Human Gut Microbiome and Body Metabolism.docx

1、Human Gut Microbiome and Body MetabolismThe Human Gut Microbiome and Body Metabolism: Implications for Obesity and DiabetesSridevi Devaraj,1,2Peera Hemarajata,1,2andJames Versalovic1,2,*Author informationCopyright and License informationThe publishers final edited version of this article is availabl

2、e free atClin ChemSee other articles in PMC thatcitethe published article.Go to:AbstractBACKGROUNDObesity, metabolic syndrome, and type 2 diabetes are major public health challenges. Recently, interest has surged regarding the possible role of the intestinal microbiota as potential novel contributor

3、s to the increased prevalence of these 3 disorders.CONTENTRecent advances in microbial DNA sequencing technologies have resulted in the widespread application of whole-genome sequencing technologies for metagenomic DNA analysis of complex ecosystems such as the human gut. Current evidence suggests t

4、hat the gut microbiota affect nutrient acquisition, energy harvest, and a myriad of host metabolic pathways.CONCLUSIONAdvances in the Human Microbiome Project and human metagenomics research will lead the way toward a greater understanding of the importance and role of the gut microbiome in metaboli

5、c disorders such as obesity, metabolic syndrome, and diabetes.Obesity, metabolic syndrome, and type 2 diabetes are major public health challenges, affecting approximately 26 million children and adults in the US. More than 8% of the US population has diabetes, of which 17.9 million people have the m

6、etabolic syndrome(1). During the past 20 years, obesity has dramatically increased in prevalence in the US. More than 1 in 3 US adults (36%) are obese, and approximately 12.5 million (17%) of children and adolescents (age 219 years) are obese(2). In the US in 2010(2), all of the states had a prevale

7、nce of obesity of over 20%. The heterogeneity of these disorders has been demonstrated through both anthropometric and genetic studies. These metabolic disorders are believed to be caused by a combination of genetic susceptibilities and lifestyle changes. Recently, interest has surged in the possibl

8、e role of the intestinal microbiome as a potential contributor to the rapidly increased prevalence of obesity(35). This review focuses on recent advances in the understanding of the gut microbiome and techniques to assess the microbiome and its relationship to human body metabolism, obesity, metabol

9、ic syndrome, and type 2 diabetes(Fig. 1).Hyperglycemia (HG) and increased free fatty acids (FFA), which are hallmarks of obesity, metabolic syndrome, and diabetes, combined with a high-fat, highglycemic load diet, could result in increased activation of the inflammasome complex as well.The Human Gut

10、 Microbiome: The Toolkit behind the ScienceThe widespread application of 16S rRNA gene sequencing for detection of bacterial pathogens and microbial ecology has provided a robust technical platform for the evaluation of the bacterial composition of the human microbiome. Sequencing of 2 primary targe

11、ts within bacterial 16S rRNA genes yielded valuable compositional data pertaining to the human fecal microbiome of 242 healthy adults(6,7). In the Human Microbiome Project, 18 different body sites were sampled and sequenced. Stool specimens were the single specimen type used to study the intestinal

12、microbiome. Previously published studies demonstrated the variation in composition of the gut microbiome among locations within the gastrointestinal tract in different mammalian species. For example, 16S rRNA gene sequencing has been deployed to study the maturation of murine cecal microbiota, and t

13、hese studies demonstrated the existence of a large number of yet-unidentified bacteria that inhabit the mammalian intestine(6). Such sequencing strategies, which are culture independent, are essential for determining bacterial composition of the microbiome and its relative stability and diversity ov

14、er time. Thus, it is essential to develop robust experimental models of the human microbiome to delineate important mechanistic processes in the development of human disease states.Advances in sequencing technologies have resulted in the widespread application of whole-genome (WG)3sequencing technol

15、ogies for metagenomic DNA analysis of complex ecosystems such as the human intestine(7). WG sequencing strategies provide microbial compositional as well as functional information. WG data can be used to infer bacterial composition, and these data yield information similar to that generated by 16S r

16、RNA gene sequencing. The genome sequences of highly abundant species are well represented in a set of random shotgun reads, whereas less abundant species are represented by fewer sequences generated in a next-generation sequencing run. This relative richness permits the comprehensive measurement of

17、the compositional responses of an ecosystem to dietary changes, drug therapy, epigenetic alterations, and environmental perturbations. Alternatively, most genes (usually approximately 2000 genes per bacterium) in the microbiome are sequenced so that metabolic and other functional pathways can be eva

18、luated in each individuals metagenome. Functional WG data provide opportunities to find out which metabolic pathways are affected and how the microbiome may contribute mechanistically to health and disease states. This technology creates the formidable challenge of managing vast data sets. Advances

19、in next-generation DNA sequencing yielded 576.7 Gb of microbial DNA sequence data, which were generated with an Illumina genome analyzer (Illumina) from total DNA from the stool samples of 124 European adults(8). The relationship between the commensal microbiota that comprise the gut microbiota and

20、those that are in the intestinal barrier is complex and differs spatially throughout different areas of the gastrointestinal tract. Fecal metagenomics measures ecosystem changes in stool or the distal intestine, but it does not compare the microbiomes in different regions of the intestine. It is als

21、o important to note that metagenomic analysis of fecal samples does not include all important molecular interactions within the gastrointestinal tract. Turnbaugh et al. have proposed the idea of a core set of functions within the microbiome, and the tools of proteomics and metabolomics may be requir

22、ed for more in-depth functional analyses(7,9). From a systems perspective, metagenomic analyses may provide further details on specific intraindividual changes and thus have major implications for personalized medicine strategies.Metatranscriptomics, metaproteomics, and metabonomics will be useful t

23、o explore the functional aspects of the gut microbiome from the top down. Realtime analysis of the intestinal microbiome is a useful tool in the development of personalized approaches to targeted therapies. Metabonomics can be described as the study of metabolic responses to chemicals, the environme

24、nt, and diseases and involves the computational analysis of spectral metabolic data that provide information on temporal changes to specific metabolites. In addition, metabonomics provides global metabolic profiling of an individual in real time. It is possible, with such approaches, to elucidate co

25、mplex pathways and networks that are altered in specific disease states. The combination of metabolic profiling and metagenomic studies of gut microbiota permits the study of host and microbial metabolism in great detail. Such analysis of functional components of the microbiome that affect metabolis

26、m and human health is referred to as functional metagenomics.Metagenomics and the science of the human microbiome have arrived at the forefront of biology primarily because of major technical and conceptual developments. The major technical development was the deployment in many centers of next-gene

27、ration DNA sequencing technologies with greatly enhanced capabilities for sequencing collections of microbial genomes in the metagenome. Technological advances have created new opportunities for the pursuit of large-scale sequencing projects that were difficult to imagine a decade ago. The key conce

28、ptual development was the emerging paradigm of the essential nature of complex microbial communities and their importance to mammalian biology and human health and disease. The Human Microbiome Project was approved in May 2007 as 1 of 2 major components (in addition to the human epigenomics program)

29、 of NIH RoadMap version 1.5 (now known as the Common Fund). Recently, 2 seminal reports from the Human Microbiome Project consortium(10,11)described investigations in which a population of 242 healthy adults were sampled at 15 or 18 body sites up to 3 times, 5177 microbial taxonomic profiles were ge

30、nerated from 16S rRNA genes, and more than 3.5 T bases of metagenomic sequences were generated. In addition, in parallel, the Human Microbiome Project consortium has sequenced approximately 800 human-associated reference genomes. This resource will provide a framework for future studies of disease s

31、tates and a reference collection of healthy human microbiome data. The data set will enable future investigations into the epidemiology and ecology of the human microbiome in various disease states, and treatment strategies will evolve from these studies. Using compositional and functional approache

32、s, the relationships between pathological variations in the gut microbiome and several disease states have been delineated.Urine metabolomics provides an opportunity for studies of the microbiomes impact on whole-body metabolism. The advantages of using urinary samples include relatively large sampl

33、e volumes and the convenience of noninvasive collection. In addition, urine samples can be used for the investigation of the chronology of metabolic changes and thus are a valuable tool for investigations related to the pathogenesis or progression of disease and for screening and diagnosis as well as prognostic evaluat