1、Accepted ManuscriptRole of the Gut Microbiome in the Pathogenesis of Obesity and Obesity-RelatedMetabolic DysfunctionKristien E.Bouter,Danil H.van Raalte,Albert K.Groen,Max NieuwdorpPII:S0016-5085(17)30141-5DOI:10.1053/j.gastro.2016.12.048Reference:YGAST 60968To appear in:GastroenterologyAccepted Da
2、te:30 December 2016Please cite this article as:Bouter KE,van Raalte DH,Groen AK,Nieuwdorp M,Role of theGut Microbiome in the Pathogenesis of Obesity and Obesity-Related Metabolic Dysfunction,Gastroenterology(2017),doi:10.1053/j.gastro.2016.12.048.This is a PDF file of an unedited manuscript that has
3、 been accepted for publication.As a service toour customers we are providing this early version of the manuscript.The manuscript will undergocopyediting,typesetting,and review of the resulting proof before it is published in its final form.Pleasenote that during the production process errors may be
4、discovered which could affect the content,and alllegal disclaimers that apply to the journal pertain.MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPT1 Title:role of the gut microbiome in the pathogenesis of obesity and obesity-related metabolic dysfunction Kristien E.Bouter1,Danil H.van Raalte2,3,Albert K.Gro
5、en1,4 and Max Nieuwdorp1,2,3,5*1 Department of Vascular Medicine,Academic Medical Center(AMC),University of Amsterdam,The Netherlands;2 Diabetes Center,Department of Internal Medicine,VU University Medical Center,Amsterdam,The Netherlands;3 Institute for Cardiovascular Research(ICaR),VU University M
6、edical Center,Amsterdam,The Netherlands;4 Department of Pediatrics,Laboratory of Metabolic Diseases,University of Groningen,UMCG,Groningen,the Netherlands;5 Wallenberg Laboratory,University of Gothenberg,Gothenberg,Sweden.*Corresponding author:Max Nieuwdorp.Department of Experimental Vascular Medici
7、ne,Meibergdreef 9,Room F4-159.2,1105 AZ Amsterdam,The Netherlands.Tel.:+31 20 5666612;E-mail:m.nieuwdorpamc.uva.nl Abstract:146 words Manuscript:5813 words including references Figures:1 MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPT2 Abstract The potential role of intestinal microbiota in the etiology of v
8、arious human diseases has attracted massive attention in the last decade.As such,the intestinal microbiota has been advanced as an important partaker in the development of obesity and obesity-related metabolic dysfunctions,amongst others.Experiments in animal models have produced evidence for a caus
9、al role of intestinal microbiota in the etiology of obesity and insulin resistance.However,with a few exceptions such causal relation is lacking for humans.and most publication merely report associations between intestinal microbial composition and metabolic disorders such as obesity and type 2 diab
10、etes(T2DM).Thus,the reciprocal relation between the bacteria and these metabolic disorders remains a matter of debate.The main objective of this review is to critically assess the driving role of intestinal microbe composition in the etiology,prevention and treatment of obesity and obesity-related m
11、etabolic dysfunction,including T2DM.MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPT3 Introduction The current and worldwide obesity pandemic is associated with lifestyle changes that are characterized by an excess energy intake and reduced physical activity.The obesity pandemic strongly contributes to the in
12、cidence and prevalence of type 2 diabetes(T2DM)which through its macrovascular and microvascular complications,poses a heavy burden on the healthcare system.The mechanisms by which obesity results in T2DM have been partly clarified and include the development of insulin resistance at the level of ad
13、ipose tissue,skeletal muscle and liver,with concurrent impaired insulin secretion by the pancreatic beta-cell.More recently,the influence of intestinal microbiota as an underlying mechanistic driver of obesity and its related comorbidities has come into focus.The gut microbiota,referring to bacteria
14、 as well as viruses,fungi,archaea,phages and protozoa residing in the human intestine,1 equal the amount of all human cells 2 and they have the capability to interact with the host in several ways.These include,but are not limited to,functions like nutrient metabolism upon dietary intake,xenobiotic
15、metabolism,maintenance of gut barrier function and the(gastrointestinal)immune system,as well as protection against translocation of intestinal pathogens.3,4 The composition of the gutmicrobiota is considered to be influenced by many factors,starting from early life.During birth,the neonatal intesti
16、nal tract is colonized with maternal microbes originating from vaginal,fecal and skin flora.5 Thus,the mode of birth-vaginal versus caesarian section-might influence the composition of the microbiome of the newborns intestinal tract.6,7 However,the mode of delivery is only one factor involved in the
17、 regulation of the composition of the microbial MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPT4 community.Multiple studies indicated that composition of the microbiota varies in breast-fed infants compared to formula fed infants 8,9 and that the introduction of solid food is another important determinant of
18、 microbial composition 10.In humans,the microbiome changes considerably until at least year 3 when a more stable period sets in regarding the most predominant bacterial phyla.11,12 Interestingly,the intestinal microbiota composition is only to a limited extent heritable as was observed in monozygoti
19、c twin studies 13.Only in the last stage of life the composition changes again.Nevertheless,intestinal bacterial composition during life can be altered by changes in the diet as well as factors like medication use as will be discussed below.As previously indicated,alterations in the gut microbiota c
20、omposition and diversity have been linked to obesity and T2DM in association studies.In addition,various mechanisms have been proposed to explain how gut microbiota drive obesity and its metabolic complications,including interaction with metabolic processes and the immune system of the host.This rev
21、iew will provide a critical overview of the current knowledge of gut microbiota and its potential pathogenic role in the development of human disease with a focus on obesity and T2DM.Moreover,we will also discuss the potential role of gut microbiota in prevention and treatment of this adverse metabo
22、lic state.Shaping factors of the intestinal microbial community:diet and the innate immune system The human gut lumen contains a broad variety of microorganisms,most notably bacteria.Although bacteria were generally considered as pathogens,an essential MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPT5 symbiot
23、ic interaction between the human host and intestinal bacteria is the forging and maintenance of the immune system in the gut.The first recognition of this cross-talk came from findings in germ-free(GF)mice,where defects in the development and function of their immune system were described 14 The cro
24、ss-talk between bacteria and host immune system is probably instrumental for the fact that the gut microbiota composition is unique for each individual.Despite the intra-individual variation,five phyla dominate the intestinal community.These phyla are the Actinobacteria,Bacteroidetes,Firmicutes,Prot
25、eobacteria and Verrucomicrobia.The microbial composition changes along the gastro-intestinal tract,caused by the high-acidity and higher oxygen content in the stomach and duodenum.The proximal gastro-intestinal tract is thus enriched with Firmicutes,Lactobacilli and Proteobacteria,while more distall
26、y Bacteroidetes,Firmicutes and Akkermansia municiphilia are present 15.In healthy individuals,the composition of the intestinal microbiota is diverse.This seems to be an important characteristic because diversity has been shown to be decreased in obese subjects as well as T2DM patients 16.Marked dif
27、ferences in microbial composition have been reported in obese and T2DM patients.Qin et al 17 reported decreased occurrence of butyrate producing bacteria such as Clostridiales,Eubacterium rectale,Faecalibacterium prausnitzii and Roseburia intestinalis.Interestingly,mucin degrading bacteria such as A
28、kkermansia muciniphila and Desulfovirbrio were enriched in samples derived from T2DM patients.Paradoxically,a membrane protein of Akkermansia mucinophilia was recently shown to improve obesity and T2D in mice 18 Changes in the Firmicutes/Bacteroidetes ratio have been repeatedly reported to associate
29、 with obesity and insulin resistance 19.These alterations were related to measures of glycemic control including fasting glucose and HbA1c concentrations.MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPT6 Moreover,obese subjects with low gene diversity and a less diverse composition of the microbiota are chara
30、cterized by higher BMI and fat mass,lower insulin sensitivity,dyslipidemia as well as increased markers of inflammation.Nevertheless,these data should be interpreted with caution as,a recent meta-analysis of Finucane et al.20 indicated that the reproducibility of these human studies is limited.When
31、pooling four studies,differences in phylum-level taxonomic composition were confirmed in lean and obese subjects and although the authors conclude that no association between BMI and taxonomic composition of fecal microbes was found in the largest cohorts(Human Microbiome Project and MetaHit).The au
32、thors conclude that perhaps the differences found between studies are possibly due to differences in diet,geography or metabolic(diabetes)status.In this regard,it is important to note that glucose-lowering agents may have a large impact.While this has been documented for metformin 21,22,the extent t
33、o which other drugs affect the microbiome remains to be studied.Thus,larger studies with more power to investigate the association of the microbiome and obesity and T2DM are eagerly awaited.It has recently become clear that gut microbiota as well as their endogenous metabolic function enabling the d
34、igestion of food components,is related to dietary intake.A large cohort study showed a few years ago that specific dietary intake is closely associated with development of obesity in humans 23 With every 4-year interval,weight increase was positively associated with the intake of processed foods(lik
35、e potato chips),sugar-sweetened beverages and red meat,while weight loss in these intervals was associated with the intake of vegetables,fibers and yogurt.In this respect,it is interesting to note many of these specific dietary compounds have been linked to altered gut microbiota MANUSCRIPT ACCEPTED
36、ACCEPTED MANUSCRIPT7 composition.Both food emulsifiers(like carboxymethylcellulose and polysorbate-80 often found in processed foods)24 and artificial sweeteners 21 have been associated with altered microbial composition and the development of obesity and metabolic syndrome.Moreover,red meat intake(
37、via carnitine and choline)has been linked to altered gut microbiota composition and an adverse cardiometabolic state 25.The dietary compounds that are associated with weight reduction in the above mentioned paper,including vegetables 26,fibers 27 and yogurt 28 are all reported to alter fecal microbi
38、al composition.With regard to intake of probiotics,a double blinded randomized placebo controlled intervention trial in overweight subjects with a BMI between 24,2 and 30,7 showed beneficial effects of lactobacillius Gasseri on weightreduction compared to fermented milk use only29 suggesting that ta
39、rgeted(microbiota based)dietary interventions might exert beneficial metabolic effects.,In this respect the landmark paper by Zeevi et al 30is quite interesting,since this group elegantly demonstrated in over 800 subjects that it is indeed possible to use microbiota composition of individual subject
40、s to predict their metabolic(glycemic)response to a diet.Moreover,although preliminary,their data suggest that these effects are partly mediated via dietary-derived metabolites affecting our innate immune system 31.Despite these interesting findings,two large and independent Caucasian-based cohorts
41、recently showed that the influence of endogenous factors,previous disease,medication and lifestyle(including diet)could explain only 18.7%of the inter-individual variation of fecal microbial composition.These results underscore that there are still important steps to be made towards a better underst
42、anding of environment-diet-microbe-host interactions.32,33.MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPT8 As mentioned above,in addition to diet oral medication can also influence the gut microbiome.Antibiotics can alter microbiome(decrease in Bifidobacterium genus)33,34 whereas antibiotics use at early ag
43、e has been associated with higher weight gain 35.In line,other frequently used medication in obese subjects and T2DM like proton pump inhibitors 36 and metformin 21,22 been reported to affect gut microbial composition.Thus,the composition of the gut microbiota is determined by a complex interplay of
44、 host genetic and(innate)immunologic factors,the environment and inter-species competition.However,a recent study 37 challenged this notion indicating that microbial cross talk is dominant over exogenous (host)factors.Applying a procedure called dissimilarity overlap curves(DOC),the authors looked a
45、t general relationships between the presence of bacterial species independent of the host.If bacterial cross-talk is independent of the host,presence of a bacterial species should be predictive of the relative proportion of that species in the microbial community.This was indeed observed,suggesting
46、that the influence of the host on the major species distribution may be small.Although recent studies in monozygote twins provided evidence for heritability of a number of microbial species 38,it cannot be excluded that these observed differences might be due to the immune system than genetic backgr
47、ound.39 Mechanisms by which gut microbiota may drive obesity and type 2 diabetes Microbiota-derived metabolites How gut microorganisms interact with the host is still largely enigmatic,probably due to the multiple pathways that may be involved.Bacteria may provide the host with up to 10%of energy vi
48、a fermentation of dietary components that otherwise cannot be MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPT9 digested by the intestinal digestive system of the host.Digestion of dietary fibers in the large intestine produces metabolites like short chain fatty acids(SCFA),comprising mainly acetate,propionat
49、e and butyrate.The latter has been shown to be an important energy source for colonocytes whereas propionate and acetate are rapidly absorbed and serve as energy substrates for the liver.However,a small amount of these SCFA is released into the circulation,exerting a diverse array of metabolic and b
50、rain-related effects 40.SCFAs can also activate the energy sensor AMP-activated protein kinases(AMPK)in the liver and muscle triggering the activation of peroxisome proliferator-activated receptor-gamma coactivator(PGC-1alpha)and members of the peroxisome proliferator-activated receptor family,there
