Microbiota changes and intestinal microbiota t.pdf

SummaryPatients with chronic liver disease and cirrhosis demonstrate a global mucosal immune impairment,which is associated with altered gut microbiota composition and functionality.These changes progressalong with the advancing degree of cirrhosis and can be linked with hepatic encephalopathy,infectionsand even prognostication independent of clinical biomarkers.Along with compositional changes,func-tional alterations to the microbiota,related to short-chain fatty acids,bioenergetics and bile acidmetabolism,are also associated with cirrhosis progression and outcomes.Altering the functional andstructural profile of the microbiota is partly achieved by medications used in patients with cirrhosis suchas rifaximin,lactulose,proton pump inhibitors and other antibiotics.However,the role of faecal or in-testinal microbiota transplantation is increasingly being recognised.Herein,we review the challenges,opportunities and road ahead for the appropriate and safe use of intestinal microbiota transplantation inliver disease.2020 European Association for the Study of the Liver.Published by Elsevier B.V.All rights reserved.IntroductionChanges in the composition and functionality ofintestinal microbiota contribute to the progressionof chronic liver disease and make an attractivetarget for intervention.1,2While various intrinsicand extrinsic factors,such as ethnicity,age,diet,co-morbid conditions and medications affect theintestinal microbiota(Fig.1),3further unique co-variates,such as alcohol,disease aetiology,stage ofliverdisease,andthemultiplemicrobiota-modifyingmedications need to be considered in these pa-tients.4In addition,it is important to remember thatmost liver diseases are lifestyle-related and thera-pies targeting the microbiota represent only oneaspectofthemulti-prongedinterventionalapproachthat is needed in these patients.46Of late,faecal or intestinal microbiota trans-plantation or FMT/IMT has been increasingly usedin chronic liver disease.7This review will focus onmicrobiota changes in human patients with chronicliver disease and the current and future FMT/IMTstudies in this population.We will discuss FMT/IMTfrom a pharmacological perspective and refer to thetreatment strategy as IMT,as recently advocated toavoid the common tendency to morph it into theinaccurate faecal transplant.8The focus of this re-view is to describe studies on the use of IMT inpatients with cirrhosis.It also includes a briefoverview of changes in the pre-cirrhotic and alco-holic hepatitis stages.Further reading on interpre-tation and evaluation of microbiota in general andspecifically in alcoholic liver disease and alcoholichepatitis are discussed in reviews by Allaband et al.3and Bajaj et al.6Of note,most studies in cirrhosis inhumans have used 16S rRNA sequencing and notthe more in-depth metagenomics.Also,severalstudies have performed linkages between metab-olomics and bacterial function and microbiotacomposition,while others have reported composi-tion and/or implied functionality.Composition and functional changes inmicrobiota in patients with chronic liverdiseaseMicrobiota changes in pre-cirrhotic liver diseaseChanges in microbiota are found in several liverdiseaseswith distinctaetiologiesin thepre-cirrhotic stage.Most studies have been performedin non-alcoholic fatty liver disease(NAFLD)andalcohol-related liver disease,while autoimmunehepatitis(AIH),primary biliary cholangitis(PBC)and primary sclerosing cholangitis(PSC)have beenstudied in a few instances.Alcohol and microbiota:multiple studies evalu-ated the stool,salivary and circulating microbiotaacross the spectrum of alcohol-related liver dis-ease.6This ranges from healthy controls whoconsume alcohol to patients who develop alcoholichepatitis.9Most patients with alcoholic hepatitishavecirrhosis,therefore,thesechangesaredescribed in the section below.These changes arecommensurate with bacterial and fungal compo-sition,as well as their products such as secondarybile acids.10,11Continuing alcohol misuse in pa-tients with cirrhosis and alcohol-related liver dis-ease further worsens dysbiosis,changes bile acidsand can lead to the development of alcoholic1Division of Gastroenterology,Hepatology and Nutrition,VirginiaCommonwealth University andMcGuire VA Medical Center,Richmond,Virginia,USA;2Division of GastroenterologyHepatology and Nutrition,University of Minnesota,Minneapolis,Minnesota,USA*Corresponding author.Address:Division of Gastroenterology,Hepatology and Nutrition,VirginiaCommonwealth University andMcGuire VA Medical Center,1201Broad Rock Boulevard,Richmond,Virginia,23249.Tel.:(804)6755802,fax:(804)675 5816.E-mail address:jasmohan.bajajvcuhealth.org(J.S.Bajaj).https:/doi.org/10.1016/j.jhep.2020.01.017Microbiota changes and intestinal microbiota transplantation inliver diseases and cirrhosisJasmohan S.Bajaj1,*,Alexander Khoruts2Keywords:Faecal microbiotatransplant;Bile acids;Gut-liver-axis;Gut-brain-axis;Hepatic encephalopathy;Alcohol.Received 30 November 2019;received in revised form 7January 2020;accepted 20January 2020;available online28 January 2020Key pointCirrhosis and chronicliver disease are associ-ated with alterations inmicrobiota compositionand function,which startin the pre-cirrhotic phasefor most disease aetiol-ogies and are affected byseveral cirrhosis-relatedand unrelated factors.Journal of Hepatology 2020 vol.72j10031027Seminarhepatitis.12Increasing severity of liver disease isassociated with worsening of dysbiosis,charac-terised by a decrease in bacterial diversity andincreases in relative abundances of Enterobacteri-aceae and Enterococcaceae,which are potentiallypathogenic as they are more prone to gut trans-location.1315Thesemicrobialchangesandconcomitantincreasedintestinalpermeabilityarevariablyreversedaftersuccessfulalcoholcessation.16NAFLD and microbiota:NAFLD,which includessimplesteatosis,non-alcoholicsteatohepatitis(NASH)and cirrhosis,has been studied exten-sively from a microbiota standpoint.A specialchallenge when assessing changes in the micro-biota in NAFLD is the overlay of diabetes,meta-bolic syndrome and obesity.17This often makes itdifficult to differentiate between the contributionof the liver disease vs.the underlying metabolicfactors that co-exist with it.Most studies haveshown an increase in relative abundances ofEnterobacteraceae in stool and endotoxemia asdisease progresses.18In paediatric NASH,wherethe concomitant impact of alcohol use is unlikely,there have been interesting reports of alcohol-producing bacteria.19This finding was subse-quently confirmed in adult studies.20Thus,it ispossiblethatendogenouslyproducedalcoholfrom microbiota can cause fatty liver disease.These widespread microbial changes have beendescribed in the circulating and hepatic micro-biome in recent studies,21,22although changes inthe circulating microbiome have been disputedvis-vis contaminants.23While the contributionof gut microbiota towards NAFLD developmentisbeinginvestigated,furtherstudiesdisen-tangling NAFLD from the overlay of diseases suchas diabetes are needed.In addition,microbiotacomposition and metabolites have been success-fully used to differentiate between NASH-relatedcirrhosis and non-cirrhotic populations in single-centre studies,which will be reviewed in detailbelow.24Autoimmuneliverdiseases:Thesediseasescompriseaspectrumrangingfromchol-angiopathies to autoimmune liver disease.Micro-bial composition and functional changes have beendescribed in patients with AIH,PBC and PSC.PBC isassociated with gut microbial alterations whetheror not it is being treated with ursodeoxycholic acid(UDCA).25In patients with PBC Bacteroidetes spp.,Sutterella,Oscillospira and Faecalibacterium werelower while Haemophilus,Veillonella,Clostridium,Lactobacillus,Streptococcus,PseudomonasandKlebsiella were higher.Moreover,Haemophilusspp.,Streptococcus spp.and Pseudomonas spp.decreased after UDCA treatment,while Bacter-oidetes spp,Sutterella spp.and Oscillospira spp.increased.Patients with AIH have been shown to havealtered microbiota even before the initiation ofsteroids in a large Chinese study.26These includeexpansionofpathobiontssuchasVeillonella,especially V.dispar and reduction of obligate an-aerobes.These results need to be corroborated inother cohorts as well.PSC is a prototype of alteredgut-liver axis with several variables related to in-flammatory bowel disease(IBD)and its activity,stage of scarring,cholangitis episodes and chol-angiocarcinoma.Studies of the stool bacteria andfungi have been performed in patients with PSC,PSC+IBD and IBD without PSC.27,28These studiesshow distinctive changes in PSC independent ofIBD with lower diversity,higher Enterococcus,Fusobacterium and Lactobacillus.27,29Changes havealso been shown in biliary microbiota in thiscondition.30Viral hepatitis:Hepatitis B and hepatitis Chave variable impact on gut microbial composi-tion.Studies of HCV-associated liver disease onthe microbiota are not very clear with resultssuggesting that the microbiota changes beforecirrhosisandaftercirrhosis.3133Microbiotacomposition is variably affected by the eradica-tion of the virus.34There is an increasing bodyof literature on HBV before the development ofcirrhosis.However,most of the changes thatoccur with HBV progression are largely similarto those seen with advancing fibrosis in otherliver diseases.35In addition,few studies havedirectly compared HBV to other liver diseaseaetiologies.Insomeofthestudiesofpre-cirrhotic patients,the ratio of Bacteroidetes toFirmicutes was evaluated as a measure of bac-terial dysbiosis.36Microbiota changes in cirrhosisCirrhosis,the end-stage of liver disease,is associ-ated with several complications that are directly orindirectlylinkedwiththegutmicrobiota.7,37Decompensationofcirrhosis,characterisedbyvariceal bleeding,hepatic encephalopathy(HE),ascites,spontaneous bacterial peritonitis(SBP)orjaundice,is the more advanced stage of cirrhosis,Microbiotastructure andfunctionAntibioticsLiverdiseasestage ActivealcoholCo-morbidconditionscoMedicinesDietDOrganfailuresHostgeneticsLiverdiseaseaetiology Fig.1.Multiple factors can influence the gut microbiotacomposition and function.Key pointChanges in microbiotacomposition and functionare the lynchpin in thealtered gut-liver-axis incirrhosis and these havebeen shown in the stool,intestinal mucosa,ascitesfluid,portal blood and liverparenchyma.1004Journal of Hepatology 2020 vol.72j10031027Seminarwhile patients who have not developed any ofthesecomplicationsareconsideredcompen-sated.38,39Thesecomplicationsformamajorburdenfromamedicalandpsycho-socialperspective and strategies to improve their prog-nosis have largely depended on gut microbialmodulation.7Patients with cirrhosis have liversynthetic failure and a decrease in bile acid secre-tion,accompanied by impaired local and systemicimmune responses and intestinal barrier dysfunc-tion that lead to systemic and neuro-inflammation.A summary of compositional and simultaneousfunctional studies in human cirrhosis that haveused stool and other tissues in outpatients are lis-ted in Table 1,while those focused on inpatientsand acute-on-chronic liver failure(ACLF)are listedin Table 2.Specific changes in alcoholic hepatitis-associated microbiota are an important aspect ofthis disease spectrum.13These changes are char-acterised by alterations in structure and function ofthe gut and serum microbiota.13,40,41Specificallyincreases in gram-negative rods,and specific spe-cies of Enterococcus predominate with advancingdisease states.13,14,42These changes are also asso-ciated with specific interactions with immune cellsand bile acids.13,14,43These changes in alcoholichepatitis make IMT a promising option for thispopulation.This global mucosal immune impair-ment in cirrhosis leads to microbiome alterationsin components of the gut-liver axis but also in theskin,the serum,liver,portal blood and the saliva.Microbial changes have been most prominentlydescribed in the stool and intestinal mucosa withrelatively higher abundances of gram-negative taxaand species of oral origin.These are most oftencomponents of Enterobacteriaceae,which are themajor causative organisms in the pathogenesis ofSBP and express a potently immunostimulatoryendotoxin.44,45Taxa of oral origin,especially thosebelongingtoStreptococcaceaeandPorphyr-omonadaceae,increase in relative abundance withadvancing cirrhosis and can be modulated by oralhealth and the use of proton pump inhibitors(PPIs).4648Bacterial taxa that are usually lacking incirrhosis belong to Firmicutes,specifically Lachno-spiraceae and Ruminococcaceae families.4951Thesechanges are found in the stool,serum and intesti-nal mucosa of patients with cirrhosis and worsenwith the advancing or decompensation of cirrhosis.Intheskin,especiallyinthosewhohavepruritus,there is a higher relative abundance ofGammaproteobacteria,theorderthatincludesEnterobacteriaceae.52Altered gut-liver-brain axis in cirrhosisHepatic encephalopathy is a major clinical mani-festation of an altered gut-liver-brain axis,whichranges from covert/minimal(CHE/MHE)to overtHE(OHE).CHEischaracterisedbycognitiveimpairmentwithoutmentalstatuschanges,53which can lead to poor function,increased pro-gression to OHE,impaired driving skills and poorsurvival.54OHE is associated with mental statuschanges ranging from disorientation to lethargyand coma.53The pathophysiology of HE is likely related tothe activity of gut microbiota.Although cirrhosisingerm-freemiceisassociatedwithhyper-ammonaemia,it is not accompanied by neuro-inflammation.55In humans,there is evidenceofneuro-inflammation,systemicinflammation,hyperammonaemiaandlow-gradecerebraloedema.56HE is associated with decreases inrelative abundances of Lachnospiraceae and Rumi-nococcacae and increases in relative abundances ofEnterobacteriaceae,Streptococcaceae and Porphyr-omonadaceae.Ammonia-associatedastrocyteswelling was negatively correlated with Lachno-spiraceaeandRuminococcaceae,andpositivelycorrelated with Enterobactericeae,while Porphyr-omonadaceaewerepositivelyassociatedwithwhite-matterchangesonbrainMRI.57Otherstudies have shown Streptococcaceae,likely due toitsureaseproduction,tobeassociatedwithMHE.58At the other end,inpatients with cirrhosishave changes on admission,such as higher endo-toxemia,lowercirrhosis-dysbiosisratio(CDR:Lachnospiraceae+Ruminococcaceae+Veillonella-ceae/Enterobacteriaceae+Bacteroidaceae)andgreater relative abundance of Enterobacteriaceaethat can predict OHE development.59Also,pa-tients with OHE have distinct changes in micro-biotaduringhospitalisationthatcanpredictrecurrence60(Table 2).It is likely that altered functions of the micro-biotaaremechanisticallyrelatedtocognitiveimpairment.Mice colonised with altered Schae-dlers flora,which is notable for low urease activity,showanimprovementincognitivefunctionfollowing liver injury.61The role of urease in hu-mandiseaseremains unclear.Althoughsomestudies have shown that urease positive taxa suchas Streptococcaceae and Helicobacter are higher inpatients with C