EDITORIALS in patients dissatisfied with laxatives. Gut 2009; 58:357–365. Winter HS, Di Lorenzo C, Benninga MA, et al. Oral prucalopride in children with functional constipation. J Pediatr Gastroenterol Nutr 2013;57:197–203. Frampton JE. Prucalopride. Drugs 2009;69:2463–2476. Nurko S, Garcia-Aranda JA, Worona LB, et al. Cisapride for the treatment of constipation in children: a doubleblind study. J Pediatr 2000;136:35–40. Liem O, Mousa HM, Benninga MA, et al. Tegaserod use in children: a single-center experience. J Pediatr Gastroenterol Nutr 2008;46:54–58. Saps M, Youssef N, Miranda A, et al. Multicenter, randomized, placebo-controlled trial of amitriptyline in children with functional gastrointestinal disorders. Gastroenterology 2009;137:1261–1269. Travaglio E, Lemma M, Cuccia F, et al. Prevalence of constipation in a tertiary referral Italian Colorectal Unit. Ann Ital Chir 2014;85:287–291. Klauser AG1, Voderholzer WA, Heinrich CA, et al. Behavioral modification of colonic function. Can constipation be learned? Dig Dis Sci 1990;35:1271–1275. Nurko S, Youssef NN, Sabri M, et al. PEG3350 in the treatment of childhood constipation: a multicenter,
10.
11. 12.
13.
14.
15.
16.
17.
double-blinded, placebo-controlled trial. J Pediatr 2008; 153:254–261, 261 e1. 18. Thomson MA, Jenkins HR, Bisset WM, et al. Polyethylene glycol 3350 plus electrolytes for chronic constipation in children: a double blind, placebo controlled, crossover study. Arch Dis Child 2007;92:996–1000. 19. Bharucha AE, Pemberton JH, Locke GR 3rd. American Gastroenterological Association technical review on constipation. Gastroenterology 2013;144:218–238. 20. Voskuijl W, de Lorijn F, Verwijs W, et al. PEG 3350 (Transipeg) versus lactulose in the treatment of childhood functional constipation: a double blind, randomised, controlled, multicentre trial. Gut 2004;53:1590–1594.
Reprint requests Address requests for reprints to: Samuel Nurko, MD, Center for Motility and Functional Gastrointestinal Disorders, Children’s Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02155. e-mail: [email protected]. Conflicts of interest The authors disclose no conflicts. © 2014 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2014.10.024
Microbial Therapy in Liver Disease: Probiotics Probe the Microbiome–Gut–Liver–Brain Axis See “Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial,” by Dhiman RK, Rana B, Agrawal S, et al, on page 1327.
H
epatic encephalopathy (HE) is a frequently encountered complication of end stage liver disease; it has been estimated that 30%–40% of patients with cirrhosis will experience an episode of overt HE (OHE) during their lifetime. HE has grave prognostic implications with survival rates after the first episode being as low as 42% and 23% at 1 and 3 years, respectively.1 Furthermore, recurrence is likely being reported in 40% of those who experience 1 episode of OHE.2 Traditionally, secondary prophylaxis after recovery from an episode of OHE has been based on the use of either nonabsorbable disaccharides (such as lactulose) and/or oral antibiotics (such as rifaximin). Lactulose may be poorly tolerated and long-term antibiotic use raises the specter of resistance and the theoretical possibility of opportunistic infection. Should other strategies be considered? The concept of modulating the microbiome in HE is scarcely novel; decades ago, the role of nitrogenous compounds derived from bacterial metabolism of dietary protein was recognized as central to its pathogenesis and the 1216
beneficial impact of antibiotic therapy clearly demonstrated. Although utilized primarily for its laxative effects, it must also be recognized that lactulose has prebiotic effects3 and, indeed, that laxatives, in general, can modulate the microbiome.4 Furthermore, evidence accumulates to indicate that the composition of the microbiome is disturbed in cirrhosis and its complications. Not only is small intestinal bacterial overgrowth common in advanced liver disease,5 but, thanks to modern sequencing technology, it is now clear that qualitative and quantitative changes in the gut microbiome and its metabolic functions are prevalent in chronic liver disease6 and some of these change have been linked to HE, be it overt or subclinical.7,8 There also exists a burgeoning literature on the potential contribution of an altered microbiome to metabolic derangements, as well as inflammatory and immunologic processes, that may initiate or perpetuate several common liver diseases.9–11 It is timely, therefore, that Dhiman et al12 should embark on an ambitious study, reported in this issue of Gastroenterology, designed to assess the efficacy of the probiotic cocktail, VSL#3, as secondary prophylaxis in patients with OHE.12 There is precedence for this approach; animal experiments and small trials have demonstrated positive results with the use of probiotics in liver disease and a recent metaanalysis suggested that probiotics, in general, were beneficial in the prophylaxis of HE.13 It should also be noted, however, that a prior Cochrane systematic review cautioned
EDITORIALS that the weight of evidence remained insufficient to permit a recommendation supporting the use probiotics in HE.14 Data in relation to secondary prophylaxis remain sparse, rendering the study by Dhiman et al12 of particular interest. These authors identified cirrhotic patients who had experienced and completely recovered from an episode of OHE within the prior month after treatment with lactulose and rifaximin along with other clinically indicated therapies. One week before randomization, lactulose (thus avoiding its prebiotic effects) and rifaximin were withdrawn and patients randomized to receive either VSL#3 or placebo. The goal was to follow patients for 6 months. This was a relatively large study involving 130 patients in all, the majority being Child–Turcotte–Pugh (CTP) class C. Compliance with therapy was extremely high >95%, in sharp contrast with clinical experience with oral disaccharide therapy. As expected, given the advanced stage of their liver disease, many patients failed to make it to the 6-month assessment point: Only 20% in the placebo group and 24% in the treatment group. Although numerically lower in the probiotic group at 34.8% (in comparison with 51.6% in the placebo group), the rate of recurrent/breakthrough OHE, the primary endpoint of the study, was not statistically lower on the probiotic product. It also needs to be borne in mind that, at baseline, the placebo group contained a greater proportion of patients who had previously experienced more severe grades of OHE. Several secondary endpoints suggested benefit for the probiotic cocktail: Fewer hospitalizations for severe encephalopathy, better quality of life, and decreases in both CTP class and Model for End-Stage Liver Disease (MELD) scores. Of these, the former, if confirmed in an appropriately powered study, would certainly be clinically important and potentially cost saving by allowing more patients with HE to be managed in an outpatient rather than an in-patient setting. Indeed, the efficacy of VSL#3 in preventing hospitalization (hazard ratio, 0.52) was similar to that reported for the combination of rifaximin and lactulose.15 Impressive as this observation relating to VSL#3 may be it needs to be stressed that Bass and colleagues showed that rifaximin significantly prolonged the time to breakthrough HE.15 Although one can readily bemoan the failure of this randomized, placebo-controlled, clinical trial to achieve its primary endpoint, one needs to accept the challenges that confront any study in this context. As expected, the dropout rate was extremely high, resulting in comparisons between the groups of clinical (such as MELD scores and CTP class) and laboratory variables (ie, plasma renin, aldosterone, and brain-type natriuretic peptide) at the designated endpoint of the study (6 months) being based on very few subjects and, thereby, limiting the interpretability of any observed differences between placebo and probiotic. Why did the study fail to achieve its primary endpoint? There are several possibilities. First, the probiotic may not be effective or, more specifically, this probiotic preparation may not be appropriate for this indication. Indeed, a prior study failed to document an effect of VSL#3 on portal pressures in decompensated cirrhosis.16 Second, it may have been overly ambitious to expect an impact from this
intervention in a population with such advanced liver disease and overt encephalopathy. More success may have emanated from a study of MHE. Third, although microbiologically appropriate, the decision to remove lactulose may have limited, in this context, the investigator’s ability to achieve the goal of secondary prophylaxis. Despite its multiple limitations, lactulose continues to be the recommended first-line therapy for both the treatment of OHE and its secondary prophylaxis2 and the strategy of combining lactulose with a probiotic (in effect a synbiotic) has been proposed in the context of minimal HE.17 Data on the microbiota would have been of great interest. Could baseline patterns predict, as some have suggested, progression of liver disease and the likelihood of the occurrence of HE?7,8,18 What changes in microbial composition resulted from probiotic therapy and how did these correlate with therapeutic success? Studies on the impact of rifaximin suggest that the effect of this therapy on the microbiome may be quite subtle and exerted more on bacterial metabolic functions than on the relative numbers of species or strain19; does the same hold true for a probiotic strategy? Could, as has been suggested by other studies, carried out in mice, of the microbiota–gut–brain axis unrelated to liver disease or HE, a probiotic exert its effects directly on the central nervous system and independent of any discernable changes in the luminal milieu?20,21 Interestingly, in one of the aforementioned animal studies which demonstrated the ability of an orally administered probiotic to dampen a centrally mediated stress response, this effect was associated with altered central nervous system levels of gamma amino butyric acid,20 a neurotransmitter that has been linked with HE. Whether such findings translate to human HE remains to be studied. Dhiman et al12 have provided us with much to ponder on. Reassuringly, this study attests yet again to the safety of probiotics in liver disease. Although their study suggests that a probiotic cocktail may have a role in HE, one cannot, as yet, and pending a study that convincingly demonstrates a clinically meaningful reduction in recurrence rate for HE, recommend this or any other probiotic for inclusion in the armamentarium of the clinician treating HE. The identification of those bacterial populations whose presence, or absence, is causally linked with HE should inform the development of probiotic formulations best suited for its therapy or prevention, a task that is being actively pursued. Further clinical trials should be undertaken to confirm the benefits suggested by the positive secondary endpoints in this study; with a tailored intervention and in the right patient population these may well be achievable. For now, Dhiman et al12 have raised the hope that a probiotic formulation may add another arrow to that very limited quiver that is the repertoire of effective approaches to the therapy and/or prophylaxis of HE. DAVID W. VICTOR, 3RD EAMONN M. M. QUIGLEY Gastroenterology and Hepatology Houston Methodist Hospital and Weill Cornell Medical College Houston, Texas 1217
EDITORIALS References 1. Bustamante J, Rimola A, Ventura PJ, et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 1999;30:890–895. 2. Vilstrup H, Amodio P, Bajaj J, et al. 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;60:715–735. 3. De Preter V, Vanhoutte T, Huys G, et al. Effect of lactulose and Saccharomyces boulardii administration on the colonic urea-nitrogen metabolism and the bifidobacteria concentration in healthy human subjects. Aliment Pharmacol Ther 2006;23:963–974. 4. van der Wulp MY, Derrien M, Stellaard F, et al. Laxative treatment with polyethylene glycol decreases microbial primary bile salt dehydroxylation and lipid metabolism in the intestine of rats. Am J Physiol Gastrointest Liver Physiol 2013;305:G474–G482. 5. Quigley EM, Stanton C, Murphy EF. The gut microbiota and the liver pathophysiological and clinical implications. J Hepatol 2013;58:1020–1027. 6. Qin N, Yang F, Li A, et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 2014;513:59–64. 7. Bajaj JS, Ridlon JM, Hylemon PB, et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2012;302: G168–G175. 8. Bajaj JS. The role of microbiota in hepatic encephalopathy. Gut Microbes 2014;5:397–403. 9. Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases. Gastroenterology 2014;146:1513–1524. 10. Dumas ME, Kinross J, Nicholson JK. Metabolic phenotyping and systems biology approaches to understanding metabolic syndrome and fatty liver disease. Gastroenterology 2014;146:46–62. 11. Chassaing B, Etienne-Mesmin L, Gewirtz AT. Microbiotaliver axis in hepatic disease. Hepatology 2014;59:328–339. 12. Dhiman RK, Rana B, Agrawal S, et al. Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial. Gastroenterology 2014;147:1327–1337.
1218
13. Xu J, Ma R, Chen LF, et al. Effects of probiotic therapy on hepatic encephalopathy in patients with liver cirrhosis: an updated meta-analysis of six randomized controlled trials. Hepatobiliary Pancreat Dis Int 2014;13:354–360. 14. McGee RG1, Bakens A, Wiley K, et al. Probiotics for patients with hepatic encephalopathy. Cochrane Database Syst Rev 2011;(11):CD008716. 15. Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010;362: 1071–1081. 16. Jayakumar S, Carbonneau M, Hotte N, et al. VSL#3 ® probiotic therapy does not reduce portal pressures in patients with decompensated cirrhosis. Liver Int 2013; 33:1470–1477. 17. Sharma P, Sharma BC, Puri V, et al. An open-label randomized controlled trial of lactulose and probiotics in the treatment of minimal hepatic encephalopathy. Eur J Gastroenterol Hepatol 2008;20:506–511. 18. Bajaj JS, Heuman DM, Hylemon PB, et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol 2014;60:940–947. 19. Bajaj JS, Heuman DM, Sanyal AJ, et al. Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy. PLoS One 2013;8:e60042. 20. Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A 2011;108: 16050–16055. 21. Smith CJ, Emge JR, Berzins K, et al. Probiotics normalize the gut-brain-microbiota axis in immunodeficient mice. Am J Physiol Gastrointest Liver Physiol 2014;307: G793–G802. Reprint requests Address requests for reprints to: Eamonn M.M. Quigley, MD, FRCP, FACP, FACG, FRCPI, Division of Gastroenterology and Hepatology, Houston Methodist Hospital, 6550 Fannin Street, SM 1001, Houston, Texas 77030. e-mail: [email protected]. Conflicts of interest The authors disclose no conflicts. © 2014 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2014.10.023
10.
11. 12.
13.
14.
15.
16.
17.
double-blinded, placebo-controlled trial. J Pediatr 2008; 153:254–261, 261 e1. 18. Thomson MA, Jenkins HR, Bisset WM, et al. Polyethylene glycol 3350 plus electrolytes for chronic constipation in children: a double blind, placebo controlled, crossover study. Arch Dis Child 2007;92:996–1000. 19. Bharucha AE, Pemberton JH, Locke GR 3rd. American Gastroenterological Association technical review on constipation. Gastroenterology 2013;144:218–238. 20. Voskuijl W, de Lorijn F, Verwijs W, et al. PEG 3350 (Transipeg) versus lactulose in the treatment of childhood functional constipation: a double blind, randomised, controlled, multicentre trial. Gut 2004;53:1590–1594.
Reprint requests Address requests for reprints to: Samuel Nurko, MD, Center for Motility and Functional Gastrointestinal Disorders, Children’s Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02155. e-mail: [email protected]. Conflicts of interest The authors disclose no conflicts. © 2014 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2014.10.024
Microbial Therapy in Liver Disease: Probiotics Probe the Microbiome–Gut–Liver–Brain Axis See “Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial,” by Dhiman RK, Rana B, Agrawal S, et al, on page 1327.
H
epatic encephalopathy (HE) is a frequently encountered complication of end stage liver disease; it has been estimated that 30%–40% of patients with cirrhosis will experience an episode of overt HE (OHE) during their lifetime. HE has grave prognostic implications with survival rates after the first episode being as low as 42% and 23% at 1 and 3 years, respectively.1 Furthermore, recurrence is likely being reported in 40% of those who experience 1 episode of OHE.2 Traditionally, secondary prophylaxis after recovery from an episode of OHE has been based on the use of either nonabsorbable disaccharides (such as lactulose) and/or oral antibiotics (such as rifaximin). Lactulose may be poorly tolerated and long-term antibiotic use raises the specter of resistance and the theoretical possibility of opportunistic infection. Should other strategies be considered? The concept of modulating the microbiome in HE is scarcely novel; decades ago, the role of nitrogenous compounds derived from bacterial metabolism of dietary protein was recognized as central to its pathogenesis and the 1216
beneficial impact of antibiotic therapy clearly demonstrated. Although utilized primarily for its laxative effects, it must also be recognized that lactulose has prebiotic effects3 and, indeed, that laxatives, in general, can modulate the microbiome.4 Furthermore, evidence accumulates to indicate that the composition of the microbiome is disturbed in cirrhosis and its complications. Not only is small intestinal bacterial overgrowth common in advanced liver disease,5 but, thanks to modern sequencing technology, it is now clear that qualitative and quantitative changes in the gut microbiome and its metabolic functions are prevalent in chronic liver disease6 and some of these change have been linked to HE, be it overt or subclinical.7,8 There also exists a burgeoning literature on the potential contribution of an altered microbiome to metabolic derangements, as well as inflammatory and immunologic processes, that may initiate or perpetuate several common liver diseases.9–11 It is timely, therefore, that Dhiman et al12 should embark on an ambitious study, reported in this issue of Gastroenterology, designed to assess the efficacy of the probiotic cocktail, VSL#3, as secondary prophylaxis in patients with OHE.12 There is precedence for this approach; animal experiments and small trials have demonstrated positive results with the use of probiotics in liver disease and a recent metaanalysis suggested that probiotics, in general, were beneficial in the prophylaxis of HE.13 It should also be noted, however, that a prior Cochrane systematic review cautioned
EDITORIALS that the weight of evidence remained insufficient to permit a recommendation supporting the use probiotics in HE.14 Data in relation to secondary prophylaxis remain sparse, rendering the study by Dhiman et al12 of particular interest. These authors identified cirrhotic patients who had experienced and completely recovered from an episode of OHE within the prior month after treatment with lactulose and rifaximin along with other clinically indicated therapies. One week before randomization, lactulose (thus avoiding its prebiotic effects) and rifaximin were withdrawn and patients randomized to receive either VSL#3 or placebo. The goal was to follow patients for 6 months. This was a relatively large study involving 130 patients in all, the majority being Child–Turcotte–Pugh (CTP) class C. Compliance with therapy was extremely high >95%, in sharp contrast with clinical experience with oral disaccharide therapy. As expected, given the advanced stage of their liver disease, many patients failed to make it to the 6-month assessment point: Only 20% in the placebo group and 24% in the treatment group. Although numerically lower in the probiotic group at 34.8% (in comparison with 51.6% in the placebo group), the rate of recurrent/breakthrough OHE, the primary endpoint of the study, was not statistically lower on the probiotic product. It also needs to be borne in mind that, at baseline, the placebo group contained a greater proportion of patients who had previously experienced more severe grades of OHE. Several secondary endpoints suggested benefit for the probiotic cocktail: Fewer hospitalizations for severe encephalopathy, better quality of life, and decreases in both CTP class and Model for End-Stage Liver Disease (MELD) scores. Of these, the former, if confirmed in an appropriately powered study, would certainly be clinically important and potentially cost saving by allowing more patients with HE to be managed in an outpatient rather than an in-patient setting. Indeed, the efficacy of VSL#3 in preventing hospitalization (hazard ratio, 0.52) was similar to that reported for the combination of rifaximin and lactulose.15 Impressive as this observation relating to VSL#3 may be it needs to be stressed that Bass and colleagues showed that rifaximin significantly prolonged the time to breakthrough HE.15 Although one can readily bemoan the failure of this randomized, placebo-controlled, clinical trial to achieve its primary endpoint, one needs to accept the challenges that confront any study in this context. As expected, the dropout rate was extremely high, resulting in comparisons between the groups of clinical (such as MELD scores and CTP class) and laboratory variables (ie, plasma renin, aldosterone, and brain-type natriuretic peptide) at the designated endpoint of the study (6 months) being based on very few subjects and, thereby, limiting the interpretability of any observed differences between placebo and probiotic. Why did the study fail to achieve its primary endpoint? There are several possibilities. First, the probiotic may not be effective or, more specifically, this probiotic preparation may not be appropriate for this indication. Indeed, a prior study failed to document an effect of VSL#3 on portal pressures in decompensated cirrhosis.16 Second, it may have been overly ambitious to expect an impact from this
intervention in a population with such advanced liver disease and overt encephalopathy. More success may have emanated from a study of MHE. Third, although microbiologically appropriate, the decision to remove lactulose may have limited, in this context, the investigator’s ability to achieve the goal of secondary prophylaxis. Despite its multiple limitations, lactulose continues to be the recommended first-line therapy for both the treatment of OHE and its secondary prophylaxis2 and the strategy of combining lactulose with a probiotic (in effect a synbiotic) has been proposed in the context of minimal HE.17 Data on the microbiota would have been of great interest. Could baseline patterns predict, as some have suggested, progression of liver disease and the likelihood of the occurrence of HE?7,8,18 What changes in microbial composition resulted from probiotic therapy and how did these correlate with therapeutic success? Studies on the impact of rifaximin suggest that the effect of this therapy on the microbiome may be quite subtle and exerted more on bacterial metabolic functions than on the relative numbers of species or strain19; does the same hold true for a probiotic strategy? Could, as has been suggested by other studies, carried out in mice, of the microbiota–gut–brain axis unrelated to liver disease or HE, a probiotic exert its effects directly on the central nervous system and independent of any discernable changes in the luminal milieu?20,21 Interestingly, in one of the aforementioned animal studies which demonstrated the ability of an orally administered probiotic to dampen a centrally mediated stress response, this effect was associated with altered central nervous system levels of gamma amino butyric acid,20 a neurotransmitter that has been linked with HE. Whether such findings translate to human HE remains to be studied. Dhiman et al12 have provided us with much to ponder on. Reassuringly, this study attests yet again to the safety of probiotics in liver disease. Although their study suggests that a probiotic cocktail may have a role in HE, one cannot, as yet, and pending a study that convincingly demonstrates a clinically meaningful reduction in recurrence rate for HE, recommend this or any other probiotic for inclusion in the armamentarium of the clinician treating HE. The identification of those bacterial populations whose presence, or absence, is causally linked with HE should inform the development of probiotic formulations best suited for its therapy or prevention, a task that is being actively pursued. Further clinical trials should be undertaken to confirm the benefits suggested by the positive secondary endpoints in this study; with a tailored intervention and in the right patient population these may well be achievable. For now, Dhiman et al12 have raised the hope that a probiotic formulation may add another arrow to that very limited quiver that is the repertoire of effective approaches to the therapy and/or prophylaxis of HE. DAVID W. VICTOR, 3RD EAMONN M. M. QUIGLEY Gastroenterology and Hepatology Houston Methodist Hospital and Weill Cornell Medical College Houston, Texas 1217
EDITORIALS References 1. Bustamante J, Rimola A, Ventura PJ, et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 1999;30:890–895. 2. Vilstrup H, Amodio P, Bajaj J, et al. 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;60:715–735. 3. De Preter V, Vanhoutte T, Huys G, et al. Effect of lactulose and Saccharomyces boulardii administration on the colonic urea-nitrogen metabolism and the bifidobacteria concentration in healthy human subjects. Aliment Pharmacol Ther 2006;23:963–974. 4. van der Wulp MY, Derrien M, Stellaard F, et al. Laxative treatment with polyethylene glycol decreases microbial primary bile salt dehydroxylation and lipid metabolism in the intestine of rats. Am J Physiol Gastrointest Liver Physiol 2013;305:G474–G482. 5. Quigley EM, Stanton C, Murphy EF. The gut microbiota and the liver pathophysiological and clinical implications. J Hepatol 2013;58:1020–1027. 6. Qin N, Yang F, Li A, et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 2014;513:59–64. 7. Bajaj JS, Ridlon JM, Hylemon PB, et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2012;302: G168–G175. 8. Bajaj JS. The role of microbiota in hepatic encephalopathy. Gut Microbes 2014;5:397–403. 9. Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases. Gastroenterology 2014;146:1513–1524. 10. Dumas ME, Kinross J, Nicholson JK. Metabolic phenotyping and systems biology approaches to understanding metabolic syndrome and fatty liver disease. Gastroenterology 2014;146:46–62. 11. Chassaing B, Etienne-Mesmin L, Gewirtz AT. Microbiotaliver axis in hepatic disease. Hepatology 2014;59:328–339. 12. Dhiman RK, Rana B, Agrawal S, et al. Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial. Gastroenterology 2014;147:1327–1337.
1218
13. Xu J, Ma R, Chen LF, et al. Effects of probiotic therapy on hepatic encephalopathy in patients with liver cirrhosis: an updated meta-analysis of six randomized controlled trials. Hepatobiliary Pancreat Dis Int 2014;13:354–360. 14. McGee RG1, Bakens A, Wiley K, et al. Probiotics for patients with hepatic encephalopathy. Cochrane Database Syst Rev 2011;(11):CD008716. 15. Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010;362: 1071–1081. 16. Jayakumar S, Carbonneau M, Hotte N, et al. VSL#3 ® probiotic therapy does not reduce portal pressures in patients with decompensated cirrhosis. Liver Int 2013; 33:1470–1477. 17. Sharma P, Sharma BC, Puri V, et al. An open-label randomized controlled trial of lactulose and probiotics in the treatment of minimal hepatic encephalopathy. Eur J Gastroenterol Hepatol 2008;20:506–511. 18. Bajaj JS, Heuman DM, Hylemon PB, et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol 2014;60:940–947. 19. Bajaj JS, Heuman DM, Sanyal AJ, et al. Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy. PLoS One 2013;8:e60042. 20. Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A 2011;108: 16050–16055. 21. Smith CJ, Emge JR, Berzins K, et al. Probiotics normalize the gut-brain-microbiota axis in immunodeficient mice. Am J Physiol Gastrointest Liver Physiol 2014;307: G793–G802. Reprint requests Address requests for reprints to: Eamonn M.M. Quigley, MD, FRCP, FACP, FACG, FRCPI, Division of Gastroenterology and Hepatology, Houston Methodist Hospital, 6550 Fannin Street, SM 1001, Houston, Texas 77030. e-mail: [email protected]. Conflicts of interest The authors disclose no conflicts. © 2014 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2014.10.023
