EDITORIALS Treating Constipation With Prucalopride: One Size Does Not Fit All See “Prucalopride is no more effective than placebo for children with functional constipation,” by Mugie SM, Korczowski B, Bodi P, et al, on page 1285.
F
unctional constipation (FC) is among the most common functional gastrointestinal (GI) disorders in children. Epidemiologic studies conducted throughout the world cite a prevalence as high as 29.6%.1,2 FC is associated with poor school functioning,3 poor quality of life,1 and a significant economic burden.4 The results of treatment in children are suboptimal, and 30% continue to require treatment after 8 years.5 The magnitude of the problem in combination with the poor outcomes of treatment stresses the need for new therapies for FC in children.6 The results found with the use of prucalopride in placebo controlled trials in adults,7–9 as well as a small, openlabel trial in children10 raised great expectations on the possible use of this novel drug for the treatment of FC in children. Prucalopride is a selective, high-affinity, 5hydroxytryptamine receptor-4 (5HT4) agonist with GI prokinetic properties.11 It has been shown to accelerate colonic transit, and it facilitates colonic motility with the release of acetylcholine after the activation of 5-HT4 receptors on cholinergic neurons.11 Previous studies of other nonselective 5HT4 agonists like cisapride12 and tegaserod13 in children have also shown significant benefit with their use. Unfortunately these nonselective 5HT4 agonists were associated with adverse, life-threatening cardiovascular side effects because of their affinity for the hERG-encoding potassium channel, 5-HT1 or 5-HT2 receptors, something that has not been seen with prucalopride. In this issue of Gastroenterology, Mugie et al6 report the data from a large, multicenter, placebo-controlled trial of prucalopride in children with FC. They found, using response criteria that included >3 spontaneous bowel movements per week and 3 spontaneous bowel movements per week was 29.2% on prucalopride. Therefore, the overall response rate based only on bowel movements after prucalopride in children is 1214
similar to the adults. However, the results of the placebo arm (35.5%) in the pediatric study stand in contrast with the results of adult trials (9%–12%).7–9 Although this could be viewed only as another example of differences in placebo responses explaining the sometimes contradictory results of trials in adults and children, because it also occurred with the amitriptyline trial for functional abdominal pain in children,14 there are additional reasons to explain these differences. The definitions of FC, pathophysiologic mechanisms, and primary endpoints differ between pediatric and adult trials. For example, the presence of FI is not part of the adult definition of FC, whereas it constitutes an important criterion in children, because daytime FI is present in 77%.1 That prucalopride had such a limited response in the treatment of children confirms that FC in children is an heterogeneous disorder with a complex pathophysiology that is not necessarily related to an abnormal transit. In fact, the prevalence of slow transit constipation in children is lower than adults and it has been reported in only 13%– 25%1 of cases. This contrasts with adult studies that found slow transit constipation in 60%–71% of patients with intractable constipation.15 Therefore, given the prokinetic nature of prucalopride, it could have been predicted that, given that slow transit constipation is less common in children, there would be lower responses to prucalopride in children than in adults. In the present pediatric study, no colonic transit was performed, so it is not possible to know if the medication was more successful in those patients with slow transit, or if responders were those in which the colonic transit improved. A second common pathophysiologic feature in FC in children is withholding behavior, which is not as important in adults. In the trial by Mugie et al,6 61% of children had history of excessive volitional stool retention. In experimental studies in adults, it has been shown that the chronic voluntary suppression of defecation produced a lesser frequency of defecations associated with increase in total transit times. This shows that defecation habits induce changes in colonic function,16 which in part explains the effects of withholding. In children, withholding behavior leads to stool retention and secondary FI that results from overflow, mainly in the presence of fecal impaction or as a result of stool leakage from the rectum when stools approach the anus. Therefore, the influence of behavioral factors may also explain some of the differences found among studies in children and adults. Another dissimilarity between pediatric and adult trials is that primary endpoints differ as mentioned.6 FI has been used as endpoint in most trials in FC in children. In the current study, there was a decrease in FI from baseline, but
EDITORIALS there was no difference in the final FI episodes between groups. This result is similar to other studies comparing laxatives with placebo.12,17,18 In the present study there were more responders in the prucalopride arm among children 12 years of age,6 which indicates that age can have an important influence in the incidence of FI. It is possible that as children get older the mechanisms involved in FC may be similar to adults. Prucalopride is not the first type of therapy for FC where there have been different outcomes between adults and children. There are multiple controlled studies of biofeedback in children with defecation abnormalities that showed no beneficial effect. Moreover, the studies found no relationship between attaining normal defecation dynamics and response to therapy.1 These findings markedly contrast with the experience in adults, in which biofeedback has been shown to be highly effective in patients with dyssynergic defecation.19 Other laxatives have been shown to be effective for the treatment of FC in children. The use of polyethylene glycol (PEG) is the mainstay of treatment. If changes in behavior are thought to be an important pathway to solve a large proportion of cases of FC in children, the use of osmotic laxatives may be a more rational approach. Children who soften their stools lose the fear to defecate over time. The occurrence of looser stools avoids large fecal masses and perianal pain that would not be the case with the use of a stimulant laxative. Placebo-controlled studies, and studies comparing PEG-based solution with other laxatives, have consistently shown that PEG is more effective.1 In a longterm, randomized trial of PEG versus lactulose,20 using the same endpoints as Mugie et al,6 PEG-based solutions achieved a successful outcome in 56% of participants compared with 29% in the lactulose group. These results are much higher than those seen with prucalopride. In fact, recent guidelines for the evaluation and treatment of FC in children of NASPGHAN and ESPGHAN recommend PEG as the first line of treatment.1 The guidelines also recommend a minimum treatment of 2 months. The study by Muggie et al6 assessed the primary efficacy endpoint over weeks 5–8 of the study, which implies a shorter period of treatment. Given that children in the study had a mean duration of symptoms of 4.4 years and a mean age of 4.5 years, it may be unrealistic to expect substantial changes in a large proportion of children who had FC for most of their life in such a short period of time. This observation leads to the question on whether the short length of the trial could explain the negative results. Although, we are not able to respond fully to this question owing to the design of the study, the results of the open label re-randomization that followed the double-blind period (PEG or prucalopride) can give some insights. At the end of the open-label period, significantly more children who received prucalopride (40.2%) rated their constipation as severe to very severe compared with children who received PEG (28.0%). This suggests that a longer period of treatment would have probably not changed the overall conclusions of the study, and that even though the long-term phase was not a blind comparison, the response associated
with PEG was better. Therefore, this study does not provide new data to justify a change in the indication of PEG as first line of treatment for FC in children. Future head-to-head comparisons between prucalopride and other laxatives are needed in both adults and children. The advent of new molecules like the kind of oral secretagogues, or the use of ileal bile acid transporter inhibitors (that may have both a prokinetic and a secretory effect) may represent new alternatives that need to be studied further in children. In summary, the authors have shown that there is no beneficial effect of the use of prucalopride alone if compared with placebo in children. Despite the disappointing results of this clinical trial, the study may help to provide further insight to the differences in mechanisms underlying FC in adults and children and the optimal design of randomized, controlled trials in children. SAMUEL NURKO Center for Motility and Functional and Gastrointestinal Disorders Boston Children’s Hospital Boston, Massachusetts MIGUEL SAPS Pediatric Gastroenterology Ann & Robert H. Lurie Children’s Hospital of Chicago Chicago, Illinois
References 1. Tabbers MM, DiLorenzo C, Berger MY, et al. Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN. J Pediatr Gastroenterol Nutr 2014;58:265–281. 2. van den Berg MM, Benninga MA, Di Lorenzo C. Epidemiology of childhood constipation: a systematic review. Am J Gastroenterol 2006;101:2401–2409. 3. Rajindrajith S, Devanarayana NM, Weerasooriya L, et al. Quality of life and somatic symptoms in children with constipation: a school-based study. J Pediatr 2013; 163:1069–1072 e1. 4. Liem O, Harman J, Benninga M, et al. Health utilization and cost impact of childhood constipation in the United States. J Pediatr 2009;154:258–262. 5. van Ginkel R, Reitsma JB, Büller HA, et al. Childhood constipation: longitudinal follow-up beyond puberty. Gastroenterology 2003;125:357–363. 6. Mugie SM, Korczowski B, Bodi P, et al. Prucalopride is no more effective than placebo for children with functional constipation. Gastroenterology 2014;147:1285–1295. 7. Camilleri M, Kerstens R, Rykx A, et al. A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med 2008;358:2344–2354. 8. Quigley EM, Vandeplassche L, Kerstens R, et al. Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation—a 12week, randomized, double-blind, placebo-controlled study. Aliment Pharmacol Ther 2009;29:315–328. 9. Tack J, van Outryve M, Beyens G, et al. Prucalopride (Resolor) in the treatment of severe chronic constipation 1215
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
F
unctional constipation (FC) is among the most common functional gastrointestinal (GI) disorders in children. Epidemiologic studies conducted throughout the world cite a prevalence as high as 29.6%.1,2 FC is associated with poor school functioning,3 poor quality of life,1 and a significant economic burden.4 The results of treatment in children are suboptimal, and 30% continue to require treatment after 8 years.5 The magnitude of the problem in combination with the poor outcomes of treatment stresses the need for new therapies for FC in children.6 The results found with the use of prucalopride in placebo controlled trials in adults,7–9 as well as a small, openlabel trial in children10 raised great expectations on the possible use of this novel drug for the treatment of FC in children. Prucalopride is a selective, high-affinity, 5hydroxytryptamine receptor-4 (5HT4) agonist with GI prokinetic properties.11 It has been shown to accelerate colonic transit, and it facilitates colonic motility with the release of acetylcholine after the activation of 5-HT4 receptors on cholinergic neurons.11 Previous studies of other nonselective 5HT4 agonists like cisapride12 and tegaserod13 in children have also shown significant benefit with their use. Unfortunately these nonselective 5HT4 agonists were associated with adverse, life-threatening cardiovascular side effects because of their affinity for the hERG-encoding potassium channel, 5-HT1 or 5-HT2 receptors, something that has not been seen with prucalopride. In this issue of Gastroenterology, Mugie et al6 report the data from a large, multicenter, placebo-controlled trial of prucalopride in children with FC. They found, using response criteria that included >3 spontaneous bowel movements per week and 3 spontaneous bowel movements per week was 29.2% on prucalopride. Therefore, the overall response rate based only on bowel movements after prucalopride in children is 1214
similar to the adults. However, the results of the placebo arm (35.5%) in the pediatric study stand in contrast with the results of adult trials (9%–12%).7–9 Although this could be viewed only as another example of differences in placebo responses explaining the sometimes contradictory results of trials in adults and children, because it also occurred with the amitriptyline trial for functional abdominal pain in children,14 there are additional reasons to explain these differences. The definitions of FC, pathophysiologic mechanisms, and primary endpoints differ between pediatric and adult trials. For example, the presence of FI is not part of the adult definition of FC, whereas it constitutes an important criterion in children, because daytime FI is present in 77%.1 That prucalopride had such a limited response in the treatment of children confirms that FC in children is an heterogeneous disorder with a complex pathophysiology that is not necessarily related to an abnormal transit. In fact, the prevalence of slow transit constipation in children is lower than adults and it has been reported in only 13%– 25%1 of cases. This contrasts with adult studies that found slow transit constipation in 60%–71% of patients with intractable constipation.15 Therefore, given the prokinetic nature of prucalopride, it could have been predicted that, given that slow transit constipation is less common in children, there would be lower responses to prucalopride in children than in adults. In the present pediatric study, no colonic transit was performed, so it is not possible to know if the medication was more successful in those patients with slow transit, or if responders were those in which the colonic transit improved. A second common pathophysiologic feature in FC in children is withholding behavior, which is not as important in adults. In the trial by Mugie et al,6 61% of children had history of excessive volitional stool retention. In experimental studies in adults, it has been shown that the chronic voluntary suppression of defecation produced a lesser frequency of defecations associated with increase in total transit times. This shows that defecation habits induce changes in colonic function,16 which in part explains the effects of withholding. In children, withholding behavior leads to stool retention and secondary FI that results from overflow, mainly in the presence of fecal impaction or as a result of stool leakage from the rectum when stools approach the anus. Therefore, the influence of behavioral factors may also explain some of the differences found among studies in children and adults. Another dissimilarity between pediatric and adult trials is that primary endpoints differ as mentioned.6 FI has been used as endpoint in most trials in FC in children. In the current study, there was a decrease in FI from baseline, but
EDITORIALS there was no difference in the final FI episodes between groups. This result is similar to other studies comparing laxatives with placebo.12,17,18 In the present study there were more responders in the prucalopride arm among children 12 years of age,6 which indicates that age can have an important influence in the incidence of FI. It is possible that as children get older the mechanisms involved in FC may be similar to adults. Prucalopride is not the first type of therapy for FC where there have been different outcomes between adults and children. There are multiple controlled studies of biofeedback in children with defecation abnormalities that showed no beneficial effect. Moreover, the studies found no relationship between attaining normal defecation dynamics and response to therapy.1 These findings markedly contrast with the experience in adults, in which biofeedback has been shown to be highly effective in patients with dyssynergic defecation.19 Other laxatives have been shown to be effective for the treatment of FC in children. The use of polyethylene glycol (PEG) is the mainstay of treatment. If changes in behavior are thought to be an important pathway to solve a large proportion of cases of FC in children, the use of osmotic laxatives may be a more rational approach. Children who soften their stools lose the fear to defecate over time. The occurrence of looser stools avoids large fecal masses and perianal pain that would not be the case with the use of a stimulant laxative. Placebo-controlled studies, and studies comparing PEG-based solution with other laxatives, have consistently shown that PEG is more effective.1 In a longterm, randomized trial of PEG versus lactulose,20 using the same endpoints as Mugie et al,6 PEG-based solutions achieved a successful outcome in 56% of participants compared with 29% in the lactulose group. These results are much higher than those seen with prucalopride. In fact, recent guidelines for the evaluation and treatment of FC in children of NASPGHAN and ESPGHAN recommend PEG as the first line of treatment.1 The guidelines also recommend a minimum treatment of 2 months. The study by Muggie et al6 assessed the primary efficacy endpoint over weeks 5–8 of the study, which implies a shorter period of treatment. Given that children in the study had a mean duration of symptoms of 4.4 years and a mean age of 4.5 years, it may be unrealistic to expect substantial changes in a large proportion of children who had FC for most of their life in such a short period of time. This observation leads to the question on whether the short length of the trial could explain the negative results. Although, we are not able to respond fully to this question owing to the design of the study, the results of the open label re-randomization that followed the double-blind period (PEG or prucalopride) can give some insights. At the end of the open-label period, significantly more children who received prucalopride (40.2%) rated their constipation as severe to very severe compared with children who received PEG (28.0%). This suggests that a longer period of treatment would have probably not changed the overall conclusions of the study, and that even though the long-term phase was not a blind comparison, the response associated
with PEG was better. Therefore, this study does not provide new data to justify a change in the indication of PEG as first line of treatment for FC in children. Future head-to-head comparisons between prucalopride and other laxatives are needed in both adults and children. The advent of new molecules like the kind of oral secretagogues, or the use of ileal bile acid transporter inhibitors (that may have both a prokinetic and a secretory effect) may represent new alternatives that need to be studied further in children. In summary, the authors have shown that there is no beneficial effect of the use of prucalopride alone if compared with placebo in children. Despite the disappointing results of this clinical trial, the study may help to provide further insight to the differences in mechanisms underlying FC in adults and children and the optimal design of randomized, controlled trials in children. SAMUEL NURKO Center for Motility and Functional and Gastrointestinal Disorders Boston Children’s Hospital Boston, Massachusetts MIGUEL SAPS Pediatric Gastroenterology Ann & Robert H. Lurie Children’s Hospital of Chicago Chicago, Illinois
References 1. Tabbers MM, DiLorenzo C, Berger MY, et al. Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN. J Pediatr Gastroenterol Nutr 2014;58:265–281. 2. van den Berg MM, Benninga MA, Di Lorenzo C. Epidemiology of childhood constipation: a systematic review. Am J Gastroenterol 2006;101:2401–2409. 3. Rajindrajith S, Devanarayana NM, Weerasooriya L, et al. Quality of life and somatic symptoms in children with constipation: a school-based study. J Pediatr 2013; 163:1069–1072 e1. 4. Liem O, Harman J, Benninga M, et al. Health utilization and cost impact of childhood constipation in the United States. J Pediatr 2009;154:258–262. 5. van Ginkel R, Reitsma JB, Büller HA, et al. Childhood constipation: longitudinal follow-up beyond puberty. Gastroenterology 2003;125:357–363. 6. Mugie SM, Korczowski B, Bodi P, et al. Prucalopride is no more effective than placebo for children with functional constipation. Gastroenterology 2014;147:1285–1295. 7. Camilleri M, Kerstens R, Rykx A, et al. A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med 2008;358:2344–2354. 8. Quigley EM, Vandeplassche L, Kerstens R, et al. Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation—a 12week, randomized, double-blind, placebo-controlled study. Aliment Pharmacol Ther 2009;29:315–328. 9. Tack J, van Outryve M, Beyens G, et al. Prucalopride (Resolor) in the treatment of severe chronic constipation 1215
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
