review article influence of gut microbiota on subclinical inflammation and...

Hindawi Publishing CorporationMediators of InflammationVolume 2013 Article ID 986734 13 pageshttpdxdoiorg1011552013986734

Review ArticleInfluence of Gut Microbiota on Subclinical Inflammation andInsulin Resistance

Bruno Melo Carvalho and Mario Jose Abdalla Saad

Internal Medicine Department Faculty of Medical Sciences FCM UNICAMP Rua Tessalia Vieira de Camargo126 Cidade Universitaria Zeferino Vaz 13083-887 Campinas SP Brazil

Correspondence should be addressed to Mario Jose Abdalla Saad msaadfcmunicampbr

Received 3 April 2013 Accepted 16 May 2013

Academic Editor Massimo Collino

Copyright copy 2013 B M Carvalho and M J Abdalla Saad This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

Obesity is the main condition that is correlated with the appearance of insulin resistance which is the major link among itscomorbidities such as type 2 diabetes nonalcoholic fatty liver disease cardiovascular and neurodegenerative diseases and severaltypes of cancer Obesity affects a large number of individuals worldwide it degrades human health and quality of life Here wereview the role of the gutmicrobiota in the pathophysiology of obesity and type 2 diabetes which is promoted by a bacterial diversityshift mediated by overnutrition Whole bacteria their products and metabolites undergo increased translocation through the gutepithelium to the circulation due to degraded tight junctions and the consequent increase in intestinal permeability that culminatesin inflammation and insulin resistance Several strategies focusing onmodulation of the gut microbiota (antibiotics probiotics andprebiotics) are being experimentally employed in metabolic derangement in order to reduce intestinal permeability increase theproduction of short chain fatty acids and anorectic gut hormones and promote insulin sensitivity to counteract the inflammatorystatus and insulin resistance found in obese individuals

1 Introduction

Insulin resistance is the main outcome caused by nutrientoverload lipids infections and sepsis-induced inflammationthat affects insulin-sensitive tissues such as the liver muscleadipose tissue and hypothalamus and which also promotesdefects in cell signaling pathways and homeostasis [1] Theingestion of an unbalanced diet and low physical activityobserved in recent years in the global population are themaindrivers of the epidemic rates of obesity reached in the pastfew decades [2] A prospective study evaluated more than9 million people worldwide over the last three decades andobserved that globally the average body mass index (BMI)increased by 04-05 kgm2 per decade moreover subregiontrends showed that the average BMI increased by 14 kgm2in men and 19 kgm2 in women per decade [3] Howevernot only developed countries such as the United States areaffected by this epidemic of obesity but also countries underdevelopment such as Brazil and other countries are alsoaffected in a similar way [4]

The World Health Organization has observed that morethan 14 billion adults are overweight and of these at least200 million men and 300 million women are clinically obese[5] Some studies have shown that the increased rate ofobesity has slowed down over the last five years trended bysome specific population groups in eastern Europe SouthAmerica and even in some specific population groups in theUnited States However the prevalence of obesity remainshigh and the health costs associated with obese individualsare huge ranging from 2 to 7 of the health budgets inhigh income countries which is followed by the low incomenations while the mortality among obese people is increased[3 6 7]

Obesity is characterized by chronic subclinical inflamma-tion that affects insulin activity in its metabolically sensitivetissues notably the liver muscle and adipose tissue anddrives a metabolic disorder that culminates in the dereg-ulation of glucose homeostasis [8] Since the observationthat obese adipose tissue shows increased expression of theproinflammatory cytokine TNF-120572 [9] extensive research

2 Mediators of Inflammation

efforts have been made regarding inflammation in metabolictissues trying to determinewhat primes the insulin resistancephenomenon the consequences of obesity how to improvethe molecular knowledge of insulin activity attenuationmediated by obesity and how it can be managed in orderto improve patient quality of life Attempts have also beenmade to reduce or prevent the incidence of obesity and itscomorbidities

Here we will focus on reviewing the latest contributionsto the literature on the influence of the intestine on thepathogenesis of insulin resistance and the consequences ofinsulin resistance on the liver muscle adipose tissue andhypothalamus as well as the mechanisms by which the gutmicrobiota influences systemic insulin resistance

2 Intestinal Participation inInsulin Resistance

For several decades it has been known that the mammaliansintestine harbors a great number of bacteria (sim1014 bacteria)that even surpasses the total number of cells that comprisemammalian tissues systems and ultimately the entire body[10] Furthermore it is estimated that the gut microbiotacontains at least 100-fold more genes than the mammaliangenome These bacteria can live in a symbiotic way but incertain cases promote disease [11] However over the lastten years this community that lives within the mammalianbody has been gaining the status of a microbial organ thatcontributes to homeostasis and impacts directly on energymetabolism and insulin sensitivity [12 13]

3 The Obese Microbiome Has IncreasedEnergy Harvesting Ability

One of the first and foremost important observations onthe role of the gut microbiota in insulin sensitivity andbody weightmanagement was observed when germ-freemicethat were infected with the gut microbiota content of aconventionally raised mice showed an increase (by about60) in body fat content Moreover the occurrence ofinsulin resistance and glucose intolerance was seen within 14days even with a reduction in food intake (standard chow)providing novel evidence that the bacteria community insome way controlled energy metabolism [14] Additionallyit was described that the activity of a lipoprotein lipase (LPL)suppressor known as fasting-induced adipocyte factor (Fiaf)or angiopoietin-like protein 4 (ANGPTL4) controlled the fatstorage abnormalities observed in conventionalized germ-freemice where the gutmicrobiota induced selective suppressionof this protein in intestinal cells and promoted an increase inLPL activityThis resulted in increased triglyceride storage inadipocytes which was prevented upon the conventionaliza-tion of Fiafminusminus germ-freemice [14]

It was also shown that the resistance of germ-free miceagainst diet-induced obesity relied on increased liver andskeletal muscle AMPK activity and its downstream targetsThis induced the activation of fatty acid oxidation andincreased energy expenditure which regulated body weight

gain since Fiaf expression in the gut epithelium was highlysuppressed in germ-free mice fed a high-fat diet keepingthe body weight almost unaltered a feature that was notmaintained in Fiafminusminus germ-freemice [15]

The great increase in interest in the relationship betweenthe gut microbiota and mammalian metabolism has led tothe utilization of very elegant and novelmolecular techniquesbased on microbial DNA sequencing [16 17] This interesthas also brought new insight into the epidemic obesity ratesthroughout the world and the consequent incidence of type 2diabetes comorbidities and cancer

Metagenomic analyses of human volunteers showed thatalmost all bacteria present in the distal gut and feces belongto two main bacterial phyla Bacteroidetes and Firmicutes[18] The predominance of these phyla is also seen in leanmice with a balance among the bacterial phyla but ingenetically obese obob mice this balance is broken Inobese mice a great increase in bacteria from the phylumFirmicutes and a comparable decrease in the prevalence ofBacteroidetes were observed indicating gut microbiota alter-ation driven by obesity predisposing for or associated withthis metabolic condition [19] Moreover it was demonstratedthat microbiota transplantation from obob mice to germ-free recipients induced a greater increase in body fat contentwhen compared with germ-freemice that were the recipientsof lean mice gut microbiota indicating that this differencein the intestinal flora induced the obese phenotype [20]Additionally it was shown that the microbiota in the fecesof lean and obese humans was different in a similar way asthat observed in mice [20] All this information led to thehypothesis that the gut microbiota from obob geneticallyobesemice is capable of harvestingmore energy from the diet[21 22] probably by the presence andor increased prevalenceof bacteria that produce enzymes that are more efficient indegrading the nutrients available in the diet

The relationship between the phyla Bacteroidetes andFirmicutes is the main focus of discussion when obesityis studied with a considerable amount of data showingan increase in Firmicutes prevalence and a reduction inBacteroidetes [19 20 23ndash26] However this issue has not yetbeen completely addressed as we can find several studiesin the literature that maintain the opposite where theprevalence of Firmicutes is decreased in overweight and obeseindividuals as well as in obese mice with an accompanyingincrease in Bacteroidetes prevalence [27ndash30] Additionallythe presence of nonsignificant prevalent bacteria phyla inthe gut of lean mice such as Verrucomicrobia has notbeen well explored until now with very few observationson increases in pathological conditions (obesity and cancer)and no mechanistic evaluations [27 31] The differencesobserved among gut microbiota human studies still have tobe addressed evaluating the ethnics and feeding behavior ofthe studied population as well as the standardization of themethods used In animal studies the probable cause of theopposite outcomes may be a factor of different mouse strainsused The issue of the ldquohealthyrdquo bacterial group profile is avery important point in gut microbiota research and needs tobe further exploredThus no proposed treatment attempting

Mediators of Inflammation 3

to induce the proliferation of certain bacterial phyla has beensuggested until now

4 Obesity and High-Fat Diet IncreaseCirculating Endotoxin Levels and Activationof the Inflammatory Response

A structural particularity of bacteria splits them into Grampositive and Gram negative based on the cell wall structureEach of the two most prevalent phyla belongs to one ofthese groups that is Firmicutes are Gram positive andBacteroidetes are Gram negative bacteria The latter groupharbor lipopolysaccharides (LPS) in their cell wall which isa large molecule formed by a lipid and a polysaccharide thatelicits a strong immune response promoting inflammationto protect the organism from bacterial infection [32] LPS isa potent activator of pathogen-associated molecular pattern(PAMP) responses primarily via toll-like receptor 4 (TLR4)which activates an extensive cell signaling pathway thatinduces the inflammatory response and cytokine expressionand secretion [33] (Figure 1)

Several studies have shown that circulating levels of LPSare elevated in obese mice rats (genetically or induced bydiet) and humans In rodents this is directly related toincreased intestinal permeability [34ndash36] This phenomenonoccurs due to reduced expression and activity of tightjunction proteins such as zonula occludens-1 (ZO-1) andoccludin that create together with gut epithelial cells abarrier that separates the intestinal lumen and its bacte-rial population and products from peritoneal tissues Thisdegradation of tight junction function leads to the leakage ofbacterial products such as LPS and bacterial translocationwhich have recently been described as key factors in bothhuman andmice insulin resistance and inflammation [26 3537ndash39] (Figure 1) Recent evidence also indicates that LPS canbe transported along with chylomicrons into the circulationinstead of depending on epithelial injury to reach insulinsensitive organs the inhibition of chylomicron synthesisblocks endotoxin uptake [40]

LPS is a very specific TLR4 ligand with great affinityIts cell signaling pathway composed of a diverse numberof proteins culminates with the inflammatory responsemediated by LPS contact with cells [41ndash43] Beyond the highspecificity of TLR4 in identifying LPS from Gram negativebacteria which can reach insulin sensitive tissues throughthe circulation from the gut and drive the inflammatoryresponse to protect the host from bacterial infection TLR4has a direct role in insulin resistancemediated by obesity LPSfrom the gut can react with free-fatty acids (FFA) mostly thesaturated type that are increased in the circulation of obeseindividuals due to an increase in adipose tissue-mediatedlipolysis de novo liver lipogenesis and ectopic lipid accumu-lation [44] TLRs have been related to the gut microbiotawhereas single TLR-deficient mice such as TLR2minusminus [26]and TLR5minusminus [45] mice show a different microbiotic profilewhen compared to their control littermates This immunemodulation of the intestinal flora can induce symptoms ofmetabolic syndrome such as increased body weight blood

glucose and insulin resistance The TLR4minusminus mice do notpresent an altered prevalence of gut microbiota bacteria asseen in the TLR-deficient mice cited above [46] In obesityand conditions related to intestinal permeability TLR4 isknown to be involved in the inflammatory response thatculminates in insulin resistance and metabolic derangementas those responses are attenuated by the inhibition of thisprotein activity [27 34 47ndash49] such as in TLR4 loss-of-function C3HHeJ mice [50] in CD14minusminus mice [51] and inTLR4minusminus mice [52] (Figure 1) Recent investigations haveshown that fatty acids do not activate TLR4 directly ques-tioning the real influence of this receptor in lipid-inducedinsulin resistance caused by obesity [53 54] Nevertheless ahepatic protein has been identified called fetuin-A (FetA)which is a major carrier of FFAs in the circulation [55]that acts as an endogenous ligand of TLR4 thus activatingits signaling pathway promoting insulin resistance whichwas blocked in the absence of FetA and attenuating insulinresistance induced by FFA [56] There is evidence that showsincreased FetA expression in HepG2 cells a liver cell lineageafter treatment with thapsigargin an ER stress inducer ina time- and dose-dependent manner which is blocked bypretreating the cells with 4-phenylbutyrate a compound thatinhibits ER stress [57] These results were similar in diet-induced obese mice which exhibited ER stress attenuated by4-phenylbutyrate treatment and accompanied by a reductionin FetA expression and improved insulin resistance [57]Additionally it was demonstrated that in obese individualsand rodents circulating levels of FetA are increased andcorrelate with body weight [58 59] and that body weight lossbrings the FetA circulating levels back to normal in children[59] As well FetAminusminus mice are protected from obesity andinsulin resistance induced by aging [60 61]

Other PAMPs as well as damage-associated molecularpatterns (DAMPs) such as the inflammasome seem tobe related to intestinal epithelial integrity The activationof DAMPs and PAMPs in the gut is necessary for themaintenance of barrier function while nucleotide-bindingoligomerization domain protein-like receptor 3 (NLRP3) andNLRP6-deficientmice show increased intestinal permeabilityand increased risk of colitis [28 62] allowing the occurrenceof dysbiosis and insulin resistance and a greater possibilityof nonalcoholic steatohepatitis (NASH) The inflammasomeis a group of protein complexes that recognizes a widerange of bacterial damage and stress signals it resultsin caspase-1 activation and subsequent proinflammatorycytokine secretion and cell death [63] Mice deficient ininflammasome proteins show altered gut microbiota whencompared to wild-type littermates with an increased preva-lence of bacteria from the Prevotellaceae family which ispart of the Bacteroidetes phylum and higher translocationof bacterial products from the gut to the circulation Inparticular TLR4 and TLR9 agonists induced inflamma-tion and insulin resistance this feature is transmissible tonewborn and adult mice that come in direct contact withinflammasome-deficient animals [28 62] In addition to gutmicrobiotamodulation inflammasomeproteins are activatedin macrophages by LPS which enter into the circulation due


Intestinal lumen

LPS

Gut microbiota

Liver Muscle Adipose tissue

Gut epithelium

Metabolic derangement

Hypothalamus

darr Tight junctions

darr Fiaf

uarr Macrophage infiltrationdarr Insulin sensitivity darr Insulin sensitivity

uarr Macrophage infiltrationdarr Insulin sensitivity

darr PYY

uarr Food intakedarr Insulin sensitivityuarr S-Nitrosylation

darr GLP-1

uarr LPS

uarr Inflammationuarr Inflammationuarr Inflammation uarr Inflammation

Figure 1 The gut microbiota is modulated by metabolic derangement such as nutrition overload and obesity which promote a clusterof metabolic disease-associated processes that culminate in bacterial products and whole bacteria translocation to the circulation throughincreased intestinal permeability caused by a reduction in tight junction expression This triggers an immune response inflammation andimmune cell infiltration of liver and adipose tissue It induces insulin resistance in various tissues by diverse mechanisms and food intakederegulation in the hypothalamus promoted by the insulin and leptin resistance and also inhibited expression of gut-secreted anorectichormones such as GLP-1 and PYY Additionally there is a reduction in the intestinal Fiaf expression mediated by bacteria that deregulate thefat storage and lipid metabolism favoring the obese phenotype

to increased intestinal permeability under obese conditionsThe macrophage inflammatory activity is regulated by theTLR-induced activation of nuclear factor 120581B (NF-120581B) [6465]

In addition to the bacterial immune response mediatedby TLR4 viral infections also activate pattern recognitionreceptors (PRRs) and trigger a specific cellular signalingpathway that terminates with the activation of c-Jun N-terminal kinase (JNK) inhibitor of nuclear factor-120581B kinasesubunit 120573 (IKK120573) NF-120581B and transcription of proinflam-matory cytokines which are mediators of insulin resistanceThe double-stranded RNA-activated protein kinase (PKR) isone of the molecules responsible for protection from viralinfections as it identifies double-stranded RNA (dsRNA)viruses and activates the innate immune response againstthese pathogens [66 67] PKR is also related to obesity andinsulin resistance as its phosphorylation is increased in high-fat diet fed mice leading to activation of JNK [68] and IKK120573[69] and culminating in serine phosphorylation of IRS-1 andinsulin resistance [70] all these inflammatory features areabsent or attenuated in PKRminusminus mice [71 72] It has beendescribed that PKR is also activated by bacterial productssuch as LPS [73 74] in a dsRNA-independent way possiblyby the action of a cellular protein designated PKR-activatingprotein (PACT) which possesses dsRNA binding domainsand interacts with other molecules that bind to PKR [75] totrigger the same signaling pathway as viral infection [76]This could integrate the PKR signaling pathway with gut

microbiotametabolic effects on insulin resistance but has notyet been investigated (Figure 1)

The activation of inflammatory pathways by gut-derivedLPS mainly via TLR4 leads to increased expression ofinducible nitric oxide synthase (iNOS) [77 78] In obesityan increase in iNOS expression is also observed in insulinsensitive tissues which promotes a phenomenon known asS-nitrosationS-nitrosylation where nitric oxide (NO) reactswith cysteine residues to form S-nitrosothiol adducts therebymodulating protein function [79 80] Thus LPS induce S-nitrosationS-nitrosylation of the insulin signaling pathway(IR IRS-1 and Akt) inducing insulin resistance in the livermuscle and adipose tissue in a more particular way than ser-ine phosphorylation of IRS-1 [81ndash83]The targeted disruptionof iNOS and its pharmacological inhibition attenuates the S-nitrosationS-nitrosylation of insulin signaling proteins andinflammation and consequently improves insulin sensitivity[84ndash87] (Figure 1) Besides gut-derived LPS other bacteriametabolites could induce S-nitrosationS-nitrosylation ofdiverse proteins modulating their activity and promotingbiological effects in several tissues Therefore this field needsmore attention and further studies

5 Metabolic Role of Short-Chain Fatty AcidsDerived from Gut Microbiota

The gut microbiota has an impact on mammalian physiology(mostly metabolic and immune functions) through several


mechanisms Some of them are discussed previously but thegut bacteria can also interact with the host system throughtheir metabolites mainly short-chain fatty acids (SCFA)which are their principal end-products and are representedfor the most part by acetate propionate and butyratewhich have physiological effects in different tissues [88] Gutmicrobiota fermentation due to anaerobic bacteria degradespolysaccharides that are not cleaved bymammalian enzymesin other words nondigestible carbohydrates to produceshort-chain fatty acids and other subproducts in the cecumand colon [89] Moreover SCFA diversity demonstratesmetabolic cooperation among the bacterial community asno bacterial genus can hydrolyze all kinds of nutrientsnor produce all metabolites found in the gut lumen [90]indicating that most of the physiological interactions of thegut microbiota with the host are not dependent on just oneparticular bacterial type but the entire community

As metabolites SCFA have diverse effects on variouscells They are taken up by the host through passive dif-fusion and via mono-carboxylic acid transporters such asmonocarboxylate transporter 1 (MCT1) [91] Primarily theywork as an energy source for colonic epithelial cells whichderive 60ndash70 of their fuel influx from SCFA Butyratehas a particular importance as an energy source for thosecells as almost 65 is cleared by the mucosa and more than70 of oxygen consumption in isolated colonocytes is dueto butyrate oxidation [89] Butyrate may also play a criticalrole in cell growth and differentiation [92 93] Acetate islikely to be used as a cholesterol or fatty acid precursorand propionate is a gluconeogenic substrate [94 95] Therelative levels of the specific enzymes for SCFA degradation(acetyl-CoA propionyl-CoA and butyryl-CoA) in differenttissues are the determinants of SCFA metabolization [96]Other molecules with metabolic regulatory functions can bereleased by gut bacteria such as conjugated linoleic acids(CLA) [97 98] which are lipid metabolites or bile acids [99]and gases such as methane and H

2S [100 101] but they have

minor roles inmammal physiology when compared to SCFASCFA also act as anti-inflammatory molecules as acetate

propionate and butyrate are capable of inhibiting NF-120581Bactivation in the host immune cells by binding to G-protein-coupled receptor 43 and 41 (GPR43 and GPR41) therebyblocking inflammatory responses and suppressing TNF-120572and IL-6 release butyrate also reduces IL-12 and increasesIL-10 expression [102ndash105] GPR43 seems to have greatimportance in mediating acetate-induced anti-inflammatorystimuli since the deletion of this gene promotes an increasedinflammatory response in dextran sodium sulfate- (DSS-)induced colitis which is attenuated by the administrationof acetate in mice that express GPR43 [106] MoreoverGPR43minusminus immune cells are hyperactive and promote anincreased response to chemoattractants such as C5a andproinflammatory cytokines [106]

Acetate and butyrate are also important in epithelial bar-rier function maintenance as they stimulate the productionand secretion of mucus by goblet cells which protect theepithelium through increased expression of mucin [107]Butyrate increases MUC-2 expression by 23-fold in a goblet

cell line in vitro demonstrating the importance of this func-tion in modulating intestinal permeability [108] Butyratealso affects tight junction protein expression that is zonulinand occludin and even low concentrations of this SCFAseem to reduce intestinal permeability [109 110] Even withthis potent mucus releasing effect by butyrate it seems thatacetate has more pronounced effects in epithelial protectionas activation of GPR43 by acetate protects mice from a lethalinfection with an E coli strain [111] Moreover the inhibitionof GPR strongly attenuates the effects of acetate in terms ofepithelial survival and integrity [112]

The products of gut microbiota fermentation such asacetate and butyrate are able to increase fatty acid oxidationand energy expenditure There is evidence that acetate intakeby humans promotes a reduction in body weight circulatingcholesterol and triglyceride levels [113] The administrationof acetate or an increase in gut production mediated by thegut microbiota modulates activated 51015840-AMP-activated pro-tein kinase (AMPK) which inhibits acetyl-CoA carboxylase(ACC) thereby promoting fatty acid oxidation and energyexpenditure [114] and leading to increased insulin sensitivityand reduced glucose intolerance in diabetic rats and inhigh-fat diet fed mice [27 115] Butyrate administrationalso increases AMPK activation in muscle culminating inincreased energy expenditure as observed by an increase inbrown adipose tissue mass and UCP1 expression [116]

It has been shown in cell culture experiments that short-chain fatty acids in particular propionate and butyrate canmodulate the expression of Fiaf in intestinal cells which wasproposed as a gut microbiota mediator of fat storage [14]Intestinal cell culture lines were exposed to short-chain fattyacids which promoted an increase in Fiaf expression viaPPAR120574 in colon cells This was not reproduced in adipocytecell lines leading to the inhibition of LPL adipogenesis anda proposed increase in fat storage mechanism control andmetabolic improvement [117ndash119]

The activity of gut hormones in the control of appetitehas been shown [120] and it is likely that the gut microbiotashould interfere with the expression and activity of thesehormones Gut bacteria seem to modulate the secretion ofglucagon-like peptide-1 (GLP-1) which is produced by L-cellsin the colon and peptide YY (PYY) [121] produced by ileumand colon cells as well as leptin production by adipose tissuecells via GPR41 [122] All of these have anorectic effects inthe hypothalamus and thus promote satietyThis modulationseems to be at least in part mediated by the SCFA producedby fermentative bacteria Evidence of SCFA and satiety showthat an acetate infusion induces an increase in the circulatinglevels of GLP-1 and PYY in hyperinsulinemic overweightwomen [123] Propionate reduces food intake in animalfeeding studies [124ndash126] whereas supplementation of a dairybeverage fermented by propionic acid bacteria produceralso increases satiety in humans [127] In a similar way topropionate butyrate induces satiety upregulating anorecticneuropeptide expression such as PYY and proglucagon inrat epithelial cells [126 128] It is possible that these SCFAmechanisms of appetite regulation are mediated by GPR41and dependent on the intestinal transit rate as a deficiency inthis receptor is associated with reduced PYY expression and


faster intestinal transit with reduced energy harvesting fromthe diet [129] Most of the observations on SCFA-regulatedappetite are descriptive and the mechanisms controlled bythese gut microbiota-derived molecules are not yet known

6 Gut Microbiota Modulation

In the last decade a great body of evidence and knowl-edge about the gut microbiota and its interaction with thehost immunity and metabolism has provided new insightregarding the influence of this forgotten ldquoorganrdquo on the mostprevalent metabolic disease obesity By several mechanismsgut bacteria influence the chronic low grade inflammationthat culminates in insulin resistance and the increase in fatdeposition and body weight gain characteristic of obeseindividuals With the acknowledgement of these obesity andinflammation induction mechanisms several strategies toblock or attenuate them are being developed and tested inorder to benefit obese and type 2 diabetic patients

61 Antibiotic Therapy It has been shown that the useof broad spectrum antibiotic therapy greatly modifies thegut microbiota profile in mice improving the metabolicderangement induced by genetic obesity andor high-fat dietfeeding but the prevalence of surviving bacteria and thebenefits for the host have not been determined as the conceptof a ldquohealthyrdquo gut microbiota is still under investigationThe main mechanism suggested by antibiotic administrationis a reduction in circulating LPS levels which attenuatesinflammation and improves the insulin resistance inducedby obesity in the liver muscle and adipose tissue [27 35130 131] Additionally intestinal permeabilitymay be reducedafter the evaluation of tight junction protein expressionin epithelial cells of antibiotic-treated animals showingincreased expression and function [35]This improvement ininsulin resistance was also observed in high-fat diet fed miceeven in absence of a difference in body weight which wasachieved by submitting a group of animals to pair-feedingin comparison to the antibiotic-treated animals which pre-sented lower circulating LPS levels and TLR4 activationThisprobably led to reduced intestinal permeability leading to areduction in JNK and IKK120573 activation and reduced serinephosphorylation of IRS-1 in the liver muscle and adiposetissue altogether seen as increased activation of the insulinsignaling pathway and to inhibition of macrophage infil-tration into adipose tissue Moreover antibiotic treatmentincreases the portal acetate levels which activates AMPKfatty acid oxidation and possibly energy expenditure [27]However even with this striking metabolic improvement inantibiotic therapy experiments it seems that translating thisstrategy to humans is not the best option as there are complexissues such as antibiotic resistance in chronic administrationpanels and evidence that indicates a relationship betweenchronic low-dose antibiotic therapy and body weight gain[132 133] (Figure 2)

62 Probiotics Probiotics are defined as live microorganismsthat confer unspecified health benefits to the host [134]

Evidence frommetagenomic profiles indicates that the obesephenotype shows an increased prevalence of Firmicutes[20 26] in the gut microbiota profile inferring a negativecorrelationwithmetabolism and insulin sensitivity Howeverapart from these inconclusive observations on the ldquohealthyrdquogut microbiota the most commonly used probiotics areLactobacillus which belong to Firmicutes and Bifidobac-terium [135] Lactobacillus strain administration leads toseveral metabolic benefits in both rodents and humansthat is a reduction in adipocyte cell size and body fat inhigh-fat diet fed mice [136] a reduction in fat mass andBMI the promotion of insulin sensitivity [137 138] andrestriction of excessive body weight gain in the first yearsof life of young children [139] Although the mechanism bywhich Lactobacillus control excessive adiposity has not beendescribed changes in fat storage genes expression such asFiaf have been proposed to mediate this probiotic effect[140] Data from Bifidobacterium administration show thatthe production of acetatemediates gut epithelial integrity andbarrier function protecting animals from a lethal bacterialinfection [111] but no mechanism as to how acetate inducesthis effect has been proposed It is tempting to suggest thatacetate binding to GPR43 and its activation mediate thebeneficial effects of treatment with Bifidobacterium

A probiotic compound that has been well studied andappears in a great number of articles named VSL3 com-posed of a blend of probiotic bacteria modulates the gutmicrobiota profile [141] and shows interesting effects suchas the promotion of epithelial integrity by modulation oftight junctions [142] a reduction in inflammatory status ina chronic colitis animal model [141] protection against DSS-induced colitis and near reversal of atherosclerotic lesions inApoEminusminus mice which develop atherosclerosis spontaneously[143] In a clinical trial VSL3 promoted reduced intestinalpermeability and improved immune activity [144] Bacterialtranslocation to mesenteric adipose tissue which seems toprecede type 2 diabetes onset is prevented by probiotictreatment Apparently thismechanism ismediated by acetateproduction and increased gut epithelial integrity [39] Ithas also been shown that probiotic treatment-induced gutmicrobiota modulation can suppress high-fat-diet inducedNF-120581B activation and inflammation-induced insulin resis-tance [145] Probiotics can also mimic commensal bacte-ria and modulate protective epithelial mucus productionreduce bacterial adhesion increase tight junction expres-sion enhance epithelial and immune cell survival inducedefensins and stimulate IgA production as well as stimulateTLRs to promote gut homeostasis [146ndash148] (Figure 2)

63 Prebiotics Prebiotics are defined as a nonviable foodcomponent that confers a health benefit on the host asso-ciated with gut microbiota modulation [149] The mostcommon prebiotics used in gut microbiota modulationstudies are the inulins fructooligosaccharides various typesof galactooligosaccharides and resistant starches Prebioticsact by modulation of the gut microbiota profile and serveas a substrate for the production of metabolically activemetabolites in particular SCFA that are acetate propionate


uarr Tight junctions

darr LPS

uarr Fiaf

darr Macrophage infiltrationuarr Insulin sensitivity uarr Insulin sensitivity

darr Macrophage infiltrationuarr Insulin sensitivity

darr Food intakeuarr Insulin sensitivity

uarr PYY

darr S-Nitrosylation

uarr GLP-1

darr Inflammation darr Inflammation darr Inflammation darr Inflammation

Intestinal lumenLPSGut microbiota


Probiotic prebiotic and antibiotic treatment

Gut epithelium

Hypothalamus

Figure 2The advent of products (antibiotics probiotics and prebiotics) capable of modulating the gut microbiota profile their products andmetabolites (ie LPS short-chain fatty acids) promotes a shift on the bacterial community prevalence which favored the increase in tightjunctions expression and function reducing intestinal permeability and bacterial products circulation levels Thus the LPS circulating levelsand inflammatory status in insulin-sensitive tissues are reduced as well as muscle S-nitrosylation and liver and adipose tissue macrophageinfiltration promoting increased insulin sensitivity and the whole body metabolism GLP-1 and PYY circulating levels are increased aftertreatment with gut microbiota modulators which together with the improvement in insulin sensitivity in the hypothalamus promotedreduction in food intake by satiety mechanisms and in conjunction with the increased Fiaf expression contributed to reduce body weight

and butyrate [150 151] Several studies have related prebiotictreatment to a reduction in ectopic lipid accumulation suchas steatosis reduced fat storage in white adipose tissuein systemic inflammation and insulin resistance in high-fat diet fed and genetically obese models [152ndash154] andalso reduced endotoxemia [155] In clinical experimentsbeneficial effects of prebiotic administration were observedsuch as a reduction in BMI waist circumference fat massand insulin resistance [156ndash158] The food intake regulationis another important feature of gut microbiota modulationby prebiotics which induce gut hormone production suchas GLP-1 and PYY that signal via anorectic pathways inthe hypothalamus and a reduction in ghrelin expressiona gastric orexigenic peptide thereby reducing food intake[159 160] Even fibers that do not change the gut microbiotaprofile in a similar way to inulin-type fructans induce foodintake reduction by increasing circulating levels of GLP-1and PYY [161ndash165] evidencing the important role of SCFAderived from prebiotic fermentation Data from a 12-weekprebiotic treatment in obese subjects showed a modulatedgut microbiota profile increased PYY and decreased ghrelincirculating levels while a single dose of prebiotics (inulin)also decreased plasma ghrelin and increasedGLP-1 [166 167]Prebiotics also induce the production and secretion of GLP-2by L cells this hormone has relevant activity on gut barrierfunction and reduces gut permeability in obese animals [168](Figure 2)

64 Bariatric Surgery Recent data on obese subjects whohave undergone gastric bypass surgery indicate that sixmonths after the procedure the gut microbiota profile waschanged and bacteria diversity was reduced in comparisonwith the subjects that were obese and did not undergothe surgical procedure [169] In addition to the changespromoted by gastric bypass physiologically and anatomicallya number of factors could contribute to this gut profilealteration throughout this six months primarily food intakebehavior and weight loss placing the direct influence ofbariatric surgery in doubt An early evaluation of the gutmicrobiota after the procedure is not viable due to the antibi-otic treatment indicated for surgical recovery Neverthelessa recent study brought new light to this issue where micethat underwent gastric bypass surgery presented a distinct gutmicrobiota profile when compared with the sham-operatedmice one week after of the procedure when no body weightdifference was detected Furthermore the authors placed agroup of mice under diet restriction to mimic the weightloss achieved by the gastric bypass group for 10ndash12 weeksand found that the microbiota profile was different as wellindicating that indeed the bariatric surgery modifies thebacterial composition of the gut [170] In addition theyshowed that gut microbiota transplantation from a sham-operated animal to germ-free mice increased adiposity aswell as circulating leptin levels concomitantly with reducedfood intake as was previously demonstrated [14] However


in the recipients of gut microbiota frommice that underwentgastric bypass none of those parameters were altered whencompared to germ-free mice There was also a reduction inbodyweight suggesting that the gastric bypass-associated gutmicrobiotamay either reduce energy harvesting from the dietor produce signals to regulate energy expenditure andor lipidmetabolism in a Fiaf-independentmanner since colonizationof germ-free mice with either sham or gastric bypass gutmicrobiota inhibits Fiaf expression in intestinal cells but thisis still unknown [170] Based on the studies cited previouslygastric bypass seems to promote gut microbiota modulationthat induces beneficial effects in obese humans and rodents

7 Conclusions

In summary the literature presents incontestable data that thegut microbiota and its modulation by nutrients and excessiveenergy intake heavily influence glucose metabolism lipidstorage inflammation and insulin activity in a negative wayas observed in obesity and diabetes Furthermore there areintense investigations going on in this field highlightingseveral strategies to modulate the gut microbiota profile to aldquohealthierrdquo status in an attempt to increase insulin sensitivityby blockage of the insulin resistance inductors mediated bythe interaction between bacteria and the intestinal environ-ment of the host

Some issues have been raised from these studies andhave not been fully explored until now such as PKR activitymodulated by gut microbiota Besides bacterial productsviruses are also found in metagenomic profiles and viralsignaling could contribute to the increased inflammationpromoted by intestinal products in obesity In a similar waythe nitrosative contribution from gut microbiota has not yetbeen raised as having an impact on the metabolic derange-ment mediated by obesity and microbial products Also it isunknown if attempts to ameliorate themetabolic status by gutmicrobiota modulation will regulate both phenomena SCFAseem to have an important role in food intake regulationbut the mechanisms of inducing GLP-1 and PYY productionin intestinal cells are still poorly described and need furtherinvestigation Saturated fatty acids are known to promoteinflammation and insulin resistance and are prevalent in thehigh-fat diet administered to experimental rodents in thesestudies and in the western diet that has led to epidemicrates of obesity However the utilization of unsaturated fattyacid supplementation which is known as a lipid with anti-inflammatory properties has not yet been related to gutmicrobiota modulation This is an interesting nutritionalfield as probiotic and prebiotic strategies can have irrefutablebenefits to the hostrsquos metabolism

Ongoing efforts will try to determine the best set ofsymbiotic bacteria for mammals to harbor in the intestine ina metabolic evaluation avoid excessive energy uptake fromthe diet preserve gut barrier function and reduce bacteriaand the translocation of their inflammatory products it ishoped that this will culminate in reduced inflammationThisissue is under debate as articles do not show coherenceregarding bacterial prevalencemodulation in the gut induced

by obesity and its treatment which will need further studiesand standardization It seems that studies from differentfacilities bring distinct results This issue has to be addressedin order to define what bacterial colony is more interesting tohave grown in the mammalians gut

References

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[2] P G Kopelman ldquoObesity as a medical problemrdquo Nature vol404 no 6778 pp 635ndash643 2000

[3] M M Finucane G A Stevens M J Cowan et al ldquoNationalregional and global trends in body-mass index since 1980systematic analysis of health examination surveys and epi-demiological studies with 960 country-years and 9sdot1 millionparticipantsrdquoThe Lancet vol 377 no 9765 pp 557ndash567 2011

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[5] WHO ldquoObesity and overweightrdquo Fact sheet 311 2013httpwwwwhointmediacentrefactsheetsfs311en

[6] K M Flegal M D Carroll C L Ogden and L R CurtinldquoPrevalence and trends in obesity amongUS adults 1999ndash2008rdquoThe Journal of the American Medical Association vol 303 no 3pp 235ndash241 2010

[7] A B de Gonzalez P Hartge J R Cerhan et al ldquoBody-massindex and mortality among 146 million white adultsrdquoThe NewEngland Journal ofMedicine vol 363 no 23 pp 2211ndash2219 2010

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[9] G S Hotamisligil N S Shargill and B M SpiegelmanldquoAdipose expression of tumor necrosis factor-120572 direct role inobesity-linked insulin resistancerdquo Science vol 259 no 5091 pp87ndash91 1993

[10] JQin R Li J Raes et al ldquoAhumangutmicrobial gene catalogueestablished by metagenomic sequencingrdquo Nature vol 464 no7285 pp 59ndash65 2010

[11] J Xu and J I Gordon ldquoHonor thy symbiontsrdquo Proceedings of theNational Academy of Sciences of theUnited States of America vol100 no 18 pp 10452ndash10459 2003

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[43] S I Miller R K Ernst and M W Bader ldquoLPS TLR4 andinfectious disease diversityrdquo Nature Reviews Microbiology vol3 no 1 pp 36ndash46 2005

[44] V T Samuel and G I Shulman ldquoMechanisms for insulinresistance common threads and missing linksrdquo Cell vol 148no 5 pp 852ndash871 2012

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[50] D M L Tsukumo M A Carvalho-Filho J B C Carvalheira etal ldquoLoss-of-function mutation in toll-like receptor 4 preventsdiet-induced obesity and insulin resistancerdquo Diabetes vol 56no 8 pp 1986ndash1998 2007

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[54] C Erridge and N J Samani ldquoSaturated fatty acids do notdirectly stimulate toll-like receptor signalingrdquo ArteriosclerosisThrombosis and Vascular Biology vol 29 no 11 pp 1944ndash19492009

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[69] M C Arkan A L Hevener F R Greten et al ldquoIKK-120573 linksinflammation to obesity-induced insulin resistancerdquo NatureMedicine vol 11 no 2 pp 191ndash198 2005

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[79] J S Stamler D I Simon J A Osborne et al ldquoS-nitrosylationof proteins with nitric oxide synthesis and characterizationof biologically active compoundsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 89 no1 pp 444ndash448 1992

[80] J S Stamler E J Toone S A Lipton and N J Sucherldquo(S)NO signals translocation regulation and a consensusmotifrdquo Neuron vol 18 no 5 pp 691ndash696 1997

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[82] M A Carvalho-Filho M Ueno S M Hirabara et al ldquoS-nitrosation of the insulin receptor insulin receptor substrate1 and protein kinase BAkt a novel mechanism of insulinresistancerdquo Diabetes vol 54 no 4 pp 959ndash967 2005


[83] H Ovadia Y Haim O Nov et al ldquoIncreased adipocyte S-nitrosylation targets anti-lipolytic action of insulin relevance toadipose tissue dysfunction in obesityrdquoThe Journal of BiologicalChemistry vol 286 no 35 pp 30433ndash30443 2011

[84] M A Carvalho-Filho M Ueno J B C Carvalheira L AVelloso and M J A Saad ldquoTargeted disruption of iNOSprevents LPS-induced S-nitrosation of IR120573IRS-1 and Akt andinsulin resistance in muscle of micerdquo The American Journal ofPhysiology vol 291 no 3 pp E476ndashE482 2006

[85] E R Ropelle J R Pauli D E Cintra et al ldquoTargeted disruptionof inducible nitric oxide synthase protects against aging S-nitrosation and insulin resistance in muscle of male micerdquoDiabetes vol 62 no 2 pp 466ndash470 2013

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[97] E Devillard F M McIntosh S H Duncan and R J WallaceldquoMetabolism of linoleic acid by human gut bacteria differentroutes for biosynthesis of conjugated linoleic acidrdquo Journal ofBacteriology vol 189 no 6 pp 2566ndash2570 2007

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[99] J R Swann E J Want F M Geier et al ldquoSystemic gutmicrobial modulation of bile acid metabolism in host tissuecompartmentsrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 108 no 1 pp 4523ndash45302011

[100] A B Sahakian S R Jee and M Pimentel ldquoMethane and thegastrointestinal tractrdquo Digestive Diseases and Sciences vol 55no 8 pp 2135ndash2143 2010

[101] P Marquet S H Duncan C Chassard A Bernalier-Donadilleand H J Flint ldquoLactate has the potential to promote hydrogensulphide formation in the human colonrdquo FEMS MicrobiologyLetters vol 299 no 2 pp 128ndash134 2009

[102] S Tedelind F Westberg M Kjerrulf and A Vidal ldquoAnti-inflammatory properties of the short-chain fatty acids acetateand propionate a study with relevance to inflammatory boweldiseaserdquo World Journal of Gastroenterology vol 13 no 20 pp2826ndash2832 2007

[103] S H Al-Lahham H Roelofsen M Priebe et al ldquoRegulationof adipokine production in human adipose tissue by propionicacidrdquo European Journal of Clinical Investigation vol 40 no 5pp 401ndash407 2010

[104] J Fukae Y Amasaki Y Yamashita et al ldquoButyrate suppressestumor necrosis factor 120572 production by regulating specificmessenger RNA degradation mediated through a cis-actingAU-rich elementrdquo Arthritis and Rheumatism vol 52 no 9 pp2697ndash2707 2005

[105] M D Saemann G A Bohmig C H Osterreicher et al ldquoAnti-inflammatory effects of sodium butyrate on humanmonocytespotent inhibition of IL-12 and up-regulation of IL-10 produc-tionrdquoThe FASEB Journal vol 14 no 15 pp 2380ndash2382 2000

[106] K M Maslowski A T Vieira A Ng et al ldquoRegulation ofinflammatory responses by gutmicrobiota and chemoattractantreceptorGPR43rdquoNature vol 461 no 7268 pp 1282ndash1286 2009

[107] A Barcelo J Claustre F Moro J A Chayvialle J C Cuber andP Plaisancie ldquoMucin secretion is modulated by luminal factorsin the isolated vascularly perfused rat colonrdquoGut vol 46 no 2pp 218ndash224 2000

[108] E Gaudier A Jarry H M Blottiere et al ldquoButyrate specificallymodulates MUC gene expression in intestinal epithelial gobletcells deprived of glucoserdquo The American Journal of Physiologyvol 287 no 6 pp G1168ndashG1174 2004

[109] M Bordin F DrsquoAtri L Guillemot and S Citi ldquoHistone deacety-lase inhibitors up-regulate the expression of tight junctionproteinsrdquoMolecular Cancer Research vol 2 no 12 pp 692ndash7012004

[110] L Peng Z He W Chen I R Holzman and J Lin ldquoEffectsof butyrate on intestinal barrier function in a caco-2 cellmonolayer model of intestinal barrierrdquo Pediatric Research vol61 no 1 pp 37ndash41 2007

[111] S Fukuda H Toh K Hase et al ldquoBifidobacteria can pro-tect from enteropathogenic infection through production ofacetaterdquo Nature vol 469 no 7331 pp 543ndash547 2011

[112] T Suzuki S Yoshida and H Hara ldquoPhysiological concentra-tions of short-chain fatty acids immediately suppress colonicepithelial permeabilityrdquoTheBritish Journal of Nutrition vol 100no 2 pp 297ndash305 2008


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[114] B B Kahn T Alquier D Carling and D G Hardie ldquoAMP-activated protein kinase ancient energy gauge provides clues tomodern understanding of metabolismrdquo Cell Metabolism vol 1no 1 pp 15ndash25 2005

[115] S Sakakibara T Yamauchi Y Oshima Y Tsukamoto and TKadowaki ldquoAcetic acid activates hepatic AMPK and reduceshyperglycemia in diabetic KK-A(y) micerdquo Biochemical andBiophysical Research Communications vol 344 no 2 pp 597ndash604 2006

[116] Z Gao J Yin J Zhang et al ldquoButyrate improves insulinsensitivity and increases energy expenditure in micerdquo Diabetesvol 58 no 7 pp 1509ndash1517 2009

[117] CGrootaert T van deWiele I vanRoosbroeck et al ldquoBacterialmonocultures propionate butyrate and H

2O2modulate the

expression secretion and structure of the fasting-inducedadipose factor in gut epithelial cell linesrdquo Environmental Micro-biology vol 13 no 7 pp 1778ndash1789 2011

[118] S Alex K Lange T Amolo et al ldquoShort-chain fatty acidsstimulate angiopoietin-like 4 synthesis in human colon adeno-carcinoma cells by activating peroxisome proliferator-activatedreceptor 120574rdquo Molecular and Cellular Biology vol 33 no 7 pp1303ndash1316 2013

[119] Y H Hong Y Nishimura D Hishikawa et al ldquoAcetate andpropionate short chain fatty acids stimulate adipogenesis viaGPCR43rdquo Endocrinology vol 146 no 12 pp 5092ndash5099 2005

[120] C J Small and S R Bloom ldquoGut hormones and the control ofappetiterdquo Trends in Endocrinology and Metabolism vol 15 no6 pp 259ndash263 2004

[121] O B Chaudhri V Salem K G Murphy and S R BloomldquoGastrointestinal satiety signalsrdquo Annual Review of Physiologyvol 70 pp 239ndash255 2008

[122] Y Xiong N Miyamoto K Shibata et al ldquoShort-chain fattyacids stimulate leptin production in adipocytes through the Gprotein-coupled receptor GPR41rdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no4 pp 1045ndash1050 2004

[123] K R Freeland and T M S Wolever ldquoAcute effects of intra-venous and rectal acetate on glucagon-like peptide-1 peptideYY ghrelin adiponectin and tumour necrosis factor-120572rdquo TheBritish Journal of Nutrition vol 103 no 3 pp 460ndash466 2010

[124] C A Baile ldquoMetabolites as feedbacks for control of feed intakeand receptor sites in goats and sheeprdquo Physiology and Behaviorvol 7 no 6 pp 819ndash826 1971

[125] M H Anil and J M Forbes ldquoFeeding in sheep duringintraportal infusions of short-chain fatty acids and the effect ofliver denervationrdquo Journal of Physiology vol 298 pp 407ndash4141980

[126] H V Lin A Frassetto E J Kowalik Jr et al ldquoButyrate andpropionate protect against diet-induced obesity and regulate guthormones via free fatty acid receptor 3-independent mecha-nismsrdquo PLoS ONE vol 7 no 4 Article ID e35240 2012

[127] R M A J Ruijschop A E M Boelrijk and M C T GiffelldquoSatiety effects of a dairy beverage fermented with propionicacid bacteriardquo InternationalDairy Journal vol 18 no 9 pp 945ndash950 2008

[128] J Zhou M Hegsted K L McCutcheon et al ldquoPeptide YY andproglucagon mRNA expression patterns and regulation in thegutrdquo Obesity vol 14 no 4 pp 683ndash689 2006

[129] B S Samuel A Shaito T Motoike et al ldquoEffects of the gutmicrobiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor Gpr41rdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 105 no 43 pp 16767ndash16772 2008

[130] M Membrez F Blancher M Jaquet et al ldquoGut microbiotamodulation with norfloxacin and ampicillin enhances glucosetolerance in micerdquo The FASEB Journal vol 22 no 7 pp 2416ndash2426 2008

[131] C J ChouMMembrez and F Blancher ldquoGut decontaminationwith norfloxacin and ampicillin enhances insulin sensitivity inmicerdquo Nestle Nutrition Workshop Series Pediatric Program vol62 pp 127ndash140 2008

[132] I Cho S Yamanishi L Cox et al ldquoAntibiotics in early life alterthemurine colonicmicrobiome and adiposityrdquoNature vol 488no 7413 pp 621ndash626 2012

[133] G Ternak ldquoAntibiotics may act as growthobesity promotersin humans as an inadvertent result of antibiotic pollutionrdquoMedical Hypotheses vol 64 no 1 pp 14ndash16 2005

[134] M Caselli F Cassol G Calo J Holton G Zuliani and AGasbarrini ldquoActual concept of ldquoprobioticsrdquo is itmore functionalto science or businessrdquoWorld Journal of Gastroenterology vol19 no 10 pp 1527ndash1540 2013

[135] L Macia A N Thorburn L C Binge et al ldquoMicrobialinfluences on epithelial integrity and immune function as abasis for inflammatory diseasesrdquo Immunological Reviews vol245 no 1 pp 164ndash176 2012

[136] N Takemura T Okubo and K Sonoyama ldquoLactobacillusplantarum strainNo 14 reduces adipocyte size inmice fed high-fat dietrdquo Experimental Biology and Medicine vol 235 no 7 pp849ndash856 2010

[137] Y Kadooka M Sato K Imaizumi et al ldquoRegulation of abdom-inal adiposity by probiotics (Lactobacillus gasseri SBT2055) inadults with obese tendencies in a randomized controlled trialrdquoEuropean Journal of Clinical Nutrition vol 64 no 6 pp 636ndash643 2010

[138] A S Andreasen N Larsen T Pedersen-Skovsgaard et alldquoEffects of Lactobacillus acidophilus NCFM on insulin sensitiv-ity and the systemic inflammatory response in human subjectsrdquoThe British Journal of Nutrition vol 104 no 12 pp 1831ndash18382010

[139] R Luoto M Kalliomaki K Laitinen and E Isolauri ldquoTheimpact of perinatal probiotic intervention on the developmentof overweight and obesity follow-up study from birth to 10yearsrdquo International Journal of Obesity vol 34 no 10 pp 1531ndash1537 2010

[140] L Aronsson Y Huang P Parini et al ldquoDecreased fat storageby Lactobacillus paracasei is associated with increased levels ofangiopoietin-like 4 protein (ANGPTL4)rdquo PLoS ONE vol 5 no9 Article ID e13087 2010

[141] J M Uronis J C Arthur T Keku et al ldquoGutmicrobial diversityis reduced by the probiotic VSL3 and correlates with decreasedTNBS-induced colitisrdquo Inflammatory Bowel Diseases vol 17 no1 pp 289ndash297 2011

[142] R Mennigen K Nolte E Rijcken et al ldquoProbiotic mixtureVSL3 protects the epithelial barrier by maintaining tightjunction protein expression and preventing apoptosis in amurine model of colitisrdquo The American Journal of Physiologyvol 296 no 5 pp G1140ndashG1149 2009


[143] A Mencarelli S Cipriani B Renga et al ldquoVSL3 resets insulinsignaling and protects against NASH and atherosclerosis in amodel of genetic dyslipidemia and intestinal inflammationrdquoPLoS ONE vol 7 no 9 Article ID e45425 2012

[144] C Alberda L Gramlich J Meddings et al ldquoEffects of probiotictherapy in critically ill patients a randomized double-blindplacebo-controlled trialrdquo The American Journal of ClinicalNutrition vol 85 no 3 pp 816ndash823 2007

[145] X Ma J Hua and Z Li ldquoProbiotics improve high fat diet-induced hepatic steatosis and insulin resistance by increasinghepatic NKT cellsrdquo Journal of Hepatology vol 49 no 5 pp 821ndash830 2008

[146] S Rakoff-Nahoum J Paglino F Eslami-Varzaneh S Edbergand R Medzhitov ldquoRecognition of commensal microflora bytoll-like receptors is required for intestinal homeostasisrdquo Cellvol 118 no 2 pp 229ndash241 2004

[147] S Resta-Lenert and K E Barrett ldquoLive probiotics protectintestinal epithelial cells from the effects of infection withenteroinvasive Escherichia coli (EIEC)rdquo Gut vol 52 no 7 pp988ndash997 2003

[148] A A Zyrek C Cichon S Helms C Enders U Sonnenbornand M A Schmidt ldquoMolecular mechanisms underlying theprobiotic effects of Escherichia coliNissle 1917 involve ZO-2 andPKC120577 redistribution resulting in tight junction and epithelialbarrier repairrdquo Cellular Microbiology vol 9 no 3 pp 804ndash8162007

[149] M Pineiro N G Asp G Reid et al ldquoFAO Technical meetingon prebioticsrdquo Journal of Clinical Gastroenterology vol 42supplement 3 part 2 pp S156ndashS159 2008

[150] A M Bakker-Zierikzee E A F van Tol H Kroes M S AllesF J Kok and J G Bindels ldquoFaecal SIgA secretion in infantsfed on pre- or probiotic infant formulardquo Pediatric Allergy andImmunology vol 17 no 2 pp 134ndash140 2006

[151] F Campeotto A Suau N Kapel et al ldquoA fermented formulain pre-term infants clinical tolerance gut microbiota down-regulation of faecal calprotectin and up-regulation of faecalsecretory IgArdquo The British Journal of Nutrition vol 105 no 12pp 1843ndash1851 2011

[152] P D Cani C Knauf M A Iglesias D J Drucker N MDelzenne and R Burcelin ldquoImprovement of glucose toleranceand hepatic insulin sensitivity by oligofructose requires afunctional glucagon-like peptide 1 receptorrdquo Diabetes vol 55no 5 pp 1484ndash1490 2006

[153] P D Cam A M Neyrinck N Maton and N M DelzenneldquoOligofructose promotes satiety in rats fed a high-fat dietinvolvement of glucagon-like peptiderdquoObesity Research vol 13no 6 pp 1000ndash1007 2005

[154] C Daubioul N Rousseau R Demeure et al ldquoDietary fructansbut not cellulose decrease triglyceride accumulation in the liverof obese Zucker fafa ratsrdquo Journal of Nutrition vol 132 no 5pp 967ndash973 2002

[155] P D Cani A M Neyrinck F Fava et al ldquoSelective increases ofbifidobacteria in gut microflora improve high-fat-diet-induceddiabetes in mice through a mechanism associated with endo-toxaemiardquo Diabetologia vol 50 no 11 pp 2374ndash2383 2007

[156] S A Abrams I J Griffin K M Hawthorne and K J EllisldquoEffect of prebiotic supplementation and calcium intake onbody mass indexrdquo Journal of Pediatrics vol 151 no 3 pp 293ndash298 2007

[157] S Genta W Cabrera N Habib et al ldquoYacon syrup beneficialeffects on obesity and insulin resistance in humansrdquo ClinicalNutrition vol 28 no 2 pp 182ndash187 2009

[158] M Roberfroid G R Gibson L Hoyles et al ldquoPrebiotic effectsmetabolic and health benefitsrdquoThe British Journal of Nutritionvol 104 supplement 2 pp S1ndashS63 2010

[159] P D Cani S Hoste Y Guiot and N M Delzenne ldquoDietarynon-digestible carbohydrates promote L-cell differentiation inthe proximal colon of ratsrdquoThe British Journal of Nutrition vol98 no 1 pp 32ndash37 2007

[160] N M Delzenne P D Cani C Daubioul and A M NeyrinckldquoImpact of inulin and oligofructose on gastrointestinal pep-tidesrdquo The British Journal of Nutrition vol 93 pp S157ndashS1612005

[161] J M Gee and I T Johnson ldquoDietary lactitol fermentationincreases circulating peptide YY and glucagon-like peptide-1 inrats and humansrdquoNutrition vol 21 no 10 pp 1036ndash1043 2005

[162] A A Aziz L S Kenney B Goulet and E S Abdel-Aal ldquoDietarystarch type affects body weight and glycemic control in freelyfed but not energy-restricted obese ratsrdquo Journal of Nutritionvol 139 no 10 pp 1881ndash1889 2009

[163] M J Keenan J Zhou K L McCutcheon et al ldquoEffects ofresistant starch a non-digestible fermentable fiber on reducingbody fatrdquo Obesity vol 14 no 9 pp 1523ndash1534 2006

[164] L ShenM J Keenan R JMartin et al ldquoDietary resistant starchincreases hypothalamic POMC expression in ratsrdquoObesity vol17 no 1 pp 40ndash45 2009

[165] J Zhou R J Martin R T Tulley et al ldquoDietary resistantstarch upregulates total GLP-1 and PYY in a sustained day-long manner through fermentation in rodentsrdquo The AmericanJournal of Physiology vol 295 no 5 pp E1160ndashE1166 2008

[166] J A Parnell and R A Reimer ldquoWeight loss during oligofruc-tose supplementation is associated with decreased ghrelin andincreased peptide YY in overweight and obese adultsrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 6 pp 1751ndash1759 2009

[167] J Tarini and T M S Wolever ldquoThe fermentable fibre inulinincreases postprandial serum short-chain fatty acids andreduces free-fatty acids and ghrelin in healthy subjectsrdquoAppliedPhysiology Nutrition and Metabolism vol 35 no 1 pp 9ndash162010

[168] P D Cani S Possemiers T van de Wiele et al ldquoChanges ingut microbiota control inflammation in obese mice througha mechanism involving GLP-2-driven improvement of gutpermeabilityrdquo Gut vol 58 no 8 pp 1091ndash1103 2009

[169] H Zhang J K DiBaise A Zuccolo et al ldquoHuman gutmicrobiota in obesity and after gastric bypassrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 106 no 7 pp 2365ndash2370 2009

[170] A P Liou M Paziuk J M Luevano Jr S Machineni PJ Turnbaugh and L M Kaplan ldquoConserved shifts in thegut microbiota due to gastric bypass reduce host weight andadiposityrdquo Science Translational Medicine vol 5 no 178 ArticleID 178ra141 2013

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


efforts have been made regarding inflammation in metabolictissues trying to determinewhat primes the insulin resistancephenomenon the consequences of obesity how to improvethe molecular knowledge of insulin activity attenuationmediated by obesity and how it can be managed in orderto improve patient quality of life Attempts have also beenmade to reduce or prevent the incidence of obesity and itscomorbidities

Here we will focus on reviewing the latest contributionsto the literature on the influence of the intestine on thepathogenesis of insulin resistance and the consequences ofinsulin resistance on the liver muscle adipose tissue andhypothalamus as well as the mechanisms by which the gutmicrobiota influences systemic insulin resistance

2 Intestinal Participation inInsulin Resistance

For several decades it has been known that the mammaliansintestine harbors a great number of bacteria (sim1014 bacteria)that even surpasses the total number of cells that comprisemammalian tissues systems and ultimately the entire body[10] Furthermore it is estimated that the gut microbiotacontains at least 100-fold more genes than the mammaliangenome These bacteria can live in a symbiotic way but incertain cases promote disease [11] However over the lastten years this community that lives within the mammalianbody has been gaining the status of a microbial organ thatcontributes to homeostasis and impacts directly on energymetabolism and insulin sensitivity [12 13]

3 The Obese Microbiome Has IncreasedEnergy Harvesting Ability

One of the first and foremost important observations onthe role of the gut microbiota in insulin sensitivity andbody weightmanagement was observed when germ-freemicethat were infected with the gut microbiota content of aconventionally raised mice showed an increase (by about60) in body fat content Moreover the occurrence ofinsulin resistance and glucose intolerance was seen within 14days even with a reduction in food intake (standard chow)providing novel evidence that the bacteria community insome way controlled energy metabolism [14] Additionallyit was described that the activity of a lipoprotein lipase (LPL)suppressor known as fasting-induced adipocyte factor (Fiaf)or angiopoietin-like protein 4 (ANGPTL4) controlled the fatstorage abnormalities observed in conventionalized germ-freemice where the gutmicrobiota induced selective suppressionof this protein in intestinal cells and promoted an increase inLPL activityThis resulted in increased triglyceride storage inadipocytes which was prevented upon the conventionaliza-tion of Fiafminusminus germ-freemice [14]

It was also shown that the resistance of germ-free miceagainst diet-induced obesity relied on increased liver andskeletal muscle AMPK activity and its downstream targetsThis induced the activation of fatty acid oxidation andincreased energy expenditure which regulated body weight

gain since Fiaf expression in the gut epithelium was highlysuppressed in germ-free mice fed a high-fat diet keepingthe body weight almost unaltered a feature that was notmaintained in Fiafminusminus germ-freemice [15]

The great increase in interest in the relationship betweenthe gut microbiota and mammalian metabolism has led tothe utilization of very elegant and novelmolecular techniquesbased on microbial DNA sequencing [16 17] This interesthas also brought new insight into the epidemic obesity ratesthroughout the world and the consequent incidence of type 2diabetes comorbidities and cancer

Metagenomic analyses of human volunteers showed thatalmost all bacteria present in the distal gut and feces belongto two main bacterial phyla Bacteroidetes and Firmicutes[18] The predominance of these phyla is also seen in leanmice with a balance among the bacterial phyla but ingenetically obese obob mice this balance is broken Inobese mice a great increase in bacteria from the phylumFirmicutes and a comparable decrease in the prevalence ofBacteroidetes were observed indicating gut microbiota alter-ation driven by obesity predisposing for or associated withthis metabolic condition [19] Moreover it was demonstratedthat microbiota transplantation from obob mice to germ-free recipients induced a greater increase in body fat contentwhen compared with germ-freemice that were the recipientsof lean mice gut microbiota indicating that this differencein the intestinal flora induced the obese phenotype [20]Additionally it was shown that the microbiota in the fecesof lean and obese humans was different in a similar way asthat observed in mice [20] All this information led to thehypothesis that the gut microbiota from obob geneticallyobesemice is capable of harvestingmore energy from the diet[21 22] probably by the presence andor increased prevalenceof bacteria that produce enzymes that are more efficient indegrading the nutrients available in the diet

The relationship between the phyla Bacteroidetes andFirmicutes is the main focus of discussion when obesityis studied with a considerable amount of data showingan increase in Firmicutes prevalence and a reduction inBacteroidetes [19 20 23ndash26] However this issue has not yetbeen completely addressed as we can find several studiesin the literature that maintain the opposite where theprevalence of Firmicutes is decreased in overweight and obeseindividuals as well as in obese mice with an accompanyingincrease in Bacteroidetes prevalence [27ndash30] Additionallythe presence of nonsignificant prevalent bacteria phyla inthe gut of lean mice such as Verrucomicrobia has notbeen well explored until now with very few observationson increases in pathological conditions (obesity and cancer)and no mechanistic evaluations [27 31] The differencesobserved among gut microbiota human studies still have tobe addressed evaluating the ethnics and feeding behavior ofthe studied population as well as the standardization of themethods used In animal studies the probable cause of theopposite outcomes may be a factor of different mouse strainsused The issue of the ldquohealthyrdquo bacterial group profile is avery important point in gut microbiota research and needs tobe further exploredThus no proposed treatment attempting










Intestinal lumen

LPS

Gut microbiota


Gut epithelium


Hypothalamus


darr Fiaf



darr PYY


darr GLP-1

uarr LPS































darr LPS

uarr Fiaf




uarr PYY


uarr GLP-1





Gut epithelium

Hypothalamus






7 Conclusions





References



























































































































2O2modulate the





























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























Intestinal lumen

LPS

Gut microbiota


Gut epithelium


Hypothalamus


darr Fiaf



darr PYY


darr GLP-1

uarr LPS































darr LPS

uarr Fiaf




uarr PYY


uarr GLP-1





Gut epithelium

Hypothalamus






7 Conclusions





References



























































































































2O2modulate the





























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






































darr LPS

uarr Fiaf




uarr PYY


uarr GLP-1





Gut epithelium

Hypothalamus






7 Conclusions





References



























































































































2O2modulate the





























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















7 Conclusions





References



























































































































2O2modulate the





























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























































































































2O2modulate the





























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article influence of gut microbiota on subclinical inflammation and...

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