ISSN 1007-9327 (print) ISSN 2219-2840 (online) World Journal Of

World J Gastroenterol 2017 December 7; 23(45): 7952-7964Submit a Manuscript: http://www.f6publishing.comDOI: 10.3748/wjg.v23.i45.7952ISSN 1007-9327 (print) ISSN 2219-2840 (online)MINIREVIEWSProbiotics for gastrointestinal disorders: proposedrecommendations for children of the Asia-Pacific regionDonald Cameron, Quak Seng Hock, Musal Kadim, Neelam Mohan, Eell Ryoo, Bhupinder Sandhu, YuichiroYamashiro, Chen Jie, Hans Hoekstra, Alfredo GuarinoDonald Cameron, Department of Gastroenterology and ClinicalNutrition, Royal Children’s Hospital, Melbourne 3052, AustraliaGuarino A reviewed and evaluated the literature, and designed thescientific program of the initial meeting in Paris at the SorbonneUniversity and the second meeting in Osaka.Quak Seng Hock, Yong Loo Lin School of Medicine, NationalUniversity of Singapore, Singapore 119228, SingaporeSupported by a medical educational grant from Biocodex, France.Conflict-of-interest statement: The working group meetingwas funded by a medical education grant from Biocodex, France.Professor Yamashiro has received research funding from YakultHonsha Co. Ltd. Japan. All other authors have no conflicts ofinterest to declare.Musal Kadim, Child Health Department, Cipto MangunkusumoHospital, University of Indonesia, Jakarta 12220, IndonesiaNeelam Mohan, Department of Pediatric Gastroenterology,Hepatology And Liver Transplantation, Medanta The Medicity122001, Gurugram Haryana, IndiaOpen-Access: This article is an open-access article which wasselected by an in-house editor and fully peer-reviewed by externalreviewers. It is distributed in accordance with the CreativeCommons Attribution Non Commercial (CC BY-NC 4.0) license,which permits others to distribute, remix, adapt, build upon thiswork non-commercially, and license their derivative works ondifferent terms, provided the original work is properly cited andthe use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/Eell Ryoo, Department of Pediatrics, Gachon University, GilGachon Children’s Hosptial, Incheon 21565, South KoreaBhupinder Sandhu, Department of Paediatric Gastroenterology,Royal Hospital for Children, Bristol BS2 8BJ, United KingdomYuichiro Yamashiro, Probiotics Research Laboratory, JuntendoUniversity Graduate School of Medicine, Tokyo 113-0033, JapanManuscript source: Unsolicited manuscriptChen Jie, The Children’s Hospital, Zhejiang University Schoolof Medicine, Hangzhou 610041, Zhejiang Province, ChinaCorrespondence to: Donald Cameron, MD, PhD, Professor,Department of Gastroenterology and Clinical Nutrition, RoyalChildren’s Hospital, 50 Flemington Road, Parkville Victoria,Melbourne 3052, Australia. don.cameron@rch.org.auTelephone: 61-3-93456644Fax: 61-3-88889944Hans Hoekstra, Department of Pediatrics, Hieronymus BoschHospital, ’s-Hertogenbosch 5223GZ, The NetherlandsAlfredo Guarino, Unit of Pediatrics Infectious Diseases andClinical Nutrition of the Department of Translational MedicalScience-Section of Pediatrics, University of Naples Federico II,Naples 80131, ItalyReceived: January 24, 2017Peer-review started: January 31, 2017First decision: April 21, 2017Revised: September 29, 2017Accepted: November 1, 2017Article in press: November 1, 2017Published online: December 7, 2017ORCID number: Donald Cameron (0000-0002-3175-6965);Quak Seng Hock (0000-0003-4570-2375); Musal Kadim (0000-0001-7519-191X); Neelam Mohan (0000-0002-7055-192X);Eell Ryoo (0000-0002-0785-5314); Bhupinder Sandhu (0000-0002-5979-0823); Yuichiro Yamashiro (0000-0002-9679-8699);Chen Jie (0000-0002-4031-5619); Hans Hoekstra (0000-0001-7224-4758); Alfredo Guarino (0000-0003-0199-0336).Author contributions: All of the authors attended the workinggroup meeting of international experts, and read, edited, andapproved the manuscript at each draft stage; Hoekstra H andWJG www.wjgnet.comAbstractRecommendations for probiotics are available in7952December 7, 2017 Volume 23 Issue 45

Cameron D et al . Probiotics for gastrointestinal disorders in childrenseveral regions. This paper proposes recommendationsfor probiotics in pediatric gastrointestinal diseasesin the Asia-Pacific region. Epidemiology and clinicalpatterns of intestinal diseases in Asia-Pacific countrieswere discussed. Evidence-based recommendationsand randomized controlled trials in the region wererevised. Cultural aspects, health management issuesand economic factors were also considered. Finalrecommendations were approved by applying the Likertscale and rated using the GRADE system. Saccharomycesboulardii CNCM I-745 (Sb) and Lactobacillus rhamnosusGG (LGG ) were strongly recommended as adjuncttreatment to oral rehydration therapy for gastroenteritis.Lactobacillus reuteri could also be considered. Probioticsmay be considered for prevention of (with the indicatedstrains): antibiotic-associated diarrhea (LGG or Sb);Clostridium difficile -induced diarrhea (Sb); nosocomialdiarrhea (LGG); infantile colic (L reuteri ) and as adjuncttreatment of Helicobacter pylori (Sb and others). Specificprobiotics with a history of safe use in preterm and terminfants may be considered in infants for prevention ofnecrotizing enterocolitis. There is insufficient evidencefor recommendations in other conditions. Despite adiversity of epidemiological, socioeconomical and healthsystem conditions, similar recommendations apply wellto Asia pacific countries. These need to be validated withlocal randomized-controlled trials.INTRODUCTIONGastrointestinal illnesses are a major cause of morbidity[1]and mortality in children in developing countries , withdiarrheal diseases being one of the top five causes of[2]death in children younger than five years . Worldwide,[2,3]the most important enteric pathogen is rotavirus ;other major pathogens include Escherichia coli, Vibriocholera, and Shigella, Campylobacter, Salmonella, and[4,5]Cryptosporidium species .In the Asia-Pacific region, the distribution of entericpathogens shows marked regional variations, withdifferences largely corresponding to the predominant[2]socioeconomic status of each region . The AsiaPacific region, comprising more than half of the world’s total population, is an area that is particularly diversepolitically, economically, and culturally, including someof the world’s least and some of the most developed[6]nations . While many in the Asia-Pacific region struggleto meet the most basic survival needs, a substantialproportion of the population in this region is moving[6]towards Western diets and unhealthy lifestyles .The human gut microbiota is emerging as a majordeterminant of intestinal and non-intestinal diseases.The human gut is home to a diverse collection ofmicrobes, collectively termed gut microbiota, thedisruption of which is associated with gastrointestinal[7]diseases . Moreover, it is becoming clear thatgeographic variations in the composition of the gutmicrobiota are likely to affect the risk of developing[8]specific diseases . These geographic variations maybe due to a number of factors, including diet, culture,[9]and genetics . The relationship between disruptionof gut microbiota and the risk of disease developmentand symptom severity suggests that the use ofcertain probiotics strains may prevent or reduce theprogression of damage caused by some gastrointestinalillnesses.Probiotics are live microorganisms that whenadministered in adequate amounts confer a health[10]benefit . While there exists a substantial body ofliterature regarding the use of probiotics in numeroushuman diseases, the quality of evidence for theiruse is variable, with evidence lacking for manyindications. A number of organizations and institutionshave reviewed the currently available evidence anddeveloped recommendations for probiotics use at[10-14]national or international level. In order to proposerecommendations for the use of probiotics in childrenof the Asia-Pacific region, a group of experts met toreview and discuss existing recommendations, as wellas the relevant available data regarding the proposedrecommendations for Asia-Pacific.Key words: Lactobacillus rhamnosus ; gastroenteritis;Guidelines; probiotics; children; recommendations;Asia-Pacific; Saccharomyces boulardii The Author(s) 2017. Published by Baishideng PublishingGroup Inc. All rights reserved.Core tip: This paper includes recommendations basedon guidelines and local data for use of probiotics strainsin the prevention or treatment of intestinal diseases inchildren of Asia-Pacific region. Notwithstanding majordifferences in health management and local conditionsbetween countries, recommendations for children livingin various countries of Asia-Pacific region are similar.Saccharomyces boulardii and Lactobacillus rhamnosusGG may be used in gastroenteritis, nosocomial infections,antibiotic-associated diarrhea. Selected strains mayhave a place in infantile colic, Helicobacter pyloritreatment, and necrotizing enterocolitis. This documentprovides a helpful guidance to use probiotics in childrenbased on local data and considerations.Cameron D, Hock QS, Kadim M, Mohan N, Ryoo E, SandhuB, Yamashiro Y, Jie C, Hoekstra H, Guarino A. Probioticsfor gastrointestinal disorders: proposed recommendations forchildren of the Asia-Pacific region. World J Gastroenterol 2017;23(45): 7952-7964 Available from: URL: htm DOI: http://dx.doi.org/10.3748/wjg.v23.i45.7952WJG www.wjgnet.comMETHODSWith the objective of formulating recommendations for7953December 7, 2017 Volume 23 Issue 45

Cameron D et al . Probiotics for gastrointestinal disorders in childrenon the effect of probiotics on gastrointestinal diseases,which were conducted in the Asia-Pacific region, writtenin English and published in peer review journals after2005 were also evaluated. The discussion includedepidemiological data, local practices and traditions,availability of probiotics and other drugs , standards ofcare, perception of specific disease risk and the needfor prevention, economic considerations, and otherhealth management issues (e.g., private vs publicmedicine).The final recommendations were based on these[15]steps using the GRADE systemand the strength ofeach individual recommendation was rated as weak orstrong.An overview of the steps used for designing therecommendations for acute gastroenteritis is shown inFigure 2.Once the recommendations were designed, theparticipants from the Asia-Pacific region were asked toprovide a consensus on the proposed recommendations[16]using the Likert scale . The recommendations werefurther revised based on the feedback received aftercirculating the proposed recommendations to countriesin the Asia-Pacific region until final consensus wasachieved as judged by agreement by all participantswith grade 4 or 5 in the Likert scale (correspondingto “agree” and “strongly agree”, respectively). Thefinal steps will be the validation of recommendationsthrough field trials to evaluate their applicability and[17]efficacy using previously tested methodology .Agree upon definitionsAgree upon outcomesLook for local evidenceRevise setting and populationBuild draft recommendationsAgree upon recommendationsValidate recommendations at local levelFigure 1 Steps for designing the recommendations for the use ofprobiotics in pediatric population in the Asia-Pacific region.use of probiotics in pediatric gastrointestinal disorders inthe Asia-Pacific region, a working group of internationalexperts in adult and pediatric gastroenterologyfrom Asia-Pacific countries (Australia, China, India,Indonesia, Japan, South Korea, and Singapore), as wellas from several countries outside the region (UnitedStates, Uruguay, United Kingdom, The Netherlands,and Italy) met to discuss the indication for use ofprobiotics based on local epidemiological conditions.Workshops on the gastrointestinal epidemiology of therepresented countries and the use of probiotics in bothadults and children were held. This article describesthe proposed recommendations for use of probiotics inintestinal diseases in children in the Asia-Pacific region.The main considerations in the development of theseconsensus recommendations were the epidemiologyand etiology of gastrointestinal diseases in the AsiaPacific region, and the evidence from the region andinternationally to support the use of probiotics fordifferent pediatric gastrointestinal conditions.The method used to develop the recommenda tions consisted of multiple steps (Figure 1). Initially,target diseases and their impact were defined, andthe definitions and outcomes for each disease wereagreed upon. Published data and available evidencebased recommendations and guidelines from the AsiaPacific region and from other organizations, such asthe World Gastroenterology Organization (WGO),European Society for Pediatric Gastroenterology,Hepatology and Nutrition (ESPGHAN), North AmericanSociety for Pediatric Gastroenterology, Hepatology andNutrition (NASPGHAN), Latin American Society forPediatric Gastroenterology and Nutrition (LASPGAN),were studied and discussed. Subsequently, the localepidemiological and clinical features of the mainintestinal diseases commonly seen in the Asia-Pacificregion were discussed to determine their impact on therecommendations. Randomized-controlled trials (RCTs)WJG www.wjgnet.comTHE HUMAN GUT MICROBIOMEThe human gut microbiota includes a vastly diversecommunity of microorganisms that, together with thecollection of all of the genomic elements of the specific[18]microbiota, comprises the human gut microbiome .With the development of increasingly advancedmolecular methods in recent years, such as highthroughput sequencing, our interest in and unders tanding of the human gut microbiome have significantlyincreased.It has become apparent that the microbiome isinfluenced by numerous factors, including age, geography,[9,19,20]diet, lifestyle, disease, and antibiotic exposure.Notably, while it has long been known that a courseof antibiotics impacts the gut microbiome in the shortterm, there is also evidence to suggest that exposureto antibiotics may have a long-term impact on thehuman intestinal microbiota that persists for as long as[19]2 years after treatment .While much of the function of the human gut micro biome remains to be fully elucidated, we do know thatthe microbiota plays an important role in maintaining[20]health . The role of microbiota includes the preventionof colonization by pathogens and development andactivation of the immune system, as well as an[20]important role in stability of metabolism . When thegut microbiota is functioning as expected in a healthy7954December 7, 2017 Volume 23 Issue 45

Cameron D et al . Probiotics for gastrointestinal disorders in children[26]as well as nutritional factors . Moreover, effectiveinterventions are not provided equitably across all[26]communities .Infectious diarrhea is a major concern in the AsiaPacific region. Worldwide, the most frequent causativepathogen for infectious diarrhea is rotavirus, responsiblefor approximately 40% of all hospital admissions for[5]diarrhea of infants and young children . A specificfeature of certain Asian countries is the circulation ofV. cholerae that may be multidrug-resistant and cause[27]severe diarrhea . Other major pathogens include E.coli, Shigella, Campylobacter, and Salmonella species,as well as the protozoan pathogen Cryptosporidiumthat is an important enteric pathogen in children of[5]some Asian Countries . The pathogens responsible[2]for diarrheal deaths vary between regions . In arecent study, 5304 stool samples from Africa and Asia(Bangladesh, India and Pakistan) were analyzed andresults show that approximately 80% of gastroenteritisin children are caused by six pathogens (Shigella,Rotavirus, Adenovirus 40/41, Heat-stable enterotoxinproducing E coli or ST-ETEC, Cryptosporidium and[28]Campylobacter) . Interestingly, Clostridium difficile(C. difficile) was an important pathogen in high-incomecountries, while Shigella and Aeromonas infectionsoccurred at a higher frequency in areas with poor[2]sanitation .In addition to infectious diarrhea, there are severalother diseases of importance in the Asia-Pacific region,such as AAD (including C. difficile-associated diarrhea),H. pylori infection, irritable bowel syndrome (IBS), andIBD. The incidence of the latter condition is sharplyincreasing in some locations; however, the relativeprevalence of individual diseases differs from regionto region, as well as across countries within the Asia[29-31]Pacific region. For example, H. pylori is found inhalf of the world’s population, although its prevalenceand clinical manifestations vary markedly in relationto numerous factors, including geography, age andsocioeconomic factors, with prevalence much higher in[32]developing countries .In addition to epidemiological factors, the organi zational and economic features that differ throug hout Asia-Pacific countries play a major role in the[33]implementation of treatment guidelines .Agree upon definitionsAgree upon outcomesDiarrhoea duration, cost, death?Degree of dehydrationNeed for hospitalisationDuration of hospital stayCosts? (cost efficiency ratio)Death rateIndicated strains (purity, dose, preparations)Revise setting and populationEtiology of diarrhoea: Prevalence of viral/bacterialdiarrhoea similar to that reported in guidelineRotavirus immunisation coverage in your area?Prevalence of malnutrition in your country?What is the standard treatment of acutegastroenteritis in your country?Look for local evidenceIs there any randomised controlled trial in childrenwith acute gastroenteritis in your country?If yes, do the results report efficacy?Which probiotic strain has been testedIs the tested probiotic available in the market?Is there any other intervention currently used?Are probiotics a priority for the treatment of acutegastroenteritis in your country?Figure 2 Steps for designing the recommendations for acute gastroenteritis.person, it is in balance or eubiosis. In contrast, in anumber of diseases the gut microbiota exists in a state[20]of dysbiosis .The composition of microbiota is altered in cer tain disease states, including enteric infections, He licobacter pylori (H. pylori) infection and antibiotic[20]associated diarrhea (AAD) . Furthermore, aberrationsin microbial configuration are often associated withspecific chronic diseases, producing a “microbial[21,22]signature” of the specific disease, although thecause-effect relationship between microbial changeand disease is not clear. There appears to be a linkbetween dysbiosis and disease, including inflammatorybowel diseases (IBD), celiac disease, diabetes, cancer,[22-24]obesity, and cystic fibrosis.PROBIOTICSProbiotics are live microorganisms that when admi [10]nistered in adequate amounts confer a health benefit .A substantial body of evidence suggests that the clinicaleffects of probiotics in humans include preventionand treatment of diarrhea, immunomo dulation, and[14]modulation of intestinal flora . The short-term effectsof probiotics, such as those seen in patients withacute diarrhea, are due to the direct effect of specificprobiotic strains on pathogens present in the humangut, whereas many of their long-term effects are theEPIDEMIOLOGY OF GASTROINTESTINALDISEASES IN THE ASIA-PACIFIC REGIONWhile patterns of diseases worldwide are constan tly changing, diarrhea remains a leading cause of[25]mortality among children younger than five years .The burden of this disease is not shared equally, butis disproportionately borne by children in low incomecountries, largely due to water and sanitation issues,WJG www.wjgnet.com7955December 7, 2017 Volume 23 Issue 45

Cameron D et al . Probiotics for gastrointestinal disorders in childrenresult of an interaction between selected strains andthe host immune response or the reconstitution of the[34]disrupted intestinal barrier .In general, the effects of probiotics are strain-,[14]disease- and age-specific . Administration of multi ple strains is not necessarily better or worse than asingle strain, rather use of specific probiotic strainsor preparations should rely on clinical data from atleast one well-designed trial of a well-characterized[34]probiotic preparation . Several meta-analysescombining data from studies of different probioticstrains in different patient populations produced results[35-39]that were largely inconclusive. Furthermore, thedefinitions and outcome parameters used in differentstudies are often heterogeneous, which may limitthe interpretation of data available. Thus, althoughmeta-analyses can be used to establish the effects ofprobiotics, they may underestimate the benefits ofselected strains or amplify the efficacy of less effectivestrains if not performed appropriately. In addition,there is a high level of heterogeneity among microbialpreparations, as well as a lack of quality control forcommercially-available products. On the other hand,for selected strains and pathologies, there are a highnumber of well-conducted RCTs with compelling[40,41]proof of efficacy. Finally, it is recognized that thedose of probiotics used in children may be important,particularly when evaluating their efficacy in growingchildren, although currently data are limited.Safety and regulatory issues are also importantconsiderat

NAME OF CA 90822, United StatesJOURNAL World Journal of Gastroenterology ISSN ISSN 1007-9327 (print) ISSN 2219-2840 (online) LAUNCH DATE October 1, 1995 FREQUENCY Weekly EDITORS-IN-CHIEF Damian Garcia-Olmo, MD, PhD, Doctor, Profes-sor, Surgeon, Department of Surgery, Universidad Autonoma de Madrid; Department of General Sur-