The gut microbiota and the liver.Pathophysiological and
clinical implications
Eamonn M.M.Quigley1,2,⇑,Catherine Stanton1,3,Eileen F.Murphy1,4
1Alimentary Pharmabiotic Centre,University College Cork,Cork,Ireland;2Department of Medicine,University College Cork, Cork,Ireland;3Teagasc Food Research Centre,Biosciences Department,Moorepark,Fermoy,County Cork,Ireland;
4Alimentary Health Ltd.,Cork,Ireland
Introduction
The term microbiota is used to describe the complete population of microorganisms that populate a certain location,such as the gut,and is preferred to the termflora as the former incorporates not just bacteria but also archaea,viruses,and other microorgan-isms,such as protozoa.Though the potential role of the microbi-ota(through such concepts as‘‘the putrefactive principle associated with faeces’’and‘‘intestinal toxins’’)in the pathogen-esis of systemic disorders has been recognized since antiquity,a firm scientific basis for a role for the gut microbiome in liver dis-ease did not emerge until t
he middle of the last century with the recognition of the relationship between hepatic coma and the absorption of nitrogenous substances from the intestine[1].This was followed by the description of abundant coliforms in the small intestine of cirrhotics[2]and the role of bacteria was clinched by trials demonstrating that antibiotics led to clinical improvement in hepatic encephalopathy(HE)[3].Subsequently, these same gut-derived bacteria were implicated in another com-plication of chronic liver disease and portal hypertension,sponta-neous bacterial peritonitis.Most recently,more credence has been given to a suggestion that has lingered in the background for decades,namely,that the gut microbiota might play a role in the pathogenesis or progression of certain liver diseases, including alcoholic liver disease[4],non-alcoholic fatty liver dis-ease(NAFLD)and non-alcoholic steato-hepatitis(NASH)[5],total parenteral nutrition(TPN)/intestinal failure-related liver disease (IFALD)[6],and primary sclerosing cholangitis(PSC)[7],either through the direct effects of bacteria or their products,via inflam-matory mediators such as tumor necrosis factor a(TNF),whose release had been triggered by constituents of the microbiota,or, as in the case of primary sclerosing cholangitis(PSC),through cross-reactivity between microbial antigens and human tissue ,atypical anti-nuclear cytoplasmic antibodies (p-ANCA),in PSC,recognize both tubulin beta isoform5in human neutrophils,and the bacterial cell division protein FtsZ)[8].Indeed,inflammatory mediators have also been implicated in the development and maintenance o
f the hyperdynamic circula-tion that is a feature of portal hypertension[9],in impairing liver function and contributing to haemostatic failure[10].It is in these contexts that modulation of the microbiota has emerged as a potential therapeutic strategy in the management of liver disease.
Ó2012European Association for the Study of the Liver.Published by Elsevier B.V.All rights reserved.
The microbiota in the pathogenesis of liver disease and its complications
The human intestinal microbiota consists of trillions of microor-ganisms including150–200prevalent and 1000less common bacterial species,harbouring over100-fold more genes than those present in the human genome[11–13].This microbiota consists predominantly of bacteria,but also contains archaea,protozoa, and viruses;all have co-evolved with the human host.The micro-biota performs vital functions essential to health maintenance, including food processing,digestion of complex indigestible poly-saccharides and synthesis of vitamins[14,15].Furthermore,it secretes a range of bioactive metabolites with diverse functions, ranging from inhibition of pathogens,metabolism of toxic com-pounds to modulation of host metabolism[15].A perturbed mic-robiota has been implicated in an ever-increasing list of disorders in humans,from necrotizing enterocolitis(NEC)in infants,to obesity,diabetes,metabolic syndrome,irritable bowel syndrome (IBS),and inflammatory bowel disease
(IBD)in adults[16–21]. However,little is known about the physiological impact the mic-robiota has on host health,an area which has recently been described as‘‘one of the hottest areas in medicine’’[22].
Table1lists a number of mechanisms that might underpin the role of the microbiota in the pathogenesis of liver disease and/or its complications.
Small intestinal bacterial overgrowth(SIBO)
Among the various potential contributions of the microbiota to liver disease,small intestinal bacterial overgrowth(SIBO)has been one of the most extensively studied.Indeed,an altered
gut
Journal of Hepatology2013vol.58j
1020–1027
Keywords:Microbiota;Bacteria;Probiotics;Prebiotics;Antibiotics;Liver;Cir-
rhosis;Hepatic encephalopathy;Bacteraemia.
Received22August2012;received in revised form6November2012;accepted8
November2012
⇑Corresponding author.Address:Department of Medicine,Clinical Sciences
Building,Cork University Hospital,Cork,Ireland.
E-mail address:e.quigley@ucc.ie(E.M.M.
Quigley).
Review
microbiota was first noted by Hoefert in chronic liver disease over 80years ago [23];since then SIBO has been documented to be common in liver disease,to correlate with its severity and to be linked to minimal and overt encephalopathy and an increased risk for SBP through translocation across the gut wall [24–28].More-over,factors predisposing to SIBO such as altered small bowel motility,increased intestinal permeability,and delayed gut transit have been reported in patients with liver cirrhosis [29].Alterations in gastrointestinal motility in cirrhosis have been variably ascribed to the effects of autonomic dysfunction,altered levels of circulating neuropeptides and the effects of inflamma-tory mediators on gut muscle and nerve [9,29].With regard to intestinal permeability,changes in intestinal tight junctional pro-teins have been described in cirrhosis and,though the precise pathophysiology of barrier dysfunction is unclear,roles for metab-
olites of alcohol and/or pro-inflammatory cytokines have been
postulated [4,5,7,30,31].Impaired antimicrobial defence mecha-nisms may further contribute to the development of bacterial translocation in portal hypertension and cirrhosis [30].Taken
together,these observations have led to the development of a
schema which links intestinal motility,stasis,increased intestinal permeability and translocation of bact
eria and endotoxin to the
development of many of the complications of liver disease,as well
as in the progression of liver disease,per se (Fig.1).A more fundamental role for SIBO has been proposed in both alcoholic liver disease (through the generation of acetaldehyde)[31]and NAFLD (by promoting both steatosis and inflammation)
[5].The potential of microbes of enteric origin to induce a pro-
gressive and even fatal steato-hepatitis had been recognized some years ago in relation to the liver injury that complicated jejuno-ileal bypass operations for morbid obesity;indeed,that
procedure has provided a valuable experimental model for exploring the impact of the microbiota in liver disease.Quantitative or qualitative changes in the microbiota
The advent of molecular techniques based on sequence diver-gences of the small subunit ribosomal ribonucleic acid (16S rRNA)of bacteria [32]now permits the complete delineation of the constituents of the microbiota in health,thereby,revealing
the composition of the human gut microbiota from early infancy
[33]through to old age [34,35].Following birth,the human intes-
tine is rapidly colonized and factors known to influence coloniza-
tion include gestational age,mode of delivery (vaginal birth vs.assisted delivery),diet (breast milk vs.formula),level of sanita-tion,and exposure to antibiotics [15,36].The intestinal microbi-ota of newborn infants is characterized by low diversity and a relative dominance of the phyla Proteobacteria and Actinobacteria ;thereafter,the microbiota becomes more diverse with the emer-gence of the dominance of Firmicutes and Bacteroidetes ,which characterises the adult microbiota [12,14,37].By the end of the first year of life,infants possess a microbial profile distinct for each infant;by 2.5years of age,the microbiota fully resembles that of an adult in terms of composition [33,38].More recently,three different ‘enterotypes’have been described in the adult human microbiome [39]These distinct ‘enterotypes’are domi-nated by Prevotella ,Ruminococcus ,and Bacteroides ,respectively,Table 1.The microbiota in the pathogenesis of liver disease and its complications.Possible
factors.
trimethylamine;TMAO,trimethylamine oxide;PSC,primary sclerosing cholangitis;TNF a ,tumor necrosis factor
alpha.
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and their appearance appears to be independent of sex,age,nationality and body mass index (BMI).Once the microbiota has reached maturity,it is thought to remain stable until old age when changes are seen,possibly related to alterations in digestive physiology and diet [13,40,41].Indeed,Claesson et al.were able to identify clear correlations,in the elderly,not only between the composition of the gut microbiota and diet,but also with health status [35].These molecular approaches have,to some extent,been direc-ted at the investigation of the microbiota in liv
er disease.Chen et al.,for example,studied 36patients with cirrhosis and 24healthy controls using 454pyrosequencing of the 16S ribosomal RNA variable region 3(V3)followed by real-time quantitative
polymerase chain reaction (qPCR)and found that,in cirrhosis,
Bacteroidetes were reduced,Proteobacteria and Fusobacteria
increased,Enterobacteriaceae ,Veillonellaceae ,Streptococcaceae
increased,and Lachnospiraceae reduced [42].Some of these
changes correlated with clinical parameters such as the Child-
Turcotte-Pugh score.Several of these findings have been con-
firmed by Bajaj et al.who went on to show that Veillonellaceae
were more abundant among cirrhotics with hepatic encephalop-
athy (HE)than those without [43].As an extension of the evolv-
ing concept of the microbiota–gut–brain-axis,which includes the
suggestion that the microbiota can influence cognition and
behaviour,these authors also described an association between
certain bacterial families,cognition and inflammation in HE.The finding of an increased abundance of members of the family Enterobacteriaceae in cirrhosis by these and other authors [44]is
of interest given that this family includes such important Gram-
negative pathogens as Salmonella ,Shigella ,Yersinia pestis ,Klebsi-
ella and,especially,Escherichia coli ,a common isolate in SBP
and bacteremia in chronic liver disease.Others have documented,
not only a decrease in total bifidobacterial counts,but also fur-
ther variations in specific Bifidobacterium species (e.g.,Bifidobac-
terium dentium increased;Bifidobacterium longum decreased)in
chronic liver disease [45].
Interactions with diet and nutrients
Several mechanisms have been identified relevant to the
involvement of the microbiota in the pathogenesis of NAFLD/
NASH.In particular,a role for the microbiota and its interac-
tion with diet in the pathogenesis of obesity per se has been
extensively investigated [46,47],and pertinent findings include
the ability of Gram-negative anaerobes,such as Bacteriodes the-
taiotamicron ,to cleave most glycosidic linkages,degrade plant
polysaccharides and,thereby,supply the host with 10–15%of
its calorific requirement [11,17,46,47].The microbiota of obese
individuals,as well as the caecal microbiota of ob /ob mice,are
more efficient at the extraction of energy from the diet and in
the production of short chain fatty acids (SCFAs)[11,48].Fur-
thermore,the microbiota has been shown to stimulate hepatic triglyceride production through suppression of the lipoprotein lipase (LPL)inhibitor,fasting-induced adipose factor (Fiaf;also
known as angiopoietin-like 4),thereby leading to continued expression of LPL,a key regulator of fatty acid release from tri-glycerides in the liver [49].The gut microbiota can also modu-late systemic lipid metabolism through modification of bile acid metabolic patterns,impacting directly on the emulsifica-tion and absorption properties of bile acids and thus,indirectly,
on the storage of fatty acids in the liver.The microbiota has
also been implicated in the development of insulin resistance [49],a fundamental abnormality in the metabolic syndrome,by affecting energy balance,glucose metabolism,and the low-grade inflammatory state that has been associated with obesity and related metabolic disorders.Its role in choline metabolism [50–52],as well as in activation of pro-inflamma-tory cytokines (e.g.,TNF a ),appears relevant to the develop-ment of NAFLD and progression to NASH.Most recently,
studies in experimental models have shown that defective/defi-cient inflammasome sensing and related dysbiosis result in an abnormal accumulation of bacterial products in the portal cir-culation and promote progression of NAFLD/NASH [53].Intestine Impaired motility, stasis Increased translocation of bacteria/endotoxin/LPS to portal circulation Enhanced release of pro-inflammatory cytokines Altered composition of the gut microbiota Increased epithelial permeability SIBO SIBO Portal-systemic shunting
Review
1022Journal of Hepatology 2013vol.58j 1020–1027
Interactions with alcohol
Alcohol-related liver injury may also involve the active participa-tion of the microbiota through a number of mechanisms[31]. Firstly,alcohol promotes the growth of Gram-negative bacteria in the gut with the consequent production of endotoxin.Sec-ondly,Gram-negative bacteria metabolize alcohol to acetalde-hyde which,in turn,increases intestinal permeability.Other effects of alcohol conspire to incr
ease permeability,promote transfer of endotoxin across the intestinal epithelium and impair the host immune response[31].Protein adducts formed from metabolites of alcohol have also been shown to combine with LPS to induce liver injury[54].
Therapeutic impact of modulating the microbiota
Antibiotics
Infectious complications.Reflecting the involvement of the micro-biota in the genesis of the infectious complications of liver disease[55],the fundamental role of antibiotic therapy directed at Gram-negative enteric bacteria,in the management and pre-vention of infectious complications of liver disease and portal hypertension and chronic liver disease,such as SBP and bacter-aemia,is well established[56].Indeed,antibiotics have also been advocated to both prevent infectious complications and reduce re-bleeding rates among patients with variceal haemorrhage [10,56,57].Based on the aforementioned role of endotoxemia resulting from bacterial translocation in the pathogenesis of the hyperdynamic circulation that characterizes portal hypertension (through the induction of nitric oxide[NO]synthase),selective intestinal decontamination has also been proposed as a strategy in the management of the circulatory complications of cirrhosis [58].
Hepatic encephalopathy
The recent studies,indicating the efficacy of the poorly absorbed antibiotic with activity against enteric organisms,rif-aximin,in overt[59]and sub-clinical[60]HE,have bolstered the importance of the role of these organisms in the pathogen-esis of this common complication of liver disease;the precise nature of the changes in the composition and/or metabolic activity of the microbiota that generate these benefits remains to be determined.
Intestinal failure-associated liver disease(IFALD)
The term intestinal failure-associated liver disease has replaced that of total parenteral nutrition(TPN)-associated liver disease to describe alterations in liver morphology and function that occur among subjects with intestinal failure who may or may not also be on TPN.The etiology of intestinal failure-associated liver disease(IFALD)is multifactorial,with primary contributors including prematurity(in infants),sepsis,nutritional deficiencies or hepatotoxic effects of TPN infusates,and lack of enterally stim-ulated bileflow[61].Though SIBO may be an important feature in intestinal failure of various aetiologies and has been implicated in the pathogenesis of IFALD,there is currently insufficient evidence to support the use of antibiotics,such as metronidazole,in the prevention of IFALD[62].Probiotics and prebiotics
Experimental
NAFLD:In a pioneering study in the ob/ob mouse(an animal model of NAFLD),Li et alpared the probiotic cocktail VSL#3to an anti-TNF a antibody.Though,in comparison to the anti-TNF a antibody,VSL#3had less effect on steatosis,its impact on inflammation and liver injury was similar,yet did not appear to be exerted through a reduction in hepatic expression of TNF a [63].In a model that is more relevant to humans,diet-induced obesity,Ma et al.showed that the same probiotic preparation could prevent the development of steatosis through a natural killer T-cell(NKT)-dependent mechanism[64];in contrast,other workers found that VSL#3,while attenuatingfibrosis,had no effect on either steatosis or steatohepatitis in NASH induced by a methionine-choline-deficient diet[65].Based on their studies, Xu luded that B.longum was more effective than Lacto-bacillus acidophilus in NAFLD and that these beneficial effects were related to a modification of the gut microbiota[66].Our own studies have shown that the modulation of the enteric mic-robiota can influence the fatty acid composition of host tissues, including the liver,adipose tissue,and brain[67,68].Thus,we observed a significant elevation in c9,t11conjugated linoleic acid (CLA)in the livers of mice and pigs,after feeding with linoleic acid in combination with the probiotic organism Bifidobacterium breve NCIMB702258.CLA is a microbial metabolite that has been associated with th
e alleviation of NAFLD[69].Indeed,it is note-worthy that the VSL#3probiotic cocktail has been shown to pro-duce CLA in vitro,and the c9,t11CLA isomer,in particular[70] Prebiotic preparations have also been shown to ameliorate liver inflammation in obese mice through a glucagon-like peptide-2 (GLP-2)-dependent effect on the gut barrier[71]and hold prom-ise for the management of NAFLD and related disorders[72].
Alcoholic liver disease:In an animal model of alcoholic liver disease,Forsyth et al.found that Lactobacillus rhamnosus GG (LGG)could reduce liver fat content,necro-inflammatory score and myleoperoxidase expression.Interestingly,these beneficial effects correlated with a reduction in,or normalization of,intes-tinal permeability[73].Indeed,the concept that a significant component of the beneficial effect of probiotics in alcohol-related liver injury is exerted at the level of the intestinal barrier is sup-ported by other studies[74],as well as by a considerable litera-ture attesting to important effects of probiotics on gut tight junctional and transcellular permeability in diverse disease mod-els.Indeed,Wang et al.have provided a molecular basis for the action of the probiotic L.rhamnosus GG,one of the most widely studied organisms in this context,by demonstrating that the res-toration of barrier function,in alcohol-induced liver injury,was mediated through the recovery of hypoxia-inducible factor (HIF)and trefoil factor in gut epithelial cells[75].
Complications of liver disease:A variety of probiotic prepara-tions have been studied in relation to the various complications of liver disease.While Lactobacillus-fermented milk supplements failed to reduce bacterial translocation in an experimental model of prehepatic portal hypertension[76],in contrast,in a model of acute liver injury,Adawi et al.found that rectal administration of a number of Lactobacillus species,with or without arginine sup-plementation,led to a reduction in bacterial translocation.In this same model,Lactobacillus plantarum alone abrogated the severity of the liver injury[77].In an animal model of minimal HE,Jia and Zhang showed that a probiotic cocktail was as effective as lactu-lose in reducing HE and blood ammonia levels as well as decreas-ing endotoxaemia,liver injury and inflammation[78]
.
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Effects on acute liver injury and chronic liver disease:Probiotics have been shown to reduce the impact of a variety of forms of acute liver injury[79–83],as well as the severity of more chronic forms of liver disease,such as that related to total parenteral nutrition(TPN)[84].
Clinical
Given all that has been reviewed above,it should come as no sur-prise that here is an ever-increasing interest in the potential ther-apeutic value of probiotics in a variety of contexts in relation to the liver and its diseases[61,85,86].These include:HE,transloca-tion and infectious complications,NAFLD/NASH and the prophy-laxis of infections after liver transplantation[86].In attempting to assess the relevant literature,the reviewer is confronted,not only by the issues that bedevil the interpretation of animal stud-ies(varying probiotic strains and preparations,different animal models and outcomes),but also by limitations in study size and design,as well as variations in probiotic dose,formulation,route and duration of therapy.There is also limited data on the micro-biological impact of probiotics on the abnormal microbiota that has been described in cirrhosis and ot
her liver diseases[87]. While probiotics are generally assumed to be safe,there have been reservations regarding their use in immunosuppressed individuals;whether these preparations offer a greater risk of initiating septic complications among individuals with liver disease,given the presence of both portal-systemic shunting and impaired immune function(be it related to underlying disease or iatrogenic),is unclear and safety assessments have been limited[86].
NAFLD/NASH:A Cochrane Collaboration Systematic Review published in2007,while failing to identify any randomized clin-ical trials,concluded that preliminary data from two pilot non-randomised studies suggested that probiotics may be well toler-ated,improve conventional liver function tests and decrease markers of lipid peroxidation in NAFLD/NASH[88].Their review included one study employing L.Bulgaricus,which produced a reduction in transaminases[89],and another with L.rhamnosus GG,which resulted in lower levels of alanine transaminase[90].
Alcoholic liver disease:Kirpich et al.randomized66Russian males with alcoholic psychosis to5days of therapy with a com-bination of Bifidobacterium bifidum and L.plantarum or standard therapy.At baseline,alcoholics had fewer bifidobacteria,lactoba-cilli and enterococci;however,after5days of probiotic therapy, bifidobacteria,and lactobacilli increased and,when checked 7days after the initiation of probiotic therapy,alanine transami-nase levels had declined significantly in the probiotic b
ut not in the control group[91].
Complications of liver disease:Despite the presence,in the lit-erature,of several individual trials attesting to the benefits of var-ious probiotic preparations in HE and minimal/subclinical HE [92–95],a recent Cochrane Systematic Review concluded that, while probiotics appeared to exert a significant effect on blood ammonia levels,problems with trial interpretation(related,in turn,to shortcomings in study design)did not allow them to con-clude that probiotics were effective against clinically meaningful end points[96].It should be noted,however,that a separate sys-tematic review that focused exclusively on minimal HE con-cluded that prebiotics,probiotics,and synbiotics were effective for this indication,but that lactulose(itself a prebiotic)was supe-rior to both probiotics and synbiotics[97].Similar issues limit one’s ability to draw conclusions and generate recommendations regarding the role of probiotics in preventing infectious compli-cations of liver disease.While reported effects of probiotics on modulating the microbiota[86,98],reducing levels of endotoxe-mia[98],normalizing impaired neutrophil function[99]and reducing levels of pro-inflammatory cytokines[100]could well translate into clinical benefit,this has yet to be demonstrated. The efficacy of lactulose,a prebiotic,and antibiotics,such as neo-mycin,paromomycin,and rifaximin,in HE,has been well docu-mented.A recent meta-analysis suggested that the efficacy of rifaximin was similar to that o
f lactulose and older antibiotic regimes but associated with less adverse events[101].There have been limited studies of probiotics in other complications;the probiotic cocktail VSL#3had no effect on portal pressure in either compensated or very early decompensated cirrhosis[102].
Effects on acute liver injury and chronic liver disease:Data on the impact of probiotics on the evolution or natural history of liver disease,per se,is very limited.Though uncontrolled studies suggest that probiotics may reduce SIBO in IFALD,there is,as yet, no evidence that their administration can prevent the develop-ment or progression of this form of liver disease[61].Similarly, small studies in compensated cirrhosis[103]and PSC[104] showed no impact from the relatively short-term(3–6months) administration of probiotic on common laboratory parameters. While probiotic supplementation has been shown to reduce a biomarker of risk for hepatocellular cancer[105],the actual clin-ical impact of this approach is unknown.
Conclusions and future studies
A central role for the microbiota in the precipitation of infectious and non-infectious complications of liver disease has been estab-lished and evidence for a more fundamental role in the aetiology of certain liver diseases,such as NAFLD and NASH,continues to accumulate.However,the description o
f the microbiota and its metabolic[106]and immunological[107]functions in various forms and stages of liver disease is still far from complete,but should be nigh given the widespread availability of high-throughput sequencing and metabolomic technologies.While high quality clinical evidence supports the use of antibiotic ther-apy,presumably as a modulator of the microbiota,in the man-agement of HE,SBP,and other infectious complications,how these interventions impact on the microbiota and microbiota-host interactions has not been clearly defined.While probiotics hold promise in the management of liver disease and their poten-tial is supported by a considerable volume of laboratory work [108],high-quality clinical evidence is scanty and its paucity, together with all of the quality control,strain selection and dose optimization issues that have been an unfortunate feature of this field,precludes,for the moment,recommendations on the use of probiotics,in general,and specific strains,in particular,in clinical practice.However,there is a sufficiently strong rationale for the use of strategies that involve the modulation of the microbiota in the management of liver diseases,such as NAFLD[109–111], and their complications to suggest that these approaches are deserving of further exploration.
Conflict of interest
The authors declared that they do not have anything to disclose regarding funding or conflict of intere
st with respect to this
manuscript. Review
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References
[1]Phillips GB,Schwartz R,Gabuzda Jr GJ,Davidson CS.The syndrome of
impending hepatic coma in patients with cirrhosis of the liver given certain nitrogenous substances.N Engl J Med1952;247:239–246.
[2]Martini GA,Phear EA,Ruebner B,Sherlock S.The bacterial content of the
small intestine in normal and cirrhotic subjects:relation to methionine toxicity.Clin Sci1957;16:35–51.
[3]Phear EA,Ruebner B,Sherlock S,Summerskill WH.Methionine toxicity in
liver disease and its prevention by chlortetracycline.Clin Sci1956;15: 93–117.
[4]Szabo G,Bala S,Petrasek J,Gattu A.Gut-liver axis and sensing microbes.Dig
Dis.2010;28:737–744.
[5]Abu-Shanab A,Quigley EM.The role of the gut microbiota in nonalcoholic
fatty liver disease.Nat Rev Gastroenterol Hepatol2010;7:691–701.
[6]Quigley EMM,Marsh MN,Shaffer JL,Markin RS.Hepatobiliary complica-
tions of total parenteral nutrition.Gastroenterology1993;104:286–301. [7]Terjung B,Spengler U.Atypical p-ANCA in PSC and AIH:a hint toward a
‘‘leaky gut’’?Clin Rev Allergy Immunol2009;36:40–51.
[8]Terjung B,Söhne J,Lechtenberg B,Gottwein J,Muennich M,Herzog V,et al.
P-ANCAs in autoimmune liver disorders recognise human beta-tubulin isotype5and cross-react with microbial protein FtsZ.Gut2010;59: 808–816.
[9]Quigley EMM.Gastrointestinal dysfunction in liver disease–gut–liver
interactions revisited.Dig Dis Sci1996;41:557–561.
[10]Thalheimer U,Triantos CK,Samonakis DN,Patch D,Burroughs AK.Infection,
coagulation and variceal bleeding in cirrhosis.Gut2005;54:556–563. [11]Turnbaugh PJ,Ley RE,Mahowald MA,Magrini V,Mardis ER,Gordon JI.An
obesity-associated gut microbiome with increased capacity for energy harvest.Nature2006;444:1027–1031.
[12]Qin J,Li R,Raes J,Arumugam M,Burgdorf KS,Manichanh C,et al.A human
gut microbial gene catalogue established by metagenomic sequencing.
Nature2010;464:U59–U70.
[13]Clemente JC,Ursell LK,Parfrey LW,Knight R.The impact of the gut
microbiota on human health:an integrative view.Cell2012;148: 1258–1270.
[14]Backhed F.Programming of host metabolism by the gut microbiota.Ann
Nutr Metab2011;58:44–52.
[15]Marques TM,Wall R,Ross RP,Fitzgerald GF,Ryan CA,Stanton C.
Programming infant gut microbiota:influence of dietary and environmen-tal factors.Curr Opin Biotechnol2010;21:149–156.
[16]Kosloske AM.Pathogenesis and prevention of necrotizing enterocolitis-a
hypothesis based on personal observation and a review of the literature.
Pediatrics1984;74:1086–1092.
[17]Ley RE,Turnbaugh PJ,Klein S,Gordon JI.Microbial ecology–human gut
microbes associated with obesity.Nature2006;444:1022–1023.
[18]Kassinen A,Krogius-Kurikka L,Makivuokko H,Rinttila T,Paulin L,Corander
J,et al.The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects.Gastroenterology2007;133: 24–33.
[19]Peterson DA,Frank DN,Pace NR,Gordon JI.Metagenomic approaches for
defining the pathogenesis of inflammatory bowel diseases.Cell Host Microbe2008;3:417–427.
[20]Flint HJ,O’Toole PW,Walker AW.Special issue:the human intestinal
microbiota.Microbiology2010;156:3203–3204.
[21]Jeffery IB,Quigley EM,Ohman L,Simrén M,O’Toole PW.The microbiota link
to Irritable Bowel Syndrome:an emerging story.Gut Microbes2012:3, [Epub ahead of print].
[22]Shanahan F.The gut microbiota in2011:translating the microbiota to
medicine.Nat Rev Gastroenterol Hepatol2011;9:72–74.
[23]Hoefert B.Über die bakterienbefunde im duodenalsaft von gesunden und
kranken.Zschr Klin Med1921;92:221–235.
[24]Nieuwenhuijs VB,Verheem A,van Duijvenbode-Beumer H,Visser MR,
Verhoef J,Gooszen HG,et al.The role of interdigestive small bowel motility in the regulation of gut microflora,bacterial overgrowth,and bacterial translocation in rats.Ann Surg1998;228:188–193.
[25]Husebye E.Gastrointestinal motility disorders and bacterial overgrowth.J
Intern Med1995;237:419–427.
[26]Yang CY,Chang CS,Chen GH.Small-intestinal bacterial overgrowth in
patients with liver cirrhosis,diagnosed with glucose H2or CH4breath tests.Scand J Gastroenterol1998;33:867–871.
[27]Abu Shanab A,Scully P,Crosbie O,Buckley M,O’Mahony L,Shanahan F,
et al.Small intestinal bacterial overgrowth in non-alcoholic steato-hepa-titis;association with toll-like receptor4expression and plasma levels of interleukin8.Dig Dis Sci2011;56:1524–1534.[28]Gupta A,Dhiman RK,Kumari S,Rana S,Agarwal R,Duseja Chawla Y.Role of
small intestinal bacterial overgrowth and delayed gastrointestinal transit time in cirrhotic patients with minimal hepatic encephalopathy.J Hepatol 2010;53:849–855.
[29]Quigley EMM.The liver and gastrointestinal disease.In:Schiff ER,Sorrell
MF,Maddrey WC,editors.Schiff’s diseases of the liver.Philadelphia:Lip-pincott Raven;2002.
[30]Teltschik Z,Wiest R,Beisner J,Nuding S,Hofmann C,Schoelmerich J,et al.
Intestinal bacterial translocation in rats with cirrhosis is related to compromised Paneth cell antimicrobial host defense.Hepatology 2012;55:1154–1163.
[31]Purohit V,Bode JC,Bode C,Brenner DA,Choudhry MA,Hamilton F,et al.
Alcohol,intestinal bacterial growth,intestinal permeability to endotoxin, and medical consequences:summary of a symposium.Alcohol2008;42: 349–361.
[32]Fraher MH,O’Toole PW,Quigley EMM.Techniques used to characterise the
intestinal microbiota:a guide for the clinician.Nat Rev Gastroenterol 2012;9:312–322.
[33]Palmer C,Bik EM,DiGiulio DB,Relman DA,Brown PO.Development of the
human infant intestinal microbiota.PLoS Biol2007;5:1556–1573.
[34]Claesson MJ,Cusack S,O’Sullivan O,Greene-Diniz R,de Weerd H,Flannery
E,et al.Composition,variability,and temporal stability of the intestinal microbiota of the elderly.PNAS2011;108:4586–4591.
[35]Claesson MJ,Jeffery IB,Conde S,Power SE,O’Connor EM,Cusack S,et al.Gut
microbiota composition correlates with diet and health in the elderly.
Nature2012;488:178–184.
[36]Fouhy F,Ross RP,Fitzgerald GF,Stanton C,Cotter PD.Composition of the
early intestinal microbiota:knowledge,knowledge gaps and the use of high-throughput sequencing to address these gaps.Gut Microbes 2012;3:203–220.
[37]Eckburg PB,Bik EM,Bernstein CN,Purdom E,Dethlefsen L,Sargent M,et al.
Diversity of the human intestinal microbialflora.Science2005;308: 1635–1638.
[38]Koenig JE,Spor A,Scalfone N,Fricker AD,Stombaugh J,Knight R,et al.
Succession of microbial consortia in the developing infant gut microbiome.
PNAS2011;108:4578–4585.
[39]Arumugam M,Raes J,Pelletier E,Le Paslier D,Yamada T,Mende DR,et al.
Enterotypes of the human gut microbiome.Nature2011;473:174–180. [40]Mariat D,Firmesse O,Levenez F,Guimaraes VD,Sokol H,Dore J,et al.The
Firmicutes/Bacteroidetes ratio of the human microbiota changes with age.
BMC Microbiol2009;9:123.
[41]O’Toole PW,Claesson MJ.Gut microbiota:changes throughout the lifespan
from infancy to elderly.Int Dairy J2010;20:281–291.
[42]Chen Y,Yang F,Lu H,Wang B,Chen Y,Lei D,et al.Characterization of fecal
microbial communities in patients with liver cirrhosis.Hepatology 2011;54:562–572.
firmicutes[43]Bajaj JS,Ridlon JM,Hylemon PB,Thacker LR,Heuman DM,Smith S,et al.
Linkage of gut microbiome with cognition in hepatic encephalopathy.Am J Physiol Gastrointest Liver Physiol2012;302:G168–G175.
[44]Lu H,Wu Z,Xu W,Yang J,Chen Y,Li L.Intestinal microbiota was assessed in
cirrhotic patients with hepatitis B virus infection.Intestinal microbiota of HBV cirrhotic patients.Microb Ecol2011;61:693–703.
[45]Xu M,Wang B,Fu Y,Chen Y,Yang F,Lu H,et al.Changes of fecal
Bifidobacterial species in adult patients with hepatitis B-Virus-induced chronic liver diseases.Microb Ecol2012;63:304–313.
[46]Bäckhed F,Ley RE,Sonnenburg JL,Peterson DA,Gordon JI.Host-bacterial
mutualism in the human intestine.Science2005;307:1915–1920.
[47]Ley RE,Bäckhed F,Turnbaugh P,Lozupone CA,Knight RD,Gordon JI.Obesity
alters gut microbial ecology.PNAS2005;102:11070–11075.
[48]Schwiertz A,Taras D,Schafer K,Beijer S,Bos NA,Donus C,et al.Microbiota
and SCFA in lean and overweight healthy subject.Obesity2010;18: 190–195.
[49]Bäckhed F,Ding H,Wang T,Hooper LV,Koh GY,Nagy A,et al.The gut
microbiota as an environmental factor that regulates fat storage.PNAS 2004;101:15718–15723.
[50]Dumas ME,Barton RH,Toye A,Cloarec O,Blancher C,Rothwell A,et al.
Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice.PNAS2006;103:12511–12516. [51]Wang Z,Klipfell E,Bennett BJ,Koeth R,Levison BS,Dugar B,et al.Gutflora
metabolism of phosphatidylcholine promotes cardiovascular disease.
Nature2011;472:57–63.
[52]Rak K,Rader DJ.Cardiovascular disease:the diet-microbe morbid union.
Nature2011;472:40–41.
[53]Henao-Mejia J,Elinav E,Jin C,Hao L,Mehal WZ,Strowig T,et al.
Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity.Nature
2012;482:179–185.
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