TheRoleoftheGutMicrobiomeinCardioMetabolicDisease

Todd R. LePine, MDwww.drlepine.com

2

Relevant financial relationships in the past twelve months by

Dr. Todd LePine or spouse/partner:

Employment: NoneGrant/Research Support: None

Consultant: NeuroScienceSpeakers Bureau: Designs for Health, Genova Diagnostics Laboratory

Stock Shareholder: NoneOther: None

Status of FDA devices used for the material being presented

NA/Non-Clinical

Status of off-label use of devices, drugs or other materials that constitute the subject of this presentation

NA/Non-Clinical

4

SOURCE:TheUl9mateSocialNetwork

Scien/ficAmerican.June2012,Ackermanetal.

“ According to one common estimate, the human gut contains

at least a kilogram of bacteria alone. They contribute so much to human

biology that it is difficult to say where the body ends and the microbes

begin”

6

SOURCE:h@p://www.wired.com/magazine/2011/09/mf_microbiome/

SOURCE:h@p://www.wired.com/magazine/2011/09/mf_microbiome/

• Individuals with low bacterial gene richness (23% of study population) were characterized by more marked overall adiposity, insulin resistance, and dyslipidaemia.

• Low-bacterial-richness individuals showed a more pronounced inflammatory phenotype when compared with high-bacterial-richness individuals.

Source: Le Chatelier, E., et al. (2013). "Richness of human gut microbiome correlates with metabolic markers." Nature

500(7464): 541-546.

• Emerging evidence suggests, however, that variation in our ‘other genome’ the collective genome of the microorganisms inhabiting our body, known as the microbiome may have an even greater role than human genome variation in the pathogenesis of obesity given its direct interaction with environmental factors.

Source: Le Chatelier, E., et al. (2013). "Richness of human gut microbiome correlates with metabolic markers." Nature

500(7464): 541-546.

Source: Le Chatelier, E., et al. (2013). "Richness of human gut microbiome correlates with metabolic markers." Nature 500(7464): 541-546.

LGC (low gene count)

Commensal Bacteria

“We identified Chryseomonas in all atherosclerotic plaque samples, and Veillonella and Streptococcus in the

majority.....Taken together, our findings suggest that bacteria from the oral

cavity, and perhaps even the gut, may correlate with disease markers of

atherosclerosis.”

15

16NEnglJMed2013;368:1575-84.

Itwasoriginallybelievedthatthecomposi/onoftheintes/nal

microbiotawasrela/velystablefromearlychildhood;however,

recentevidencesuggeststhatdietcancausedysbiosis,analtera1on

inthecomposi1onofthemicrobiota,whichcouldleadtoaberrantimmuneresponses.

18

19

20

21

22

“FatBugs”• Recently,twophylaofmainlyanaerobicbeneficialbacteriahavebeenlinkedtoobesity:–Firmicutes–Bacteroidetes

• Theirimpactisthroughanimbalanceofthesephyla

• Leansubjectshaveara/oof:20%Bacteroidetes

25

“Thegutmicrobiotacontributestohostmetabolismbyseveralmechanismsincludingincreasedenergyharvestfromthediet,modula/onoflipidmetabolism,alteredendocrine

func/on,andincreasedinflammatorytone.Thegutmicrobiotacouldthusbe

consideredtobeanenvironmentalfactorthatmodulatesobesityandother

metabolicdiseases.”

26“Host remodeling of the gut microbiome and metabolic changes in pregnancy,”

Cell, 150: 470-480, 2012

Gutmicrobessome/mesmovebetweenmicethatarehousedtogether.Microbesfromobesepeopledon'treadilymovebetweenanimals,whilemicrobesfromleanpeoplecantakeholdinanothermouse'sgut,keepingtheanimalslim.Ahigh-fatdiet,however,blocksthetransferoflean-promo9ngmicrobesandtheirprotec9veeffects.Credit:NebojsaSOURCE:ScienceNewsOctober5,2013;Vol.184#7

29Gut bacterial microbiota and obesityEuropean Society of Clinical Microbiology and Infectious Diseases, CMI, 19, 305–313

30

“Weiden/fyNAS-alteredmicrobialmetabolicpathways

thatarelinkedtohostsuscep/bilitytometabolicdisease,anddemonstrate

similarNAS-induceddysbiosisandglucoseintoleranceinhealthyhumansubjects.

Collec9vely,ourresultslinkNASconsump9on,dysbiosisandmetabolic

abnormali9es,therebycallingforareassessmentof

massiveNASusage.”

“Herein, we observed that, in mice, relatively low concentrations of two commonly used emulsifiers, namely

carboxymethylcellulose and polysorbate-80, induced low-grade

inflammation and obesity/metabolic syndrome in WT hosts and promoted robust colitis in mice predisposed to

this disorder. Emulsifier-induced metabolic syndrome was associated

with microbiota encroachment, altered species composition, and

increased pro-inflammatory potential.

Inmanypeoplewithtype2diabetes,thediseasevanishesalmostimmediatelyahersurgery,tooquicklytobeexplainedbythegradualweightlossthathappenslater.Pa1entsalsodescribenotbeingas

hungry,orcravingfoodslikesaladthattheyhadn'tlikedmuchbefore.

34

35

“Microbesinthegastrointes9naltractareunderselec9vepressuretomanipulatehostea9ngbehaviortoincreasetheirfitness,some9mesattheexpenseofhostfitness.Microbesmaydothisthroughtwopoten/alstrategies:(i)genera/ngcravingsforfoodsthattheyspecializeonorfoodsthatsuppresstheircompe/tors,or(ii)inducingdysphoriaun/lweeatfoods

thatenhancetheirfitness.”

36

39

Thepathwaysofan9geninvasionthroughParacellularandTranscellularroutes.

Breakdown of Actomyosin Network

Tight Junction Dysfunction

“Viaaltera/onsintheintes/nalpermeability,intes/nalbarrier

func/onbecomescompromisedwherebyaccessofinfec/ousagentsanddietaryan/genstomucosalimmuneelementsisfacilitated,whichmay

eventuallyleadtoimmunereac/onswithdamagetopancrea/cbetacellsand

canleadtoincreasedcytokineproduc/onwithconsequentinsulin

resistance.”

48

42

“Ourfindingssupportahypothesisoftranslocatedgutbacteriaasapoten9altriggerofobesityand

diabetes,andsuggestthatthean9diabe9ceffectsofbariatricsurgerymightbemechanis9callylinkedto,andeventheresultof,areduc9on

inplasmalevelsofLPS.”

43

CONCLUSIONS “This is the first report of gut dysbiosis

in Japanese patients with type 2 diabetes as assessed by RT-qPCR. The high rate

of gut bacteria in the circulation suggests translocation of bacteria from the gut to the bloodstream.”

44

“MGWAS analysis showed that patients with type 2

diabetes were characterized by a

moderate degree of gut microbial dysbiosis, a

decrease in the abundance of some universal

butyrate-producing bacteria and an increase in

various opportunistic pathogens, as well as an

enrichment of other microbial functions conferring sulphate reduction and oxidative stress

resistance.”

45

“In conclusion, our data suggest that, in a compromised metabolic

state such as type 2 diabetes, a continual snacking routine will

cumulatively promote their conditionmore rapidly than in other individuals because of the greater exposure to

endotoxin.”

46

47

“Type2diabetes(T2DM)isbelievedtobecausedbyaseriesofmul/pleriskfactorssuchasgene/cliability,age,overweightorobesity,andan

unhealthylifestyle.Recently,accumulatedevidencehassuggestedthattheintes9nal

microbiotaplaysanimportantroleinthepathogenesisofT2DMasapoten9alnovelcontributor.”

48

49

50

Dosymbio9cbacteriasubverthostimmunity?LoraV.Hooper

NatureReviewsMicrobiology7,367-374(May2009)

“We recently isolated Akkermansia muciniphila,

which is a mucin-degrading bacterium that resides in

the mucus layer. The presence of this

bacterium inversely correlates with body weight in rodents and

humans.”

“We demonstrated that A. muciniphila treatment reversed high-fat diet-induced metabolic disorders,

including fat-mass gain, metabolic endotoxemia, adipose tissue

inflammation, and insulin resistance. A. muciniphila administration

increased the intestinal levels of endocannabinoids that control inflammation, the gut barrier,

and gut peptide secretion.”

“We recently discovered that the administration of

prebiotics (oligofructose) to genetically obese mice

increased the abundanceof A. muciniphila by

∼100-fold”

54

Conclusions: Modulation of the gut microbiota (by an increase in the Akkermansia spp. population) may

contribute to the antidiabetic effects of metformin, thereby providing a new

mechanism for the therapeutic effect of metformin in patients with T2D. This

suggests that pharmacological manipulation of the gut microbiota in

favour of Akkermansia may be a potential treatment for T2D.

55

“the authors further nailed down the concept by treating diabetic mice with the bacteria

as a probiotic and demonstrated that the

enrichment of the intestinal mucosal layer with the bacteria improved the glycaemic control and

metabolic endotoxaemia, as previously described.”

56

This last set of data is comforted by the increased number of regulatory T cells (Tregs) within the adipose

depot, which was increased by metformin or A muciniphila

treatment, suggesting that this single bacterium could attenuate metabolic

inflammation by inducing the generation of Tregs and suppressing the production of pro-

inflammatory cytokines.

57

In conclusion, we report that the pleotropic effects of metformin include alteration of the entero-hepatic recirculation of bile acids, modulation of gut microbiota and

changes in gut hormones, especially GLP-1. These findings suggest that the

gastrointestinal tract is an important target organ of metformin and are consistent with

the evidence that oral formulations of metformin are more effective than

intravenous administration.

58

59

60

“Bile acids appear to function as nutrient signaling molecules primarily during the feed/fast cycle as there is a flux of these molecules returning

from the intestines to the liver following a meal”

Bile acids as regulatory moleculesJ Lipid Res. Aug 2009; 50(8): 1509–1520.

61

62

“Oral administration of probiotics has been shown to significantly reduce

cholesterol levels by as much as 22 to 33% or prevent elevated cholesterol levels in mice fed a fat-enriched diet.

These cholesterol-lowering effects can be partially ascribed to BSH activity

(other possible mechanisms not discussed here include assimilation of cholesterol by the bacteria, binding of cholesterol to the

bacterial cell walls, or physiological actions of the end products of short- chain

fatty acid fermentation)”

63

64

65

“Bile acids are hormones that regulate their own synthesis, transport, in

addition to glucose and lipid homeostasis, and energy balance. The gut microbial community through their

capacity to produce bile acid metabolites distinct from the liver can be thought of

as an “endocrine organ” with potential to alter host physiology, perhaps to their

own favor.”

66

67

“We have observed that the pretreatment levels of bile acids derived from gut bacteria and nutrient inputs are correlated with response to simvastatin.

It is becoming increasingly clear that gut microbial symbiots are critical for normal digestion and defense, and also play an important role in development of disease and in metabolizing orally

ingested therapeutics. There is increasing recognition that intestinal bacteria can metabolize drugs and

alter an individual’s response to drug treatment depending on specific

bacterial strains present.”

68

“We identified three secondary, bacterial-derived bile acids that

contribute to predicting the magnitude of statin-induced LDL-C lowering in

good responders. Bile acids and statins share transporters in the liver and

intestine; we observed that increased plasma concentration of simvastatin

positively correlates with higher levels of several secondary bile

acids.”

69

“These findings, along with recently published results that the gut

microbiome plays an important role in cardiovascular disease, indicate that interactions between genome, gut microbiome and environmental

influences should be considered in the study and management of cardiovascular disease.”

70

DOI: 10.1161/CIRCRESAHA.115.306807 1

The Gut Microbiome Contributes to a Substantial Proportion of the Variation in Blood Lipids

Jingyuan Fu1,2, Marc Jan Bonder2, María Carmen Cenit2, Ettje Tigchelaar2,3, Astrid Maatman2, Jackie A.M. Dekens2,3, Eelke Brandsma1, Joanna Marczynska2,4, Floris Imhann5, Rinse K. Weersma5, Lude

Franke2, Tiffany W. Poon6, Ramnik J. Xavier6,7,8, Dirk Gevers6, Marten H. Hofker1, Cisca Wijmenga2, Alexandra Zhernakova2,3

1University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen,

the Netherlands; 2University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands; 3Top Institute Food and Nutrition, Wageningen, the Netherlands;

4Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland; 5University of Groningen, University Medical Center Groningen,

Department of Gastroenterology and Hepatology, Groningen, the Netherlands; 6Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; 7Gastrointestinal Unit and Center for the Study of

Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA, and; 8Center for Computational and Integrative Biology, Massachusetts General

Hospital and Harvard Medical School, Boston, Massachusetts, USA.

M.H.H., C.W., and A.Z. contributed equally to this study.

Running title: Microbiome Affects Lipids Subject codes: [112] Lipids [135] Risk Factors Address correspondence to: Dr. Jingyuan Fu Department of Pediatrics and Department of Genetics University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen The Netherlands Tel: +31-655256321 Fax +31-50-3617230 fjingyuan@gmail.com In July 2015, the average time from submission to first decision for all original research papers submitted to Circulation Research was 12.38 days.

by guest on October 18, 2015http://circres.ahajournals.org/Downloaded from by guest on October 18, 2015http://circres.ahajournals.org/Downloaded from by guest on October 18, 2015http://circres.ahajournals.org/Downloaded from by guest on October 18, 2015http://circres.ahajournals.org/Downloaded from by guest on October 18, 2015http://circres.ahajournals.org/Downloaded from by guest on October 18, 2015http://circres.ahajournals.org/Downloaded from by guest on October 18, 2015http://circres.ahajournals.org/Downloaded from by guest on October 18, 2015http://circres.ahajournals.org/Downloaded from by guest on October 18, 2015http://circres.ahajournals.org/Downloaded from by guest on October 18, 2015http://circres.ahajournals.org/Downloaded from by guest on October 18, 2015http://circres.ahajournals.org/Downloaded from by guest on October 18, 2015http://circres.ahajournals.org/Downloaded from by guest on October 18, 2015http://circres.ahajournals.org/Downloaded from by guest on October 18, 2015http://circres.ahajournals.org/Downloaded from by guest on October 18, 2015http://circres.ahajournals.org/Downloaded from by guest on October 18, 2015http://circres.ahajournals.org/Downloaded from by guest on October 18, 2015http://circres.ahajournals.org/Downloaded from by guest on October 18, 2015http://circres.ahajournals.org/Downloaded from by guest on October 18, 2015http://circres.ahajournals.org/Downloaded from

A novel risk model including the gut microbiome explained up to 25.9% of HDL variance, significantly outperforming the risk model without microbiome. Strikingly, the microbiome had

little effect on low-density lipoproteins or total cholesterol. Conclusions: Our studies suggest that the gut microbiome may play an important role in the variation in BMI and blood lipid levels, independent of age, gender and host genetics. Our findings support the potential of therapies altering the gut microbiome to control body

mass, triglycerides and HDL.

July 2015

71

“In summary, we present evidence that it is possible to identify obese individuals who

will benefit most from a simple dietary intervention based on the gut microbiota

composition before the intervention. Clostridial species, in particular, were indicative of the amenability of the gut

microbiota to dietary modification, which in turn was associated with the host’s lipid

metabolism.”

72

“Aher100yearsofsymbio/cassocia/onwiththehumanhost,themicrobiotaischaracterizedbyarearrangementintheFirmicutespopula/onand

anenrichmentinfaculta/veanaerobes,notablypathobionts.The

presenceofsuchacompromisedmicrobiotainthecentenariansisassociatedwithanincreased

inflammatorystatus,alsoknownasinflammageing,asdeterminedbyarangeofperipheralblood

inflammatorymarkers.”

ThroughAgeing,andBeyond:GutMicrobiotaandInflammatoryStatusinSeniorsandCentenarians

PLoSONEMay2010|Volume5|Issue5

Thefunc9onofourmicrobiota:whoisoutthereandwhatdotheydo?Fron/ersinCellularandInfec/onMicrobiology

August2012|Volume2|Ar/cle104

“Thismaybeexplainedbyaremodelingofthecentenarians’microbiota,withamarked

decreaseinFaecalibacteriumprauznitziiandrela/ves,symbio/cspecieswithreportedan/-inflammatory

proper/es.Assignaturebacteriaofthelonglifeweiden/fied

specificallyEubacteriumlimosumandrela/vesthatweremorethanten-fold

increasedinthecentenarians.”

ThroughAgeing,andBeyond:GutMicrobiotaandInflammatoryStatusinSeniorsandCentenariansPLoSONEMay2010|Volume5|Issue5

The Perfect Storm for CardioMetabolic Disease:SAD Diet, Dysbiosis and Tight Junction

Dysfunction

77

78

79

Gutmicrobiotacontrolsadipose9ssueexpansion,gutbarrierandglucosemetabolism:novelinsightsintomoleculartargetsandinterven9onsusingprebio9cs

BeneficialMicrobes,March2014;5(1):3-17

“Thus the “forgotten organ” of the gastrointestinal microbiota is a prime

candidate to be in influenced by evolutionarily unprecedented postprandial luminal carbohydrate concentrations. The

present hypothesis suggests that in parallel with the bacterial effects of

sugars on dental and periodontal health, acellular ours, sugars, and

processed foods produce an inflammatory microbiota via the upper gastrointestinal tract, with fat able to

effect a “double hit” by increasing systemic absorption of

lipopolysaccharide.”

81

83

84

“Althoughthesedataarecontroversial,theysuggestthatspecificphyla,classes

orspeciesofbacteria,orbacterialmetabolicac/vi/escouldbebeneficialordetrimentaltopa/entswithobesity.Thegutmicrobiotais,therefore,a

poten9alnutri9onalandpharmacologicaltargetinthe

managementofobesityandobesity-relateddisorders.”

85

88

“Theywerebalancedfortheirbaselinecharacteris/csandrandomlyassignedtothreegroupsreceivingFMcontaining10(7),10(6)or0(control)cfuLG2055/gofFM,andwereaskedtoconsume200gFM/dfor12weeks.Abdominalvisceralfatareas,whichwere

determinedbycomputedtomography,atweek12,changedfrombaselinebyanaverageof-8·5%(95%CI-11·9,-5·1;P<0·01)inthe10(7)dosegroup,andby-8·2%(95%CI-10·8,-5·7;P<0·01)inthe10(6)dosegroup.OthermeasuresincludingBMI,waistandhipcircumferences,andbodyfatmasswerealsosignificantlydecreasedfrombaselineatweek12inbothgroups;interes/ngly,the

cessa/onoftakingFMfor4weeksa@enuatedtheseeffects.Inthecontrolgroup,noneoftheseparameterssignificantlydecreasedfrombaseline.”

“Circulating zonulin increased with body mass index (BMI), waist to hip ratio (WHR), fasting insulin, fasting triglycerides, uric acid and IL-6, and

negatively correlated with HDL-cholesterol and insulin sensitivity.” In

multiple regression analysis, insulin sensitivity (p = 0.002) contributed

independently to circulating zonulin variance, after controlling for the effects of

BMI, fasting triglycerides and age.

90

REVIEW Open Access

Intestinal permeability – a new target for diseaseprevention and therapyStephan C Bischoff1*, Giovanni Barbara2, Wim Buurman3, Theo Ockhuizen4, Jörg-Dieter Schulzke5, Matteo Serino6,Herbert Tilg7, Alastair Watson8 and Jerry M Wells9

Abstract

Data are accumulating that emphasize the important role of the intestinal barrier and intestinal permeability forhealth and disease. However, these terms are poorly defined, their assessment is a matter of debate, and theirclinical significance is not clearly established. In the present review, current knowledge on mucosal barrier and itsrole in disease prevention and therapy is summarized. First, the relevant terms ‘intestinal barrier’ and ‘intestinalpermeability’ are defined. Secondly, the key element of the intestinal barrier affecting permeability are described.This barrier represents a huge mucosal surface, where billions of bacteria face the largest immune system of ourbody. On the one hand, an intact intestinal barrier protects the human organism against invasion ofmicroorganisms and toxins, on the other hand, this barrier must be open to absorb essential fluids and nutrients.Such opposing goals are achieved by a complex anatomical and functional structure the intestinal barrier consistsof, the functional status of which is described by ‘intestinal permeability’. Third, the regulation of intestinalpermeability by diet and bacteria is depicted. In particular, potential barrier disruptors such as hypoperfusion of thegut, infections and toxins, but also selected over-dosed nutrients, drugs, and other lifestyle factors have to beconsidered. In the fourth part, the means to assess intestinal permeability are presented and critically discussed. Themeans vary enormously and probably assess different functional components of the barrier. The barrier assessmentsare further hindered by the natural variability of this functional entity depending on species and genes as well ason diet and other environmental factors. In the final part, we discuss selected diseases associated with increasedintestinal permeability such as critically illness, inflammatory bowel diseases, celiac disease, food allergy, irritable bowelsyndrome, and – more recently recognized – obesity and metabolic diseases. All these diseases are characterized byinflammation that might be triggered by the translocation of luminal components into the host. In summary, intestinalpermeability, which is a feature of intestinal barrier function, is increasingly recognized as being of relevance for healthand disease, and therefore, this topic warrants more attention.

Keywords: Intestinal barrier, Intestinal permeability, Microbiota, Tight junctions, Obesity, Inflammatory bowel disease,Irritable bowel syndrome, Prebiotics, Probiotics, Gut health

IntroductionWhy do we need a gut barrier? The intestinal barriercovers a surface of about 400 m2 and requires approxi-mately 40% of the body’s energy expenditure. It preventsagainst loss of water and electrolytes and entry of antigensand microorganisms into the body [1] while allowingexchange of molecules between host and environment andabsorption of nutrients in the diet. Specialized adaptations

of the mammalian intestinal mucosa fulfill two seeminglyopposing functions: firstly to allow a peaceful co-existencewith intestinal symbionts without eliciting chronic inflam-mation and secondly to provide a measured inflammatoryand defensive response according to the threat from path-ogens [2,3]. It is a complex multilayer system, consistingof an external "physical" barrier and an inner "functional"immunological barrier. The interaction of these 2 barriersenables equilibrated permeability to be maintained [4]. Tounderstand this complex barrier, not only the functions ofits components, but also the processes of interactions ofbacterial and other luminal components with cells and

* Correspondence: bischoff.stephan@uni-hohenheim.de1Department of Nutritional Medicine/Prevention, University of Hohenheim,Fruwirthstrasse 12, 70593 Stuttgart, GermanyFull list of author information is available at the end of the article

© 2014 Bischoff et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,unless otherwise stated.

Bischoff et al. BMC Gastroenterology 2014, 14:189http://www.biomedcentral.com/1471-230X/14/189

“In the final part, we discuss selected diseases associated with increased intestinal permeability

such as critically illness, inflammatory bowel diseases, celiac

disease, food allergy, irritable bowel syndrome, and – more

recently recognized – obesity and metabolic diseases. All these

diseases are characterized by inflammation that might be

triggered by the translocation of luminal components into the

host.”

91

“Importantly,onestudyhasshownthatL.plantarumcanregulate

humanepithelialTJproteinsinvivoandtoconferprotec/veeffectsagainstchemicallyinduced

disrup/onoftheepithelialbarrierinaninvitromodel”

92

differentiated enterocytes, which can be measured in urineand plasma, has been confirmed as valuable marker forthe early diagnosis of intestinal ischemia [243]. Splanchnichypo-perfusion can be confirmed in healthy men alreadyafter cycling for 60 minutes at 70% of maximum workloadcapacity. A 15 min ischemia causes the appearance ofsmall subepithelial spaces thought to be morphologicalcorrelates of an impaired gut barrier [244].Multiple consequences of enteral ischemia have to be

anticipated including mucus barrier loss, bacterial trans-location, and enhanced Paneth cell apoptosis causingbreakdown of the defensing shield in the intestine[245,246]. Fortunately, such alterations are rapidly coun-teracted, e.g. by increased goblet cell secretory activity inthe colon [246]. Even the structural defects such as thesubepithelial spaces are quickly restored by lamina pro-pria retraction and zipper-like constriction of the epithe-lium [247]. Such repair mechanisms have been identifiedin both rodents and man [248].The classical treatment of loss of barrier functions in

the ICU patient is usage of antibiotics directed againstgram-negative bacteria and improvement of intestinalperfusion by catecholamines and volume. If pre- or pro-biotics can support prevention or treatment of sepsisand MOF is unclear at present. Some studies suggesteda beneficial effect of selected probiotics and synbioticson sepsis complications in patients with major abdom-inal surgery and in immunocompromised patients whounderwent liver transplantation; however, the trials wererather small and limited in number [249-251]. Otherstudies performed in patients with severe acute pancrea-titis yielded conflicting results. Whereas a few initialstudies suggested beneficial effects by treatment withsynbiotics [252,253], one trial reported increased mortal-ity in the verum group [254]. Although this report hatseveral methodological limitations, the results underlinethat otherwise harmless probiotics have to be selectedand assessed very carefully in severely ill patients similarto pharmaceutical evaluations. Provided that caution isconsidered, clinical trials are warranted to support thepotential use of probiotics in ICU, namely for preventionof antibiotic-associated and Clostridium difficile-associ-ated diarrhea, ventilator-associated pneumonia and sep-sis [255]. A recent meta-analysis drew the conclusionthat the administration of probiotics does not signifi-cantly reduce ICU or hospital mortality rates but doesreduce the incidence of ICU-acquired pneumonia andICU length of stay [256].

ConclusionApart from IBD, IBS, metabolic diseases and intestinalfailure in critically ill patients, other diseases might be re-lated to the gut microbiota and the intestinal barrier suchas celiac disease [175,176], colon carcinoma [257] or

inflammatory joint diseases [258]. Therefore, alteration ofthe gut barrier seems to have multiple consequences facili-tating the onset of a variety of diseases depending on otherhits and on genetic or epigenetic constellations, respect-ively. The growing significance of the gut barrier and bac-terial translocation raises the questions of how we canimprove gut barrier functions and gut microbiota.The research on modulation of gut permeability is just

starting. On the other hand, a few approaches have beenidentified among which are dietetic concepts includingprebiotics, as well as probiotics, and possibly also fecaltransplantation that can be regarded as an unspecific andglobal probiotic treatment. Indeed, fecal transplantationnow enters clinical medicine, after beneficial effects in pa-tients with therapy-refractory Clostridium difficile infec-tion have been reported [259,260]. Apart from this novelapproach, other interventions have been proposed such asparticular diets, prebiotics or probiotics (Table 8). Amongthe diets, some sound promising such as dietary restric-tion of fat and sugars, or possibly also of poorly absorbedshort-chain carbohydrates (FODMAPs) [261-263]. Clearly,more intervention trials are urgently needed now to assesthe effects of such substances as preventive or therapeuticagents in different populations and diseases, respectively.For these trials, not only known substances (see Table 8),but also new dietetic components and probiotic agents se-lected according to their beneficial effects on the gut bar-rier have to be identified and tested.To conduct such trials in a scientifically sound way, we

need a clear definition and validation of the tools neededto assess gut barrier functions and intestinal permeability.New approaches such as mucus analysis, quantification oftranslocated bacteria and bacterial products in blood ortissue, and host responses to such alterations, e.g. liversteatosis or fat infection by commensal bacteria, need tobe evaluated. Even though European authorities strictly

Table 8 Factors proposed to support the gut barrierDieteticapproach

Avoidance of high amounts of sugar and fat

Avoidance of energy-dense Western-style diet

FODMAP diet

Prebiotics/fibers

Glutamine

Other immune-modulating formula

Probioticapproach

Selected probiotics

Probiotic cocktails (multispecies concept)

Synbiotics (combination of probiotics and prebiotics)

Drugs/others Short-chain fatty acids (SCFA)

Metformin

Quercetin and other flavonoids

Bischoff et al. BMC Gastroenterology 2014, 14:189 Page 17 of 25http://www.biomedcentral.com/1471-230X/14/189

(e.g. Lactobacillus plantarum MB452)

(Fermentable, Oligo-, Di-, Mono-saccharides and Polyols)

(e.g. Butyrate)

93

“ThesedatasuggestthatGP(1%Concordgrapepolyphenols)actintheintes/netomodifygut

microbialcommunitystructure,resul/nginlowerintes/nalandsystemic

inflamma/onandimprovedmetabolicoutcomes.Thegutmicrobiotamaythus

providethemissinglinkinthemechanismofac/onofpoorlyabsorbed

dietarypolyphenols.”

94

TheFrenchParadox

95

96

“Ingeneral,studiesevidencethatdietarypolyphenolsmaycontributetothemaintenanceofintes/nalhealthbypreservingthegutmicrobialbalancethroughthe

s/mula/onofthegrowthofbenecialbacteria(i.e.,lactobacilliand

bifidobacteria)andtheinhibi/onofpathogenicbacteria,exer/ng

prebio/c-likeeffects.”

97

98

SOURCE: Laboratory Evaluations in Integrative and Functional Medicine by Richard Lord, PhD & J. Alexander Bralley, PhD pg. 370

99

100

“Ithasbeenshowntoincreasetheproduc/onofshort-chainfa@yacids,principallybutyrateandpropionate,andhasbeenshowntodecreasethegenera/onandabsorp/onofammonia.

Evidencealsoindicateshumanconsump9onoflarcharabinogalactanhasasignificanteffectonenhancingbeneficialgutmicroflora,specificallyincreasinganaerobessuchasBifidobacteria

andLactobacillus.”

“Therefore, we here review the recent arguments that support the

view that an alteration in the microbiota to host immune system

balance leads to an increased translocation of bacterial antigens

towards metabolically active tissues, and could result in a chronic

inflammatory state and consequently impaired metabolic functions such as

insulin resistance, hepatic fat deposition, insulin unresponsiveness,

and excessive adipose tissue development”

“We show that cold exposure leads to marked shift of the microbiota

composition, referred to as cold microbiota. Transplantation of the

cold microbiota to germ-free mice is sufficient to increase insulin sensitivity of the host and enable tolerance to cold

partly by promoting the white fat browning, leading to

increased energy expenditure and fat loss. During prolonged cold,

however, the body weight loss is attenuated, caused by adaptive

mechanisms maximizing caloric uptake and increasing intestinal, villi, and

microvilli lengths.”

After the intake of apples (2 apples a day for 2 weeks) by eight healthy adult humans, the number of bifidobacteria in feces increased, and the numbers of Lactobacillus and Streptococcus including

Enterococcus tended to increase. However, lecithinase-positive clostridia, including C. perfringens, decreased and Enterobacteriaceae and Pseudomonas tended to decrease

‘‘The conservative physician will recognize that much of what happens is transient, but

sometimes as he matures, he forgets unfortunately that his own methods of

therapy are trembling on the same shifting sands that cover the treatment and alas also the bones of those who have gone before.’’

—Howard M. Spiro, Introduction to Clinical Gastroenterology, 1970.