Gut Microbiota as Biosensors in Patients With Cirrhosis (2019)

Most of the cirrhosis-related burden results from complications such as hepatic encephalopathy (HE), ascites, and infections.1Arvaniti V. D'Amico G. Fede G. Manousou P. Tsochatzis E. Pleguezuelo M. Burroughs A.K. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis.Gastroenterology. 2010; 139 (1256 e1-5): 1246-1256Abstract Full Text Full Text PDF PubMed Scopus (768) Google Scholar HE, which has distinct overt and covert stages, represents a particularly challenging alteration of the gut–liver–brain axis.2Acharya C. Bajaj J.S. Current management of hepatic encephalopathy.Am J Gastroenterol. 2018; 113: 1600-1612Crossref PubMed Scopus (32) Google Scholar Indeed, most current treatments for HE are focused on the microbiome, but there remains room for improvement.3Vilstrup H. Amodio P. Bajaj J. Cordoba J. Ferenci P. Mullen K.D. Weissenborn K. Wong P. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver.Hepatology. 2014; 60: 715-735Crossref PubMed Scopus (1105) Google Scholar, 4Shawcross D.L. Is it time to target gut dysbiosis and immune dysfunction in the therapy of hepatic encephalopathy?.Expert Rev Gastroenterol Hepatol. 2015; 9: 539-542Crossref PubMed Scopus (24) Google Scholar Cirrhosis-associated gut microbial alterations are likely a consequence of factors related to advancing liver disease, reduction in bile flow, impaired mucosal and systemic immune response, and concomitant medications such as lactulose, rifaximin, absorbable antibiotics, and proton pump inhibitors.5Acharya C. Bajaj J.S. The microbiome in cirrhosis and its complications.Clin Gastroenterol Hepatol. 2019; 17: 307-321Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 6Chen Y. Yang F. Lu H. Wang B. Chen Y. Lei D. Wang Y. Zhu B. Li L. Characterization of fecal microbial communities in patients with liver cirrhosis.Hepatology. 2011; 54: 562-572Crossref PubMed Scopus (653) Google Scholar These conspire to create a milieu that can encourage potentially pathogenic taxa at the expense of those associated with benefit at all gastrointestinal tract locations.5Acharya C. Bajaj J.S. The microbiome in cirrhosis and its complications.Clin Gastroenterol Hepatol. 2019; 17: 307-321Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar Although in human beings it is difficult to determine whether the microbiota are the chicken or the egg with regard to cirrhosis, these microbial patterns can be potentially useful as prognosticators. Use of biosensors to detect internal processes has been used in several ecosystems. These can be as simple as enumeration of specific organisms or complicated based on changes in metabolic processes. An important concept in the development of biosensors is the balance between keystone organisms and indicator organisms. Keystone organisms are those that play a disproportionately large role in the prevalence and population levels of other species within their ecosystem or community.7Paine R.T. Food web complexity and species diversity.Am Natural. 1966; 100: 65-75Crossref Google Scholar On the other hand, indicator species are used to monitor environmental changes, assess the efficacy of management, and provide warning signals for impending ecologic shifts.8Siddig A.A.H. Ellison A.M. Ochs A. Villar-Leemand C. Laub M.K. How do ecologists select and use indicator species to monitor ecological change? Insights from 14 years of publication in Ecological Indicators.Ecol Indicators. 2016; 60: 223-230Crossref Scopus (275) Google Scholar These concepts can be extrapolated into the human gut microbiota to translate the immense complex clinically applicable formulae. The cirrhosis dysbiosis ratio was created to evaluate the contribution of potentially beneficial or keystone taxa (Lachnospiraceae, Ruminococcaceae) compared with those that may be indicator taxa (Enterobacteriaceae).9Bajaj J.S. Heuman D.M. Hylemon P.B. Sanyal A.J. White M.B. Monteith P. Noble N.A. Unser A.B. Daita K. Fisher A.R. Sikaroodi M. Gillevet P.M. Altered profile of human gut microbiome is associated with cirrhosis and its complications.J Hepatol. 2014; 60: 940-947Abstract Full Text Full Text PDF PubMed Scopus (636) Google Scholar Indeed, cirrhotic patients with a lower cirrhosis dysbiosis ratio were more likely to have worse disease, and this indicator was sensitive to change with progression, liver transplant, and probiotic therapy, and was stable in patients whose clinical course remained stable.5Acharya C. Bajaj J.S. The microbiome in cirrhosis and its complications.Clin Gastroenterol Hepatol. 2019; 17: 307-321Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 9Bajaj J.S. Heuman D.M. Hylemon P.B. Sanyal A.J. White M.B. Monteith P. Noble N.A. Unser A.B. Daita K. Fisher A.R. Sikaroodi M. Gillevet P.M. Altered profile of human gut microbiome is associated with cirrhosis and its complications.J Hepatol. 2014; 60: 940-947Abstract Full Text Full Text PDF PubMed Scopus (636) Google Scholar A similar ratio also was created for salivary microbial changes in cirrhosis.10Bajaj J.S. Betrapally N.S. Hylemon P.B. Heuman D.M. Daita K. White M.B. Unser A. Thacker L.R. Sanyal A.J. Kang D.J. Sikaroodi M. Gillevet P.M. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy.Hepatology. 2015; 62: 1260-1271Crossref PubMed Scopus (195) Google Scholar Both stool and salivary microbiota changes could predict the development of 90-day hospitalizations.10Bajaj J.S. Betrapally N.S. Hylemon P.B. Heuman D.M. Daita K. White M.B. Unser A. Thacker L.R. Sanyal A.J. Kang D.J. Sikaroodi M. Gillevet P.M. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy.Hepatology. 2015; 62: 1260-1271Crossref PubMed Scopus (195) Google Scholar, 11Bajaj J.S. Betrapally N.S. Hylemon P.B. Thacker L.R. Daita K. Kang D.J. White M.B. Unser A.B. Fagan A. Gavis E.A. Sikaroodi M. Dalmet S. Heuman D.M. Gillevet P.M. Gut microbiota alterations can predict hospitalizations in cirrhosis independent of diabetes mellitus.Sci Rep. 2015; 5: 18559Crossref PubMed Scopus (56) Google Scholar However, the cirrhosis complication in which microbiota may have the greatest contribution remains HE.3Vilstrup H. Amodio P. Bajaj J. Cordoba J. Ferenci P. Mullen K.D. Weissenborn K. Wong P. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver.Hepatology. 2014; 60: 715-735Crossref PubMed Scopus (1105) Google Scholar It is tempting to assume that the contribution of microbiota toward HE development stems from urease expression and resultant ammonia generation.5Acharya C. Bajaj J.S. The microbiome in cirrhosis and its complications.Clin Gastroenterol Hepatol. 2019; 17: 307-321Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 12Zhang Z. Zhai H. Geng J. Yu R. Ren H. Fan H. Shi P. Large-scale survey of gut microbiota associated with MHE via 16S rRNA-based pyrosequencing.Am J Gastroenterol. 2013; 108: 1601-1611Crossref PubMed Scopus (108) Google Scholar However, several microbial taxa associated with overt HE (OHE) are not urease positive but could be associated with local, hepatic, brain, and systemic inflammation.13Shawcross D.L. Davies N.A. Williams R. Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis.J Hepatol. 2004; 40: 247-254Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar The specific microbiota associated with ammonia-related astrocytic changes vs inflammation-associated white matter changes are distinct but have a higher relative abundance in HE patients.14Ahluwalia V. Betrapally N.S. Hylemon P.B. White M.B. Gillevet P.M. Unser A.B. Fagan A. Daita K. Heuman D.M. Zhou H. Sikaroodi M. Bajaj J.S. Impaired gut-liver-brain axis in patients with cirrhosis.Sci Rep. 2016; 6: 26800Crossref PubMed Scopus (130) Google Scholar Distinct salivary and gut microbial profiles have been used to detect covert HE in outpatients with cirrhosis.15Bajaj J.S. Fagan A. White M.B. Wade J.B. Hylemon P.B. Heuman D.M. Fuchs M. John B.V. Acharya C. Sikaroodi M. Gillevet P.M. Specific gut and salivary microbiota patterns are linked with different cognitive testing strategies in minimal hepatic encephalopathy.Am J Gastroenterol. 2019; 114: 1080-1090Crossref PubMed Scopus (36) Google Scholar However, most of these studies have been performed in stable outpatients, whereas the OHE stage usually is treated as an inpatient. OHE is treated with microbiome-modifying therapies such as lactulose and rifaximin, along with antibiotics needed for intercurrent or precipitating infections, which makes the interpretation of microbial contribution challenging.3Vilstrup H. Amodio P. Bajaj J. Cordoba J. Ferenci P. Mullen K.D. Weissenborn K. Wong P. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver.Hepatology. 2014; 60: 715-735Crossref PubMed Scopus (1105) Google Scholar In this issue of Cellular and Molecular Gastroenterology and Hepatology, Sung et al16Sung C.M. Chen K.-F. Lin Y.-F. Ke H.-M. Huang H.-Y. Gong Y.-N. Tsai W.-S. You J.-F. Lu M.J. Cheng H.-T. Lin C.-Y. Kuo C.-J. Tsai I.J. Hsieh S.-Y. Predicting clinical outcomes of cirrhosis patients with hepatic encephalopathy from the fecal microbiome.Cell Mol Gastroenterol Hepatol. 2019; 8: 302-319Google Scholar studied this very challenging population admitted with HE with appropriate inpatient and outpatient controls and longitudinal follow-up evaluation. The investigators showed, as expected, that microbial diversity was affected in the acute period, but the incomplete recovery and subsequent relative increase of Veillonella parvula is intriguing. This microbe has been associated with cirrhosis progression, and usually is an oral microbe that is affected by proton pump inhibitor therapy.17Wei X. Yan X. Zou D. Yang Z. Wang X. Liu W. Wang S. Li X. Han J. Huang L. Yuan J. Abnormal fecal microbiota community and functions in patients with hepatitis B liver cirrhosis as revealed by a metagenomic approach.BMC Gastroenterol. 2013; 13: 175Crossref PubMed Scopus (85) Google Scholar, 18Qin N. Yang F. Li A. Prifti E. Chen Y. Shao L. Guo J. Le Chatelier E. Yao J. Wu L. Zhou J. Ni S. Liu L. Pons N. Batto J.M. Kennedy S.P. Leonard P. Yuan C. Ding W. Chen Y. Hu X. Zheng B. Qian G. Xu W. Ehrlich S.D. Zheng S. Li L. Alterations of the human gut microbiome in liver cirrhosis.Nature. 2014; 513: 59-64Crossref PubMed Scopus (1264) Google Scholar The investigators were able to follow up patients longitudinally and found the key taxa belonging to a wide variety of phyla and their ratios could predict HE recurrence and mortality. There also was widespread gene function change in patients with OHE compared with the remaining groups, although function was not directly queried. Another intriguing finding was the higher concentration of Lactobacillus in patients who died. This has been shown in prior studies of cirrhosis, even in patients without lactulose.15Bajaj J.S. Fagan A. White M.B. Wade J.B. Hylemon P.B. Heuman D.M. Fuchs M. John B.V. Acharya C. Sikaroodi M. Gillevet P.M. Specific gut and salivary microbiota patterns are linked with different cognitive testing strategies in minimal hepatic encephalopathy.Am J Gastroenterol. 2019; 114: 1080-1090Crossref PubMed Scopus (36) Google Scholar, 19Dubinkina V.B. Tyakht A.V. Odintsova V.Y. Yarygin K.S. Kovarsky B.A. Pavlenko A.V. Ischenko D.S. Popenko A.S. Alexeev D.G. Taraskina A.Y. Nasyrova R.F. Krupitsky E.M. Shalikiani N.V. Bakulin I.G. Shcherbakov P.L. Skorodumova L.O. Larin A.K. Kostryukova E.S. Abdulkhakov R.A. Abdulkhakov S.R. Malanin S.Y. Ismagilova R.K. Grigoryeva T.V. Ilina E.N. Govorun V.M. Links of gut microbiota composition with alcohol dependence syndrome and alcoholic liver disease.Microbiome. 2017; 5: 141Crossref PubMed Scopus (201) Google Scholar Although several members of Lactobacillus are beneficial probiotic species, the role of this taxon needs further analysis in the setting of HE.19Dubinkina V.B. Tyakht A.V. Odintsova V.Y. Yarygin K.S. Kovarsky B.A. Pavlenko A.V. Ischenko D.S. Popenko A.S. Alexeev D.G. Taraskina A.Y. Nasyrova R.F. Krupitsky E.M. Shalikiani N.V. Bakulin I.G. Shcherbakov P.L. Skorodumova L.O. Larin A.K. Kostryukova E.S. Abdulkhakov R.A. Abdulkhakov S.R. Malanin S.Y. Ismagilova R.K. Grigoryeva T.V. Ilina E.N. Govorun V.M. Links of gut microbiota composition with alcohol dependence syndrome and alcoholic liver disease.Microbiome. 2017; 5: 141Crossref PubMed Scopus (201) Google Scholar The study builds on prior reports in which the stool microbial patterns also could predict 30-day outcomes in cirrhotic inpatients across single and multicenter platforms.20Chen Y. Guo J. Qian G. Fang D. Shi D. Guo L. Li L. Gut dysbiosis in acute-on-chronic liver failure and its predictive value for mortality.J Gastroenterol Hepatol. 2015; 30: 1429-1437Crossref PubMed Scopus (113) Google Scholar, 21Bajaj J.S. Vargas H.E. Reddy K.R. Lai J.C. O'Leary J.G. Tandon P. Wong F. Mitrani R. White M.B. Kelly M. Fagan A. Patil R. Sait S. Sikaroodi M. Thacker L.R. Gillevet P.M. association between intestinal microbiota collected at hospital admission and outcomes of patients with cirrhosis.Clin Gastroenterol Hepatol. 2019; 17: 756-765.e3Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar Interestingly, despite assumed differences pertaining to diet, disease etiology, genetic background, and socioeconomic status, the microbial profile for inpatients in Taiwan was similar to that found in prior Western studies.21Bajaj J.S. Vargas H.E. Reddy K.R. Lai J.C. O'Leary J.G. Tandon P. Wong F. Mitrani R. White M.B. Kelly M. Fagan A. Patil R. Sait S. Sikaroodi M. Thacker L.R. Gillevet P.M. association between intestinal microbiota collected at hospital admission and outcomes of patients with cirrhosis.Clin Gastroenterol Hepatol. 2019; 17: 756-765.e3Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar This indicates that the toll that cirrhosis, multiple hospitalizations, and frequent antibiotic use exact on microbial health may be high universally. This study contributes to growing evidence that microbiota not only affect the disease process in cirrhosis and HE at a given time point, but also could be used to prognosticate this underserved population. Larger multicenter studies are needed to ensure widespread generalizability of microbe-based diagnostics and predictive modeling. Predicting Clinical Outcomes of Cirrhosis Patients With Hepatic Encephalopathy From the Fecal MicrobiomeCellular and Molecular Gastroenterology and HepatologyVol. 8Issue 2PreviewGut dysbiosis plays a role in hepatic encephalopathy (HE), while its relationship at the acute episode of overt HE (AHE), the disease progression and clinical outcomes remains unclear. We aimed to identify AHE-specific microbiome and its association to patients' outcomes. Full-Text PDF Open Access