneous claim that a bacterium is causally linked with protection or the onset of a disease. In fact, environment factors such as dietary habits, drug treatments, intenstinal motility(肠动力) and stool frequence and consistency(大便次数和稠度) are all factors thar influence the composition of the microbiota and should be considered. The cases of the bacteria Prevotella copri and Akkermansia muciniphila will be discussed as key examples.

结论：

we need to provide as much as possible more complex analysis (eg, multiomics and time series measurements) if we want to finally approach the final causality.
both types of approaches are important, that is, comparing diseased and healthy conditions and then showing the causality as a proof of concept.
the general population as well as health practitioners should be rigorous when drawing conclusions from papers that assume that the discovery of differences in gut microbiota composition is potentially strongly associated with a specific disease or its overall evolution.

肠道菌群与代谢疾病：进展、机制和陷阱（综述）

①代谢疾病中，基因、食物和药物影响菌群组成和数量、代谢产物和免疫间的平衡；
②菌群组成与肠道黏液层、抗微生物信号和SCFA生成相关；
③丙酸和丁酸作用于GPCR，促进L细胞生成肠肽调节能量摄入和血糖，影响MAIT和Treg等免疫细胞，还能激活PPAR-γ以维持肠道厌氧环境，影响肠道屏障功能；
④粪便普雷沃氏菌和Akk菌的研究提示，特定细菌的有益/害作用可能受多种因素影响，而不是绝对的；
⑤谨防菌群研究中的“陷阱”，关联性不等于因果性。

Introduction：

Microbes that reside in the human gut are key contributors to host metabolism and are considered potential sources of novel therapeutics.
how should we interpret the numerous hopes, promises and threats?
The gut microbiota is now considered an important partner of human cells, interacting with virtually all human cells.
experts in this field must provide access to such knowledge with caution and without delusion.
we debate one part of the current knowledge in this field and ask the following question: how should we interpret the numerous hopes, promises and threats? 这篇综述重点关注的部分

正文组织架构：

1. Introduction

1.1 Microbes interact with host cells: immunity links microbes to metabolism

1.2 Microbial activity(微生物活性), metabolites(代谢分子) and metabolism(新陈代谢)

1.3 What matters: quality, quantity or activity of microbes? 微生物的质量、数量和活性？

1.4 Hopes, promises and threats: the indispensable need for proofs of concept

1.4.1 The case of P. copri 粪便普雷沃氏菌

1.4.2 The case of Akkermansia in cardiometabolic disorders Akk菌

1.4.3 Akkermansia and immune-based cancer therapy: proof of concept

1.4.4 The case of Akkermansia in neurodegenerative disorders(神经退行性疾病)

2. Conclusion and perspectives

正文部分内容摘录：

1.1 Microbes interact with host cells: immunity links microbes to metabolism

Thus, the GI tract not only contains a vast majority of the microbes that reside in the human body but also harbours probably the larger pool of the immune cells that are present in the body.
GI cells are continually exposed to a vast number of microbial antigens(抗原) and metabolites. In spite of this close proximity, we live with microorganisms in perfect symbiosis(共生关系).
In addition to the classical immune considerations, the interactions between gut microbes and the immune system have led to the discovery of previously unknown functions. 未知功能的发现
In addition to the specific changes in the composition of the gut microbiota, it is now accepted that several key factors contribute to the translocation of bacterial compounds from the intestinal lumen to the body.
the gut barrier is controlled by fine-tuned communications occurring between gut microbes and the host immune system. 肠道屏障由肠道微生物和宿主免疫系统之间发生的微调通信控制。
the complexity of those interactions raise the question about the level of our current understanding and eventually contribute to explain why it is relatively difficult to develop specific therapeutic targets.

1.2 Microbial activity, metabolites and metabolism

there is evidence that many different microbial metabolites also influence host metabolism mostly by binding to specific host membranes or nuclear receptors.
a distinct microbial metabolite may play different roles, ranging from the regulation of glucose levels to immunomodulatory effects, in host metabolism.
Along these lines, in reality, the role and mechanisms of action of some SCFAs might also be very different from what has previously been thought.

1.3 What matters: quality, quantity or activity of microbes?

should we focus only on the general composition at the phylum level or should we go deeper (ie, the genus and species levels)? 嗯我之前也有过的疑惑
另外一个很重要的问题：is it more relevant to explore the metabolic capacity of the intestinal microbiota and, eventually, to the metabolites produced (eg, butyrate, bile acids, TMAO) than it is to study the microbial composition alone? 探索肠道菌群的代谢能力并最终与所产生的代谢物（例如丁酸，胆汁酸，TMAO）的代谢能力是否比仅研究微生物成分更有意义？
At this stage of our knowledge, there are no clear answers to these questions.
a recent, very elegant study demonstrated that it is the absolute quantity of microbes and not the proportions of microbes that really matters. [63] 真正重要的是菌群的绝对数量，而不是比例，这个结论有意思啊~~~~大多数研究，主要是基于对微生物的相对比例的调查，可能无法抓住问题的本质。
Moreover, this observation underlines the real risk and the limitations of using relative abundance-based analysis because this type of analysis can lead to erroneous interpretations 相对丰度分析可能会导致错误的结论
对cell那篇800人实验的质疑：1.预测算法是黑盒子，无法很好地解释作用机制；2. the results does not provide enough evidence that the model is finally superior to the current methods of detecting high glucose levels and even did not demonstrated that personalised nutrition advice are superior to standard advices in view of managing high glucose levels in postprandial situations. 没有说明优于传统血糖测试方法以及没有说明个性化饮食推荐比标准化饮食推荐更利于管理餐后血糖水平。的确他们没有进行这样的实验哦
the transcription of specific gut microbial pathways may vary over time, leading to potential phenotypic changes that may be complementary to changes associated with classical metagenomic abundance.
Several interesting studies have also proposed that the microbiome should be seen as an integral part of precision medicine approach.
obtaining a more comprehensive analysis of the situation by screening not only the composition but also the metabolites in prospective conditions will likely be useful.
current difficulties to obtain a clear consensus on the best way to proceed.

1.4 Hopes, promises and threats: the indispensable need for proofs of concept

sometimes we probably rapidly (too rapidly) infer positive or negative effects without properly investigating these effects. 结论得出的过于仓促
when a putative candidate has been isolated and cultured, it is still necessary to culture it in quantities that are compatible with chronic in vivo testing.
at the level of our knowledge, it is still very difficult to fully decipher the role of any microorganism in a complex community such as the gut microbiota.
后面的case感觉后续研究不一定需要涉及，故略过。2019.11.29 打脸啪啪的。。。哈哈哈

1.4.1 The case of P. copri 粪便普雷沃氏菌

how misleading a simple association study can be and how potential factors may influence discrepant and even contrasting results from functional proof-of-concept studies.
P. copri was found to improve glucose metabolism and insulin sensitivity by a mechanism associated with the production of succinate(琥珀酸) on the fermentation of dietary fibres.
另一项研究发现The authors discovered that P. copri administration aggravates glucose intolerance, reduces insulin sensitivity and increases serum total BCAAs level. 两项研究结果相反
In conclusion, although both studies are designed and performed as proof-of-concept studies, whether P. copri should be considered as a beneficial or deleterious bacterium likely depend on the dietary environments and probably requires further investigations.

1.4.2 The case of Akkermansia in cardiometabolic disorders Akk菌

Association between Akkermansia muciniphila and several diseases: what is known? What are the major confounding factors. The picture illustrated different pathological situations where the abundance of the bacteria A. muciniphila has been found to be increased or decreased. It also highlight several confounding factors associated with the modulation of the gut microbiota and eventually the abundance of A. muciniphila according to the health situation and shows the current data for which a proof-of-concept of the link between the disease and the presence of the bacteria has been made.

1.4.3 Akkermansia and immune-based cancer therapy: proof of concept

Despite this very important finding, we may not rule out that the effects are not directly mediated by this bacterium but requires the activity (or cross-talk) with one or several other key species which drive the beneficial effects. Moreover, further human studies are needed in order to consider the bacteria as therapeutic adjuvants(辅助者) in this context.

1.4.4 The case of Akkermansia in neurodegenerative disorders(神经退行性疾病)

proof-of-concept studies
Indeed, in such diseases, the vast majority of patients experience changes in dietary habits, chronic constipation and other GI comorbidities;
In fact, a recent paper highlights the crucial importance of assessing stool frequency and consistency in microbiome studies.

Key definitions：

Microbiota(微生物群): This term refers to a collection of all taxa constituting microbial communities, such as bacteria, archeae(古细菌), fungi(真菌) and protists(原生生物). When it refers to a specific environment, the term is preceded by the said location, for example, ‘the gut microbiota’ refers to the intestinal tract and the ‘oral microbiota’ is used when speaking about all the microbes from the oral cavity.
Microbiome(微生物组): This term was initially used to refer to the genes harboured by microbes; however, currently, the term ‘microbiome’ is also commonly used to refer to the microorganisms themselves (ie, the microbiota).
Probiotics(益生菌): These are live microorganisms that, when administered in adequate amounts, confer a health benefit to
the host.
Prebiotics(益生元): These are substrates that are selectively utilised by host microorganisms conferring health benefits.
Metagenome(宏基因组): This term refers to the entire genetic material present in a sample. The metagenome is composed of the genomes of several individual organisms, for instance, the genomes of human cells and of the gut microorganisms that are present in faecal material.
Metabolome(代谢组): This term refers to the quantitative complement of all the low molecular-weight molecules present in a biological sample.
Virome(病毒组): This term refers to the entire viral genetic material present in a sample. The virome consists of the genomes of viruses.

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