INVITED COMMENTARIES
Re-CYCLing Rotavirus George J. Fuchs See ‘‘Antiviral Effects of Cyclosporin A in Neonatal Mice With Rotavirus-Induced Diarrhea’’ by Shen et al on page 11.
R
otavirus gastroenteritis affects nearly all children by age 3 to 5 years, with peak incidence between 6 and 24 months of age. Rotaviruses account for an estimated 23 million outpatient visits, 2.3 million hospitalizations (up to one-third of all pediatric diarrheal disease hospital admissions), and a half-million childhood deaths annually (1). With few exceptions, rotavirus fatalities and morbidity are the result of dehydration. As with most enteric pathogens, resource-limited countries and disadvantaged populations carry the greatest burden because of poor sanitation, inadequate use or availability of oral rehydration solution (ORS) and zinc supplementation, poor health systems, and predisposing or facilitating conditions such as malnutrition. The introduction of oral live attenuated rotavirus vaccines is a public health success story, with efficacy of present vaccines for severe illness in middle- and highincome countries of 74% to 98% and 51% to 64% in low- to middleand low-income countries. Effectiveness trials similarly have demonstrated a markedly reduced rotaviral disease burden, for example, in El Salvador, in which rotavirus-associated hospitalizations and all-cause pediatric diarrheal disease events (in- and outpatient) decreased 60% to 80% and 35% to 48%, respectively (2). In this issue of the Journal of Pediatric Gastroenterology and Nutrition, Shen et al (3) report thought-provoking results of a fascinating study exploiting antiviral properties of cyclosporin A (CSA). In dose-response fashion, CSA in a murine model of rotaviral gastroenteritis decreased diarrhea, virus shedding, and intestinal pathology, changes that were associated with a similar dose-response increase in interferon-b RNA expression and concomitant decrease in RNA expression of an inflammatory-related cytokine profile. At the highest dose of 5 mg kg 1 day 1 for 3 days, pathologic sequelae were significantly repressed and in a way that would translate into a clinically meaningful affect in human rotavirus gastroenteritis. Although these results are impressive, the potential for adverse effects of what is considered a potent immunosuppressant and the many logistical obstacles to global application of a therapeutic intervention may understandably lead clinicians and public health practitioners, respectively, to be skeptical of the practical implications of the study findings. The acknowledged success of rotavirus vaccines as described previously Received September 25, 2014; accepted September 27, 2014. From the Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock. Address correspondence and reprint requests to George J. Fuchs, MD, University of Arkansas for Medical Sciences, Little Rock, AR 722023591 (e-mail: [email protected]). The author reports no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000588
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Volume 60, Number 1, January 2015
and a highly efficacious medical intervention, ORS, seemingly further obviates the need for such a therapeutic option. Interpreting the implications of the study by Shen et al in such a way is, however, an underestimation. Beginning in 2006, countries worldwide began implementing rotavirus vaccination in their national childhood immunization programs, and in 2009, the Strategic Advisory Group of Experts of the World Health Organization recommended inclusion of rotavirus vaccines in all national immunization programs worldwide (4). Even so, most countries, including those with the highest disease burden, have not yet introduced rotavirus vaccines into their national immunization programs, with only 27 of 193 World Health Organization member states as of 2009 having incorporated rotavirus vaccine into the programs (1,5). Furthermore, the flip side of vaccine efficacy (eg, 51%–64% in low- to middle- and low-income countries) cited earlier is that a proportion (36%–49%, significantly, in low- to middle-/low-income countries) of severe disease is not prevented. And, although ORS is indeed highly efficacious in the treatment of dehydration owing to rotaviral disease, successful broad application and use of ORS has been incorrigibly difficult (6). The need for an approach to complement but not compete with prevention by immunization and treatment with ORS, therefore, is certain. Although few would suggest the use of CSA at this point in time to treat rotavirus gastroenteritis, the insights provided by the Shen et al study contribute to a potentially promising basis for further exploration and upon which new, needed interventions might be developed.
REFERENCES 1. Yen C, Tate JE, Patel MM, et al. Rotavirus vaccines: update on global impact and future priorities. Hum Vaccin 2011;7:1282–90. 2. de Palma O, Cruz L, Ramos H, et al. Effectiveness of rotavirus vaccination against childhood diarrhoea in El Salvador: case-control study. BMJ 2010;340:c2825. 3. Shen Z, Tian Z, He H, et al. Antiviral effects of cyclosporin A in neonatal mice with rotavirus-induced diarrhea. J Pediatr Gastroenterol Nutr 2015;60:11–7. 4. World Health Organization. Meeting of the Global Advisory Committee on Vaccine Safety, December 2010. Wkly Epidemiol Rec 2011;86:38–43. 5. Centers for Disease Control and Prevention. Rotavirus surveillance— worldwide, 2009. MMWR Morb Mortal Wkly Rep 2011;60:514–6. 6. Unger CC, Salam SS, Sarker MSA, et al. Treating diarrhoeal disease in children under five: the global picture. Arch Dis Child 2014;99:273–8.
Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection in Pediatric Patients: Encouragement Wrapped in Caution Susan V. Lynch See ‘‘Fecal Microbiota Transplantation Via Nasogastric Tube for Recurrent Clostridium difficile Infection in Pediatric Patients’’ by Kronman et al on page 23.
P
atients with Clostridium difficile infection that is refractory to conventional antimicrobial therapy characteristically possess
1
Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Invited Commentaries a large burden of this pathogenic species in the context of a compositionally and functionally depleted gut microbiome. Fecal microbial transplantation (FMT) aims to reconstitute and engraft a more diverse gut microbiome through instillation of a fecal slurry generated from a healthy donor. Although described anecdotally for several hundred years and clinically since the middle of the 20th century, this approach has garnered renewed interest. This is primarily because of a highly successful trial of FMT for refractory C difficile infection that reported extremely high rates of resolution (90%) in adults (1). It is also because of the growing appreciation that humans are inherently reliant on the microbial species that colonize the human body, that is, the human microbiome, to critically regulate host health status. Collectively, these factors have led to an interest in expanding application of FMT to other populations, including pediatric patients with C difficile infection. Kronman et al report on the short-term clinical outcomes of FMT of pediatric patients with C difficile infection (2). As in the aforementioned adult trial, the rate of resolution in the population of children studied was similar (90%), although the criteria that define resolution are not provided. Although this and other trials are encouraging and provide proof of principle that gut microbiome manipulation represents a viable therapeutic strategy at least for C difficile infection, one must also be cautious. The study merely considers short-term resolution of C difficile infection and, as with other similar trials, does not consider the potential longer-term consequences of FMT on host physiology and immune function. Donors in the study were exclusively adults; from a microbiome perspective, this is concerning, not in the short-term, but rather in the potential for long-term adverse events, perhaps not captured in the context of these relatively short-term trials. To understand these concerns, one must have an appreciation for the dynamic nature of the gut microbiome, which is established and rapidly develops in early infancy in parallel with physiological and immune maturation (3,4), and disassembles later in life in conjunction with immune senescence (5). Several murine studies have demonstrated that transfer of the gut microbiome of an overtly diseased individual to a healthy recipient confers disease phenotype on the latter (6,7). This raises the specter that transfer of an adult microbiome to a pediatric patient could prematurely accelerate immune aging. Although the donors in FMT studies are considered healthy primarily because they test negative for a range of traditional infectious disease agents, there remains the possibility of subclinical immune dysfunction in these donors, a feature that is neither tested for nor excluded in present-day studies. Hence, age-matched donors, more likely to be at a comparable level of microbiological and Received September 30, 2014; accepted October 10, 2014. From the Division of Gastroenterology, Department of Medicine, University of California, San Francisco. Address correspondence and reprint requests to Susan V. Lynch, PhD, University of California San Francisco, 513 Parnassus Ave, San Francisco, CA 94143 (e-mail: [email protected]). S.V.L.’s research program is currently funded by the NIH/NIAID, NIH/ NHLBI, Sloan Foundation, Cystic Fibrosis Foundation, Broad Foundation, Jannsen Pharmaceuticals, and Pfizer. She has acted as a consultant for Janssen Pharmaceuticals, Regeneron, Theravance, and Boston Consulting Group in the past and currently for Novartis. She has received payment for lectures from the American Thoracic Society, American Academy of Allergy, Asthma, and Immunology, Georgia Regents University, and Kaiser Permanente. She holds 4 patents and has been paid royalties for IP licensed by KaloBios Inc. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000612
2
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Volume 60, Number 1, January 2015
immunological maturity, represent a more relevant source of material for pediatric populations. Other concerns that this and other FMT studies raise include the transfer of microbiota across gender divides, which may also have unintended consequences. Studies have demonstrated a strong and significant relation between gut microbiome composition and sex (8), which may explain to a degree the well-established sexspecific disparities in a variety of maladies, including infectious (9) and autoimmune diseases (10). Despite these concerns, no published FMT study to date has age- or sex-matched donors with recipients, factors that may not affect short-term outcomes, but again may have large effects on long-term outcomes, particularly in pediatric populations. Other issues include the lack of objective high-resolution microbiological and immunological assessment of the patients before and following FMT. Although FMT may well resolve C difficile infection, and the recipient may now house a gut microbiome that broadly resembles that of the donor, the implications of these changes on metabolic function and host immune status remain unknown both acutely and chronically following therapy. Studies have demonstrated that subtle changes in gut microbiome composition are highly related to the degree of peripheral immune activation in human patients, and that the specific bacterial species enriched in patients with the highest degree of peripheral inflammation produce specific amino acid catabolites known to drive this immune dysfunction (11). Again, this highlights the need for more robust assessment of the microbial, immunological, and metabolic consequences of FMT and their relation with both short- and long-term health outcomes in recipients. I end this commentary with a cautionary tale. Antibiotics, which admittedly have prolonged and improved the lives of many, have been, because of their efficacy in a number of infectious diseases, widely, and frequently inappropriately, administered. Although we have reaped the short-term rewards in terms of efficacy against microbial infectious diseases, the long-term effects are now becoming apparent: alarming increases in antimicrobial resistance and pervasive and persistent effects on the composition of the human microbiome. It is incumbent on the clinical and research community as a whole to understand at a microbiological, immunological, and metabolic level both the short- and long-term implications of FMT, particularly when applied to vulnerable populations such as the pediatric population during critical periods of development. Although the initial indications are encouraging with respect to the gut microbiome as a viable therapeutic target, the emphasis moving forward must be on understanding the critical microbes and functions necessary to reprogram and rehabilitate dysfunctional microbiota, and the broader factors such as age, sex, ethnicity, and geography that influence both short-term efficacy and long-term impact of human microbiome manipulation.
REFERENCES 1. van Nood E, Dijkgraaf MG, Keller JJ. Duodenal infusion of feces for recurrent Clostridium difficile. N Engl J Med 2013;368:2145. 2. Kronman MP, Nielson HJ, Adler AL, et al. Fecal microbiota transplantation via nasogastric tube for recurrent Clostridium difficile infection in pediatric patients. J Pediatr Gastroenterol Nutr 2015; 60:23–6. 3. Sharon I, Morowitz MJ, Thomas BC, et al. Time series community genomics analysis reveals rapid shifts in bacterial species, strains, and phage during infant gut colonization. Genome Res 2013;23:111–20. 4. Palmer C, Bik EM, DiGiulio DB, et al. Development of the human infant intestinal microbiota. PLoS Biol 2007;5:e177. 5. Claesson MJ, Jeffery IB, Conde S, et al. Gut microbiota composition correlates with diet and health in the elderly. Nature 2012;488:178–84.
www.jpgn.org
Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN
Volume 60, Number 1, January 2015
6. Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006;444:1027–31. 7. Rooks MG, Veiga P, Wardwell-Scott LH, et al. Gut microbiome composition and function in experimental colitis during active disease and treatment-induced remission. ISME J 2014;8:1403–17. 8. Ding T, Schloss PD. Dynamics and associations of microbial community types across the human body. Nature 2014;509:357–60. 9. van Lunzen J, Altfeld M. Sex differences in infectious diseases— common but neglected. J Infect Dis 2014;209 (suppl 3):S79–80. 10. Ngo ST, Steyn FJ, McCombe PA. Gender differences in autoimmune disease. Front Neuroendocrinol 2014;35:347–69. 11. Vujkovic-Cvijin I, Dunham RM, Iwai S, et al. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci Transl Med 2013;5:193ra91.
Too Early to Determine Whether Fecal Microbiota Transplant has Therapeutic Promise for Ulcerative Colitis? George H. Russell See ‘‘Fecal Microbial Transplant Via Nasogastric Tube for Active Pediatric Ulcerative Colitis’’ by Suskind et al on page 27.
U
lcerative colitis (UC) is a chronic inflammatory bowel disease that can affect both children and adults. In UC, the gut bacterial ecosystem is typified by both a reduction in biodiversity and a loss of commensal flora such as Firmicutes and an increase in more proinflammatory Bacteroidetes species. Animal and human data suggest that dysbiosis may lead to immune dysregulation (1,2). Fecal microbiota transplant (FMT) is a novel therapeutic method by which stool is transferred from a screened, healthy donor to an individual with disease to modulate the gut bacterial ecosystem and theoretically promote health instead of uncontrolled inflammation. The article by Suskind et al (3) in this issue of the Journal of Pediatric Gastroenterology and Nutrition is a pilot study of 4 individuals with moderate UC activity treated with a single FMT delivered by nasogastric tube after a short course of antibiotics, acid suppression, and bowel lavage. Although FMT was feasible and adverse events were mild and self-limited, FMT was not obviously effective in moderating UC disease as measured by the Pediatric Ulcerative Colitis Activity Index or by stool or serum inflammatory biomarkers. Moreover, 3 of 4 patients in the pilot study required Received October 7, 2014; accepted October 23, 2014. From the Division of Gastroenterology & Nutrition, Boston Children’s Hospital, Boston, MA. Address correspondence and reprint requests to George H. Russell, MD, MS, Division of Gastroenterology & Nutrition, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115 (e-mail: george. [email protected]). The author reports no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000619
www.jpgn.org
Invited Commentaries progression to more aggressive standard medical management during 12 weeks of follow-up. Anecdotal and prospective reports have shown that FMT is exceptionally promising in curing recurrent Clostridium difficile infection in approximately 90% of affected individuals. Anecdotal case reports of dramatic response of UC with FMT have been published, but only limited data from prospective clinical trials are yet available. In a similar pilot study of 10 pediatric patients using daily FMT by enema for 5 days, Kunde et al showed that approximately 70% of patients had clinical response when measured by Pediatric Ulcerative Colitis Activity Index that was maintained for up to 1 month (4). A prospective randomized placebo-controlled study of 53 adult patients with UC presented in an abstract form by Moayeddi et al suggests that repeated weekly FMT by enema during 3 to 4 months can induce remission in up to 33% of patients when measured by Mayo clinical scoring (5). Our group has shown that an upper gastrointestinal route of delivery is equally effective when compared with a colonoscopic delivery approach for patients with recurrent C difficile infection, restoring the lack of gut biodiversity seen after both infection and aggressive antibiotic treatments (6). It is possible that the same is not true for UC, and that Suskind et al may have found greater success in this pilot study by using an alternative FMT delivery method. Both clinicians and patients anticipate FMT to be a potential therapeutic tool for UC with unbridled enthusiasm. The work of Suskind et al suggests that further studies are necessary. Research trials must more clearly establish clinical use, long-term safety, required dosing of donated stool, matching of donor to recipient, delivery method, duration of response, best time in disease course to use FMT, and nature of effect on the transplanted gut microbiota. Manipulation of the gut microbiota represents a new paradigm for advanced therapy of UC. There exists hope that this new therapy may ultimately spare many individuals from the need for immunosuppressive medications and biologic therapies; however, further studies on larger and well-defined UC populations are needed with a longer follow-up to establish the efficacy and long-term safety of this treatment.
REFERENCES 1. Frank DN, St Amand AL, Feldman RA, et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A 2007;104:13780–5. 2. Papa E, Docktor M, Smillie C, et al. Non-invasive mapping of the gastrointestinal microbiota identifies children with inflammatory bowel disease. PLoS One 2012;7:e39242. 3. Suskind DL, Singh N, Nielson H, Wahbeh G. Fecal microbial transplant via nasogastric tube for active pediatric ulcerative colitis. J Pediatr Gastroenterol Nutr 2015;60:27–9. 4. Kunde S, Pham A, Bonczyk S, et al. Safety, tolerability, and clinical response after fecal transplantation in children and young adults with ulcerative colitis. J Pediatr Gastroenterol Nutr 2013;56:597–601. 5. Moayeddi P, Surrette M, Wolfe M, et al. A randomized, placebo controlled trial of fecal microbiota therapy in active ulcerative colitis. Gastroenterology 2014;146:s-159. 6. Youngster I, Sauk J, Pindar C, et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors—a randomized, open label, controlled pilot study. Clin Infect Dis 2014;58:1515–22.
3
Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Re-CYCLing Rotavirus George J. Fuchs See ‘‘Antiviral Effects of Cyclosporin A in Neonatal Mice With Rotavirus-Induced Diarrhea’’ by Shen et al on page 11.
R
otavirus gastroenteritis affects nearly all children by age 3 to 5 years, with peak incidence between 6 and 24 months of age. Rotaviruses account for an estimated 23 million outpatient visits, 2.3 million hospitalizations (up to one-third of all pediatric diarrheal disease hospital admissions), and a half-million childhood deaths annually (1). With few exceptions, rotavirus fatalities and morbidity are the result of dehydration. As with most enteric pathogens, resource-limited countries and disadvantaged populations carry the greatest burden because of poor sanitation, inadequate use or availability of oral rehydration solution (ORS) and zinc supplementation, poor health systems, and predisposing or facilitating conditions such as malnutrition. The introduction of oral live attenuated rotavirus vaccines is a public health success story, with efficacy of present vaccines for severe illness in middle- and highincome countries of 74% to 98% and 51% to 64% in low- to middleand low-income countries. Effectiveness trials similarly have demonstrated a markedly reduced rotaviral disease burden, for example, in El Salvador, in which rotavirus-associated hospitalizations and all-cause pediatric diarrheal disease events (in- and outpatient) decreased 60% to 80% and 35% to 48%, respectively (2). In this issue of the Journal of Pediatric Gastroenterology and Nutrition, Shen et al (3) report thought-provoking results of a fascinating study exploiting antiviral properties of cyclosporin A (CSA). In dose-response fashion, CSA in a murine model of rotaviral gastroenteritis decreased diarrhea, virus shedding, and intestinal pathology, changes that were associated with a similar dose-response increase in interferon-b RNA expression and concomitant decrease in RNA expression of an inflammatory-related cytokine profile. At the highest dose of 5 mg kg 1 day 1 for 3 days, pathologic sequelae were significantly repressed and in a way that would translate into a clinically meaningful affect in human rotavirus gastroenteritis. Although these results are impressive, the potential for adverse effects of what is considered a potent immunosuppressant and the many logistical obstacles to global application of a therapeutic intervention may understandably lead clinicians and public health practitioners, respectively, to be skeptical of the practical implications of the study findings. The acknowledged success of rotavirus vaccines as described previously Received September 25, 2014; accepted September 27, 2014. From the Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock. Address correspondence and reprint requests to George J. Fuchs, MD, University of Arkansas for Medical Sciences, Little Rock, AR 722023591 (e-mail: [email protected]). The author reports no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000588
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Volume 60, Number 1, January 2015
and a highly efficacious medical intervention, ORS, seemingly further obviates the need for such a therapeutic option. Interpreting the implications of the study by Shen et al in such a way is, however, an underestimation. Beginning in 2006, countries worldwide began implementing rotavirus vaccination in their national childhood immunization programs, and in 2009, the Strategic Advisory Group of Experts of the World Health Organization recommended inclusion of rotavirus vaccines in all national immunization programs worldwide (4). Even so, most countries, including those with the highest disease burden, have not yet introduced rotavirus vaccines into their national immunization programs, with only 27 of 193 World Health Organization member states as of 2009 having incorporated rotavirus vaccine into the programs (1,5). Furthermore, the flip side of vaccine efficacy (eg, 51%–64% in low- to middle- and low-income countries) cited earlier is that a proportion (36%–49%, significantly, in low- to middle-/low-income countries) of severe disease is not prevented. And, although ORS is indeed highly efficacious in the treatment of dehydration owing to rotaviral disease, successful broad application and use of ORS has been incorrigibly difficult (6). The need for an approach to complement but not compete with prevention by immunization and treatment with ORS, therefore, is certain. Although few would suggest the use of CSA at this point in time to treat rotavirus gastroenteritis, the insights provided by the Shen et al study contribute to a potentially promising basis for further exploration and upon which new, needed interventions might be developed.
REFERENCES 1. Yen C, Tate JE, Patel MM, et al. Rotavirus vaccines: update on global impact and future priorities. Hum Vaccin 2011;7:1282–90. 2. de Palma O, Cruz L, Ramos H, et al. Effectiveness of rotavirus vaccination against childhood diarrhoea in El Salvador: case-control study. BMJ 2010;340:c2825. 3. Shen Z, Tian Z, He H, et al. Antiviral effects of cyclosporin A in neonatal mice with rotavirus-induced diarrhea. J Pediatr Gastroenterol Nutr 2015;60:11–7. 4. World Health Organization. Meeting of the Global Advisory Committee on Vaccine Safety, December 2010. Wkly Epidemiol Rec 2011;86:38–43. 5. Centers for Disease Control and Prevention. Rotavirus surveillance— worldwide, 2009. MMWR Morb Mortal Wkly Rep 2011;60:514–6. 6. Unger CC, Salam SS, Sarker MSA, et al. Treating diarrhoeal disease in children under five: the global picture. Arch Dis Child 2014;99:273–8.
Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection in Pediatric Patients: Encouragement Wrapped in Caution Susan V. Lynch See ‘‘Fecal Microbiota Transplantation Via Nasogastric Tube for Recurrent Clostridium difficile Infection in Pediatric Patients’’ by Kronman et al on page 23.
P
atients with Clostridium difficile infection that is refractory to conventional antimicrobial therapy characteristically possess
1
Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Invited Commentaries a large burden of this pathogenic species in the context of a compositionally and functionally depleted gut microbiome. Fecal microbial transplantation (FMT) aims to reconstitute and engraft a more diverse gut microbiome through instillation of a fecal slurry generated from a healthy donor. Although described anecdotally for several hundred years and clinically since the middle of the 20th century, this approach has garnered renewed interest. This is primarily because of a highly successful trial of FMT for refractory C difficile infection that reported extremely high rates of resolution (90%) in adults (1). It is also because of the growing appreciation that humans are inherently reliant on the microbial species that colonize the human body, that is, the human microbiome, to critically regulate host health status. Collectively, these factors have led to an interest in expanding application of FMT to other populations, including pediatric patients with C difficile infection. Kronman et al report on the short-term clinical outcomes of FMT of pediatric patients with C difficile infection (2). As in the aforementioned adult trial, the rate of resolution in the population of children studied was similar (90%), although the criteria that define resolution are not provided. Although this and other trials are encouraging and provide proof of principle that gut microbiome manipulation represents a viable therapeutic strategy at least for C difficile infection, one must also be cautious. The study merely considers short-term resolution of C difficile infection and, as with other similar trials, does not consider the potential longer-term consequences of FMT on host physiology and immune function. Donors in the study were exclusively adults; from a microbiome perspective, this is concerning, not in the short-term, but rather in the potential for long-term adverse events, perhaps not captured in the context of these relatively short-term trials. To understand these concerns, one must have an appreciation for the dynamic nature of the gut microbiome, which is established and rapidly develops in early infancy in parallel with physiological and immune maturation (3,4), and disassembles later in life in conjunction with immune senescence (5). Several murine studies have demonstrated that transfer of the gut microbiome of an overtly diseased individual to a healthy recipient confers disease phenotype on the latter (6,7). This raises the specter that transfer of an adult microbiome to a pediatric patient could prematurely accelerate immune aging. Although the donors in FMT studies are considered healthy primarily because they test negative for a range of traditional infectious disease agents, there remains the possibility of subclinical immune dysfunction in these donors, a feature that is neither tested for nor excluded in present-day studies. Hence, age-matched donors, more likely to be at a comparable level of microbiological and Received September 30, 2014; accepted October 10, 2014. From the Division of Gastroenterology, Department of Medicine, University of California, San Francisco. Address correspondence and reprint requests to Susan V. Lynch, PhD, University of California San Francisco, 513 Parnassus Ave, San Francisco, CA 94143 (e-mail: [email protected]). S.V.L.’s research program is currently funded by the NIH/NIAID, NIH/ NHLBI, Sloan Foundation, Cystic Fibrosis Foundation, Broad Foundation, Jannsen Pharmaceuticals, and Pfizer. She has acted as a consultant for Janssen Pharmaceuticals, Regeneron, Theravance, and Boston Consulting Group in the past and currently for Novartis. She has received payment for lectures from the American Thoracic Society, American Academy of Allergy, Asthma, and Immunology, Georgia Regents University, and Kaiser Permanente. She holds 4 patents and has been paid royalties for IP licensed by KaloBios Inc. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000612
2
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immunological maturity, represent a more relevant source of material for pediatric populations. Other concerns that this and other FMT studies raise include the transfer of microbiota across gender divides, which may also have unintended consequences. Studies have demonstrated a strong and significant relation between gut microbiome composition and sex (8), which may explain to a degree the well-established sexspecific disparities in a variety of maladies, including infectious (9) and autoimmune diseases (10). Despite these concerns, no published FMT study to date has age- or sex-matched donors with recipients, factors that may not affect short-term outcomes, but again may have large effects on long-term outcomes, particularly in pediatric populations. Other issues include the lack of objective high-resolution microbiological and immunological assessment of the patients before and following FMT. Although FMT may well resolve C difficile infection, and the recipient may now house a gut microbiome that broadly resembles that of the donor, the implications of these changes on metabolic function and host immune status remain unknown both acutely and chronically following therapy. Studies have demonstrated that subtle changes in gut microbiome composition are highly related to the degree of peripheral immune activation in human patients, and that the specific bacterial species enriched in patients with the highest degree of peripheral inflammation produce specific amino acid catabolites known to drive this immune dysfunction (11). Again, this highlights the need for more robust assessment of the microbial, immunological, and metabolic consequences of FMT and their relation with both short- and long-term health outcomes in recipients. I end this commentary with a cautionary tale. Antibiotics, which admittedly have prolonged and improved the lives of many, have been, because of their efficacy in a number of infectious diseases, widely, and frequently inappropriately, administered. Although we have reaped the short-term rewards in terms of efficacy against microbial infectious diseases, the long-term effects are now becoming apparent: alarming increases in antimicrobial resistance and pervasive and persistent effects on the composition of the human microbiome. It is incumbent on the clinical and research community as a whole to understand at a microbiological, immunological, and metabolic level both the short- and long-term implications of FMT, particularly when applied to vulnerable populations such as the pediatric population during critical periods of development. Although the initial indications are encouraging with respect to the gut microbiome as a viable therapeutic target, the emphasis moving forward must be on understanding the critical microbes and functions necessary to reprogram and rehabilitate dysfunctional microbiota, and the broader factors such as age, sex, ethnicity, and geography that influence both short-term efficacy and long-term impact of human microbiome manipulation.
REFERENCES 1. van Nood E, Dijkgraaf MG, Keller JJ. Duodenal infusion of feces for recurrent Clostridium difficile. N Engl J Med 2013;368:2145. 2. Kronman MP, Nielson HJ, Adler AL, et al. Fecal microbiota transplantation via nasogastric tube for recurrent Clostridium difficile infection in pediatric patients. J Pediatr Gastroenterol Nutr 2015; 60:23–6. 3. Sharon I, Morowitz MJ, Thomas BC, et al. Time series community genomics analysis reveals rapid shifts in bacterial species, strains, and phage during infant gut colonization. Genome Res 2013;23:111–20. 4. Palmer C, Bik EM, DiGiulio DB, et al. Development of the human infant intestinal microbiota. PLoS Biol 2007;5:e177. 5. Claesson MJ, Jeffery IB, Conde S, et al. Gut microbiota composition correlates with diet and health in the elderly. Nature 2012;488:178–84.
www.jpgn.org
Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN
Volume 60, Number 1, January 2015
6. Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006;444:1027–31. 7. Rooks MG, Veiga P, Wardwell-Scott LH, et al. Gut microbiome composition and function in experimental colitis during active disease and treatment-induced remission. ISME J 2014;8:1403–17. 8. Ding T, Schloss PD. Dynamics and associations of microbial community types across the human body. Nature 2014;509:357–60. 9. van Lunzen J, Altfeld M. Sex differences in infectious diseases— common but neglected. J Infect Dis 2014;209 (suppl 3):S79–80. 10. Ngo ST, Steyn FJ, McCombe PA. Gender differences in autoimmune disease. Front Neuroendocrinol 2014;35:347–69. 11. Vujkovic-Cvijin I, Dunham RM, Iwai S, et al. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci Transl Med 2013;5:193ra91.
Too Early to Determine Whether Fecal Microbiota Transplant has Therapeutic Promise for Ulcerative Colitis? George H. Russell See ‘‘Fecal Microbial Transplant Via Nasogastric Tube for Active Pediatric Ulcerative Colitis’’ by Suskind et al on page 27.
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lcerative colitis (UC) is a chronic inflammatory bowel disease that can affect both children and adults. In UC, the gut bacterial ecosystem is typified by both a reduction in biodiversity and a loss of commensal flora such as Firmicutes and an increase in more proinflammatory Bacteroidetes species. Animal and human data suggest that dysbiosis may lead to immune dysregulation (1,2). Fecal microbiota transplant (FMT) is a novel therapeutic method by which stool is transferred from a screened, healthy donor to an individual with disease to modulate the gut bacterial ecosystem and theoretically promote health instead of uncontrolled inflammation. The article by Suskind et al (3) in this issue of the Journal of Pediatric Gastroenterology and Nutrition is a pilot study of 4 individuals with moderate UC activity treated with a single FMT delivered by nasogastric tube after a short course of antibiotics, acid suppression, and bowel lavage. Although FMT was feasible and adverse events were mild and self-limited, FMT was not obviously effective in moderating UC disease as measured by the Pediatric Ulcerative Colitis Activity Index or by stool or serum inflammatory biomarkers. Moreover, 3 of 4 patients in the pilot study required Received October 7, 2014; accepted October 23, 2014. From the Division of Gastroenterology & Nutrition, Boston Children’s Hospital, Boston, MA. Address correspondence and reprint requests to George H. Russell, MD, MS, Division of Gastroenterology & Nutrition, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115 (e-mail: george. [email protected]). The author reports no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000619
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Invited Commentaries progression to more aggressive standard medical management during 12 weeks of follow-up. Anecdotal and prospective reports have shown that FMT is exceptionally promising in curing recurrent Clostridium difficile infection in approximately 90% of affected individuals. Anecdotal case reports of dramatic response of UC with FMT have been published, but only limited data from prospective clinical trials are yet available. In a similar pilot study of 10 pediatric patients using daily FMT by enema for 5 days, Kunde et al showed that approximately 70% of patients had clinical response when measured by Pediatric Ulcerative Colitis Activity Index that was maintained for up to 1 month (4). A prospective randomized placebo-controlled study of 53 adult patients with UC presented in an abstract form by Moayeddi et al suggests that repeated weekly FMT by enema during 3 to 4 months can induce remission in up to 33% of patients when measured by Mayo clinical scoring (5). Our group has shown that an upper gastrointestinal route of delivery is equally effective when compared with a colonoscopic delivery approach for patients with recurrent C difficile infection, restoring the lack of gut biodiversity seen after both infection and aggressive antibiotic treatments (6). It is possible that the same is not true for UC, and that Suskind et al may have found greater success in this pilot study by using an alternative FMT delivery method. Both clinicians and patients anticipate FMT to be a potential therapeutic tool for UC with unbridled enthusiasm. The work of Suskind et al suggests that further studies are necessary. Research trials must more clearly establish clinical use, long-term safety, required dosing of donated stool, matching of donor to recipient, delivery method, duration of response, best time in disease course to use FMT, and nature of effect on the transplanted gut microbiota. Manipulation of the gut microbiota represents a new paradigm for advanced therapy of UC. There exists hope that this new therapy may ultimately spare many individuals from the need for immunosuppressive medications and biologic therapies; however, further studies on larger and well-defined UC populations are needed with a longer follow-up to establish the efficacy and long-term safety of this treatment.
REFERENCES 1. Frank DN, St Amand AL, Feldman RA, et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A 2007;104:13780–5. 2. Papa E, Docktor M, Smillie C, et al. Non-invasive mapping of the gastrointestinal microbiota identifies children with inflammatory bowel disease. PLoS One 2012;7:e39242. 3. Suskind DL, Singh N, Nielson H, Wahbeh G. Fecal microbial transplant via nasogastric tube for active pediatric ulcerative colitis. J Pediatr Gastroenterol Nutr 2015;60:27–9. 4. Kunde S, Pham A, Bonczyk S, et al. Safety, tolerability, and clinical response after fecal transplantation in children and young adults with ulcerative colitis. J Pediatr Gastroenterol Nutr 2013;56:597–601. 5. Moayeddi P, Surrette M, Wolfe M, et al. A randomized, placebo controlled trial of fecal microbiota therapy in active ulcerative colitis. Gastroenterology 2014;146:s-159. 6. Youngster I, Sauk J, Pindar C, et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors—a randomized, open label, controlled pilot study. Clin Infect Dis 2014;58:1515–22.
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