Transjugular intrahepatic Porto-systemic shunt positively influences the composition and metabolic functions of the gut microbiota in cirrhotic patients

Published:December 16, 2022DOI:


      Background & aims

      Cirrhosis and its complications may affect gut microbiota (GM) composition. Transjugular intrahepatic portosystemic shunt (TIPS) represents the most effective treatment for portal hypertension (PH). We aimed to evaluate whether TIPS placement modifies GM composition and metabolic function.


      A compositional and functional GM analysis was prospectively performed in 13 cirrhotic patients receiving TIPS. Patients receiving systemic or non-absorbable antibiotics for any indications were excluded. Fecal samples were collected before and three months after TIPS. GM was analyzed by 16S ribosomal RNA sequencing. Small- and medium-chain fatty acids (SCFAs and MCFAs, respectively) were measured by gas chromatography/mass spectrometry.


      TIPS placement resulted in a mean 48% reduction in portal-caval pressure gradient. No recurrence of PH related complications was observed. After TIPS, increased levels of Flavonifractor spp. (p = 0.049), and decreased levels of Clostridiaceae (p = 0.024), these latter linked to abdominal infections in cirrhotic patients, were observed. No differences were found in the SCFAs signature while analysis of MCFA profiles showed a decreased abundance of pro-inflammatory isohexanoic (p<0.01), 2-ethylhexanoic (p<0.01) and octanoic acids (p<0.01) after TIPS.


      Correction of PH following TIPS results in modifications of GM composition which could be potentially beneficial and reduces the levels of fecal pro-inflammatory MCFAs.


      List of abbreviations:

      TIPS (transjugular intrahepatic portosystemic shunt), PH (portal hypertension), GM (gut microbiota), SCFAs (small-chain fatty acids), MCFAs (middle-chain fatty acids), HE (hepatic encephalopathy), RA (refractory ascites), MELD (Model for end-stage liver disease), PSPG (porto-systemic pressure gradient), OUT (operational taxonomic unit), AUD (alcohol use disorder), PCoA (Principal Coordinate Analysis), NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic steatohepatitis (NASH))
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        • Vizzutti F.
        • Schepis F.
        • Arena U.
        • et al.
        Transjugular intrahepatic portosystemic shunt (TIPS): current indications and strategies to improve the outcomes.
        Intern Emerg Med. 2020; 15: 37-48
        • Kanmani P.
        • Suganya K.
        • Kim H.
        The gut microbiota: how does it influence the development and progression of liver diseases.
        Biomedicines. 2020; 8: 501.2
        • Lloyd-Price J.
        • Abu-Ali G.
        • Huttenhower C.
        The healthy human microbiome.
        Genome Med. 2016; 8: 51
        • Koh A.
        • De Vadder F.
        • Kovatcheva-Datchary P.
        • et al.
        From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites.
        Cell. 2016; 165: 1332-1345
        • Sam Q.H.
        • Ling H.
        • Yew W.S.
        • et al.
        The divergent immunomodulatory effects of short chain fatty acids and medium chain fatty acids.
        Int J Mol Sci. 2021; 22: 6453
        • Baffy G.
        Potential mechanisms linking gut microbiota and portal hypertension.
        Liver Int. 2019; 39: 598-609
        • Arab J.P.
        • Martin-Mateos R.M.
        • Shah V.H.
        Gut–liver axis, cirrhosis and portal hypertension: the chicken and the egg.
        Hepatol Int. 2018; 12: 24-33
        • Fagiuoli S.
        • Bruno R.
        • Debernardi Venon W.
        • et al.
        AISF TIPS Special Conference. Consensus conference on TIPS management: techniques, indications, contraindications.
        Dig Liver Dis. 2017; 49: 121-137
      1. Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases.
        J Hepatol. 2014; 61: 642-659
        • Schepis F.
        • Vizzutti F.
        • Garcia-Tsao G.
        • et al.
        Under-dilated TIPS Associate with efficacy and reduced encephalopathy in a prospective, non-randomized study of patients with cirrhosis.
        Clin Gastroenterol Hepatol: Off Clin Pract J Am Gastroenterolog Assoc. 2018; 16: 1153-1162
        • Niccolai E.
        • Russo E.
        • Baldi S.
        • et al.
        Significant and conflicting correlation of IL-9 with prevotella and bacteroides in human colorectal cancer.
        Front Immunol. 2021; 11573158
        • Niccolai E.
        • Baldi S.
        • Ricci F.
        • et al.
        Evaluation and comparison of short chain fatty acids composition in gut diseases.
        World J Gastroenterol. 2019; 25: 5543-5558
        • McMurdie P.J.
        • Holmes S.
        Phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data.
        PLoS ONE. 2013; 8 (Watson M, editor): e61217
        • Love M.I.
        • Huber W.
        • Anders S.
        Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2.
        Genome Biol. 2014; 15: 550
        • Russo E.
        • Cinci L.
        • Di Gloria L.
        • et al.
        Crohn's disease recurrence updates: first surgery ≤i≥vs≤/i≥. surgical relapse patients display different profiles of ileal microbiota and systemic microbial-associated inflammatory factors.
        Front Immunol. 2022; 13 (PMID: 35967326; PMCID: PMC9374303)886468
        • Schneider K.M.
        • Mohs A.
        • Gui W.
        • et al.
        Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment.
        Nat Commun. 2022; 13: 3964
        • Rosés C.
        • Cuevas-Sierra A.
        • Quintana S.
        • et al.
        Gut microbiota bacterial species associated with Mediterranean diet-related food groups in a Northern Spanish population.
        Nutrients. 2021; 13: 636
        • Jiang W.
        • Wu N.
        • Wang X.
        • et al.
        Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease.
        Sci Rep. 2015; 5: 8096
        • Kles K.A.
        • Chang E.B.
        Short-chain fatty acids impact on intestinal adaptation, inflammation, carcinoma, and failure.
        Gastroenterology. 2006; 130: S100-S105
        • Li M.
        • Li K.
        • Tang S.
        • Lv Y.
        • et al.
        Restoration of the gut microbiota is associated with a decreased risk of hepatic encephalopathy after TIPS.
        JHEP Rep. 2022; 4100448
        • Wu S.
        • Sun C.
        • Li Y.
        • Wang T.
        • et al.
        GMrepo: a database of curated and consistently annotated human gut metagenomes.
        Nucl Acid Res. 2020; 48: D545-D553
        • Horvath A.
        • Traub J.
        • Aliwa B.
        • et al.
        Oral intake of L-ornithine-L-aspartate is associated with distinct microbiome and metabolome changes in Cirrhosis.
        Nutrients. 2022; 14: 748
        • Shen F.
        • Zheng R.-.D.
        • Sun X.-.Q.
        • et al.
        Gut microbiota dysbiosis in patients with non-alcoholic fatty liver disease.
        Hepatob Pancreat Dis Int. 2017; 16: 375-381
        • Astbury S.
        • Atallah E.
        • Vijay A.
        • et al.
        Lower gut microbiome diversity and higher abundance of proinflammatory genus Collinsella are associated with biopsy-proven nonalcoholic steatohepatitis.
        Gut Microbes. 2020; 11: 569-580
        • Chen Y.
        • Ji F.
        • Guo J.
        • Shi D.
        • et al.
        Dysbiosis of small intestinal microbiota in liver cirrhosis and its association with etiology.
        Sci Rep. 2016; 6: 34055
        • Martinson J.N.V.
        • Pinkham N.V.
        • Peters G.W.
        • et al.
        Rethinking gut microbiome residency and the Enterobacteriaceae in healthy human adults.
        ISME J. Sep 2019; 13 (PMID: 31089259; PMCID: PMC6776003): 2306-2318
        • Liu Y.
        • Jin Y.
        • Li J.
        • Zhao L.
        • et al.
        Small bowel transit and altered gut microbiota in patients with liver cirrhosis.
        Front Physiol. 2018; 9: 470
        • Fukui H.
        Role of gut dysbiosis in liver diseases: what have we learned so far?.
        Diseases. 2019; 7: 58
        • Ling Z.
        • Liu X.
        • Cheng Y.
        • Jiang X.
        • et al.
        Decreased diversity of the oral microbiota of patients with hepatitis B virus-induced chronic liver disease: a pilot project.
        Sci Rep. 2015; 5: 17098
        • Acharya C.
        • Bajaj J.S.
        Altered microbiome in patients with cirrhosis and complications.
        Clin Gastroenterol Hepatol. 2019; 17: 307-321
        • Chen Y.
        • Ji F.
        • Guo J.
        • Shi D.
        • et al.
        Dysbiosis of small intestinal microbiota in liver cirrhosis and its association with etiology.
        Sci Rep. 2016; 6: 34055
        • Rau M.
        • Rehman A.
        • Dittrich M.
        • et al.
        Fecal SCFAs and SCFA-producing bacteria in gut microbiome of human NAFLD as a putative link to systemic T-cell activation and advanced disease.
        United Eur Gastroenterol J. 2018; 6: 1496-1507
        • Hrncir T.
        • Hrncirova L.
        • Kverka M.
        • et al.
        Gut Microbiota and NAFLD: pathogenetic mechanisms, microbiota signatures, and therapeutic interventions.
        Microorganisms. 2021; 9: 957
        • Louis P.
        • Flint H.J.
        Formation of propionate and butyrate by the human colonic microbiota.
        Environ Microbiol. 2017; 19: 29-41
        • Haghikia A.
        • Jörg S.
        • Duscha A.
        • et al.
        Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine.
        Immunity. 2015; 43: 817-829
        • Roopashree P.G.
        • Shetty S.S.
        • Suchetha
        • et al.
        Effect of medium chain fatty acid in human health and disease.
        J Funct Foods. 2021; 87104724
        • Recio C.
        • Lucy D.
        • Purvis G.S.D.
        • et al.
        Activation of the immune-metabolic receptor GPR84 enhances inflammation and phagocytosis in macrophages.
        Front Immunol. 2018; 9: 1419
        • Puengel T.
        • De Vos S.
        • Hundertmark J.
        • et al.
        The medium-chain fatty acid receptor GPR84 mediates myeloid cell infiltration promoting steatohepatitis and fibrosis.
        JCM. 2020; 9: 1140
        • Zhang X.
        • Yasuda K.
        • Gilmore R.A.
        • et al.
        Alcohol-induced changes in the gut microbiome and metabolome of rhesus macaques.
        Psychopharmacology (Berl). 2019; 236: 1531-1544
        • Leclercq S.
        • Matamoros S.
        • Cani P.D.
        • et al.
        Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity.
        Proc Natl Acad Sci USA. Oct 2014; 111 (PMID: 25288760; PMCID: PMC4210345): E4485-E4493
        • Piacentino D.
        • Grant-Beurmann S.
        • Vizioli C.
        et al. Gut microbiome and metabolome in a non-human primate model of chronic excessive alcohol drinking.
        Transl Psychiatry. 2021; 11 (PMID: 34853299; PMCID: PMC8636625): 609
        • Ames N.J.
        • Barb J.J.
        • Schuebel K.
        • et al.
        . Longitudinal gut microbiome changes in alcohol use disorder are influenced by abstinence and drinking quantity.
        Gut Microbes. 2020; 11 (PMID: 32615913; PMCID: PMC7527072): 1608-1631