January 2015
Letters to the Editor
References 1.
Wald A. Clin Gastroenterol Hepatol 2014;12:1783–1788.
2.
Dodi D, et al. Gastroenterol Res Pract 2010; doi 10. 1155/2010/ 467136. Epub 2010 Dec 27.
3.
Graf W, et al. Lancet 2011;377:997–1003.
4.
Wexner SD, et al. Ann Surg 2010;251:441–449.
Conflicts of interest The author discloses no conflicts. http://dx.doi.org/10.1016/j.cgh.2014.10.016
Intestinal Microbiota Metabolism of a Prebiotic to Treat Hepatic Encephalopathy Dear Editor: In 1969 we published an article in the New England Journal of Medicine on the positive effect of lactulose in the treatment of chronic portal systemic encephalopathy (PSE).1 This was a small, double-blind clinical trial, but time did tell that lactulose was helpful in the treatment of PSE. In that early study we did stool bacteriology, and we were unable to demonstrate a change in the Lactobacillus stool counts. As time evolved, others have been able to show that lactulose can promote the growth of Bifidobacterium.2 Although there appear to be changes in the Lactobacillus bacteria, there is still a great deal of controversy as to how this is effective in treating PSE.3,4 Lunia et al5 have published a prospective, randomized, controlled trial on many more subjects in India, and they found VSL#3 to be effective in preventing PSE in patients with cirrhosis. VSL#3 contains B breve, B longum, B infantis, L acidophilus, L plantarum, L paracasei, L bulgaricus, and Streptococcus thermophilus. They did not do stool studies and did not record a change in the microbiota of the colon. However, PSE was controlled or prevented, and the probability of developing PSE in patients receiving probiotics was significant. Therefore, we have now gone 45 years since the first published documented effectiveness of lactulose, and we still do not know the clear mechanism by which it works. We do know that the microbiota appears to change, and that must indicate that the host metabolism is affected by the bacterial metabolism of the prebiotic, which definitely has a host beneficial effect. MARTIN H. FLOCH, MD Section of Digestive Diseases Yale University School of Medicine New Haven, Connecticut
1.
Conflicts of interest The author discloses no conflicts. http://dx.doi.org/10.1016/j.cgh.2014.06.008
Reply. We thank Dr Floch for reminding us of how, many decades ago, hepatic encephalopathy (HE) was shown to be a wonderful illustration of the microbiome–gut–liver–brain axis in operation. The elegant clinical studies that linked diet, bacteria, and their metabolites to HE and led to its successful treatment1–3 served as a perfect preface for the chapters delineating the extensive and complex metabolic activities of the gut microbiota,4,5 which continue to be added to this ever-evolving story. Dr Floch also is correct when he gently chides us by exposing the gaps that still exist, despite the volumes of high-quality studies that have been published in recent years on the microbiome.6 Whether in terms of its compositional and/or metabolic changes in HE per se, or its response to the administration of probiotic, prebiotic (including lactulose), or antibiotic, the microbiome still retains many secrets. It is, indeed, possible that the role of the microbiome in HE and the salutary effects of various therapies may owe more to subtle changes in bacterial metabolism rather than gross shifts in bacterial numbers or species distribution.7 Other changes in aspects of the enteric microenvironment such as in the pH or movement of luminal contents coupled, perhaps, with an increase in intestinal permeability, may be highly relevant to the efficacy of interventions, such as lactulose. We must await not only a complete description of the composition of the microbiome in HE, but also more detailed insights into how it functions (or malfunctions) in affected individuals and precisely how successful interventions restore homeostasis. With apologies to Robert Frost, there are “miles to go before we can wake those who sleep.”8 DAVID W. VICTOR III, MD EAMONN M. M. QUIGLEY, MD Division of Gastroenterology and Hepatology Houston Methodist Hospital Weill Cornell Medical College Houston, Texas
References 1. 2.
Martini GA, et al. Clin Sci 1957;16:35–51. Phear EA, et al. Clin Sci 1956;15:93–117.
4. 5.
Nicholson JK, et al. Science 2012;336:1262–1267. Nieuwdorp M, et al. Gastroenterology 2014;146:1525–1533.
6.
Victor DW 3rd, et al. Clin Gastroenterol Hepatol 2014;12: 1009–1011. Bajaj JS, et al. PLoS One 2013;8:e60042.
7.
Elkington SG, et al. N Engl J Med 1969;281:408–412.
8.
2.
De Preter V, et al. Aliment Pharmacol Ther 2006;23:963–974. Shukla S, et al. Aliment Pharmacol Ther 2001;33:662–671.
4.
Victor DW 3rd, et al. Clin Gastroenterol Hepatol 2014; 12:1009–1011.
5.
Lunia MK, et al. Clin Gastroenterol Hepatol 2014;12:1003–1008.
Phillips GB, et al. N Engl J Med 1952;247:239–246.
3.
References 3.
209
Frost R. Stopping by woods on a snowy evening. In Frost R, New Hampshire. New York, NY: Henry Holt and Company, 1923.
Conflicts of interest The authors disclose no conflicts. http://dx.doi.org/10.1016/j.cgh.2014.08.020
Letters to the Editor
References 1.
Wald A. Clin Gastroenterol Hepatol 2014;12:1783–1788.
2.
Dodi D, et al. Gastroenterol Res Pract 2010; doi 10. 1155/2010/ 467136. Epub 2010 Dec 27.
3.
Graf W, et al. Lancet 2011;377:997–1003.
4.
Wexner SD, et al. Ann Surg 2010;251:441–449.
Conflicts of interest The author discloses no conflicts. http://dx.doi.org/10.1016/j.cgh.2014.10.016
Intestinal Microbiota Metabolism of a Prebiotic to Treat Hepatic Encephalopathy Dear Editor: In 1969 we published an article in the New England Journal of Medicine on the positive effect of lactulose in the treatment of chronic portal systemic encephalopathy (PSE).1 This was a small, double-blind clinical trial, but time did tell that lactulose was helpful in the treatment of PSE. In that early study we did stool bacteriology, and we were unable to demonstrate a change in the Lactobacillus stool counts. As time evolved, others have been able to show that lactulose can promote the growth of Bifidobacterium.2 Although there appear to be changes in the Lactobacillus bacteria, there is still a great deal of controversy as to how this is effective in treating PSE.3,4 Lunia et al5 have published a prospective, randomized, controlled trial on many more subjects in India, and they found VSL#3 to be effective in preventing PSE in patients with cirrhosis. VSL#3 contains B breve, B longum, B infantis, L acidophilus, L plantarum, L paracasei, L bulgaricus, and Streptococcus thermophilus. They did not do stool studies and did not record a change in the microbiota of the colon. However, PSE was controlled or prevented, and the probability of developing PSE in patients receiving probiotics was significant. Therefore, we have now gone 45 years since the first published documented effectiveness of lactulose, and we still do not know the clear mechanism by which it works. We do know that the microbiota appears to change, and that must indicate that the host metabolism is affected by the bacterial metabolism of the prebiotic, which definitely has a host beneficial effect. MARTIN H. FLOCH, MD Section of Digestive Diseases Yale University School of Medicine New Haven, Connecticut
1.
Conflicts of interest The author discloses no conflicts. http://dx.doi.org/10.1016/j.cgh.2014.06.008
Reply. We thank Dr Floch for reminding us of how, many decades ago, hepatic encephalopathy (HE) was shown to be a wonderful illustration of the microbiome–gut–liver–brain axis in operation. The elegant clinical studies that linked diet, bacteria, and their metabolites to HE and led to its successful treatment1–3 served as a perfect preface for the chapters delineating the extensive and complex metabolic activities of the gut microbiota,4,5 which continue to be added to this ever-evolving story. Dr Floch also is correct when he gently chides us by exposing the gaps that still exist, despite the volumes of high-quality studies that have been published in recent years on the microbiome.6 Whether in terms of its compositional and/or metabolic changes in HE per se, or its response to the administration of probiotic, prebiotic (including lactulose), or antibiotic, the microbiome still retains many secrets. It is, indeed, possible that the role of the microbiome in HE and the salutary effects of various therapies may owe more to subtle changes in bacterial metabolism rather than gross shifts in bacterial numbers or species distribution.7 Other changes in aspects of the enteric microenvironment such as in the pH or movement of luminal contents coupled, perhaps, with an increase in intestinal permeability, may be highly relevant to the efficacy of interventions, such as lactulose. We must await not only a complete description of the composition of the microbiome in HE, but also more detailed insights into how it functions (or malfunctions) in affected individuals and precisely how successful interventions restore homeostasis. With apologies to Robert Frost, there are “miles to go before we can wake those who sleep.”8 DAVID W. VICTOR III, MD EAMONN M. M. QUIGLEY, MD Division of Gastroenterology and Hepatology Houston Methodist Hospital Weill Cornell Medical College Houston, Texas
References 1. 2.
Martini GA, et al. Clin Sci 1957;16:35–51. Phear EA, et al. Clin Sci 1956;15:93–117.
4. 5.
Nicholson JK, et al. Science 2012;336:1262–1267. Nieuwdorp M, et al. Gastroenterology 2014;146:1525–1533.
6.
Victor DW 3rd, et al. Clin Gastroenterol Hepatol 2014;12: 1009–1011. Bajaj JS, et al. PLoS One 2013;8:e60042.
7.
Elkington SG, et al. N Engl J Med 1969;281:408–412.
8.
2.
De Preter V, et al. Aliment Pharmacol Ther 2006;23:963–974. Shukla S, et al. Aliment Pharmacol Ther 2001;33:662–671.
4.
Victor DW 3rd, et al. Clin Gastroenterol Hepatol 2014; 12:1009–1011.
5.
Lunia MK, et al. Clin Gastroenterol Hepatol 2014;12:1003–1008.
Phillips GB, et al. N Engl J Med 1952;247:239–246.
3.
References 3.
209
Frost R. Stopping by woods on a snowy evening. In Frost R, New Hampshire. New York, NY: Henry Holt and Company, 1923.
Conflicts of interest The authors disclose no conflicts. http://dx.doi.org/10.1016/j.cgh.2014.08.020
