Consensus and contentious statements on the use of probiotics in clinical practice: a South East Asian Gastro-neuro Motility Association Working Team Report Kok-Ann Gwee1, Warren Wei-Rhen Lee2, Khoon Lin Ling3, Choon Jin Ooi3, Seng Hock Quak4 , Yock Young Dan2,5, Kewin Tien-Ho Siah5, James Guoxian Huang 4 , Andrew Seng Boon Chua6 , Ida Normiha Hilmi7, RA Raja Affendi8, Christina Ong9, Marcellus Simadibrata10 , Murdani Abdullah10, Jose D Sollano11, Somchai Leelakusolvong12, Sutep Gonlachanvit13, Yeong Yeh Lee14, Jane D RicaforteCampos15, Yee Kian Yin16 , Kuck-Meng Chong17, Chong Yuen Wong 18 1. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, and Gleneagles Hospital, Singapore 2. Camden Medical Centre &, Endocrinology Service, Dept of Paediatric Medicine, KK Hospital, Singapore 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Department of Gastroenterology and Hepatology, Singapore General Hospital, and Duke-NUS Medical School Khoo Teck Puat-National University Children's Medical Institute, National University Health System, and Department of Paediatrics Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Division of Gastroenterology and Hepatology, National University Health System, Singapore. Ipoh Gastro Centre, Ipoh, Malaysia Division of Gastroenterology and Hepatology, Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia Unit of Gastroenterology and Hepatology, Department of Medicine, Pusat Perubatan Universiti Kebangsaan Malaysia, Bandar Tun Razak, Malaysia Nutrition & Dietetics, KK Women's and Children's Hospital, Singapore Division of Gastroenterology, Dept. of Internal Medicine, Faculty of Medicine Universitas Indonesia -Cipto Mangunkusumo Hospital, Jakarta, Indonesia Section of Gastroenterology, University of Santo Tomas Hospital, Manila, Philippines Department of Internal Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand GI Motility Research Unit, Division of Gastroenterology, Department of Medicine Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu Kelantan, Malaysia
14. 15. Medical Center Manila, Ermita, Manila, Philippines
16. Klinik Pakar Y&C, Menglembu, Perak, Malaysia 17. Klnic Chong, Slim River, Perak, Malaysia 18. Hospital Fatimah, Ipoh, Malaysia Correspondence to: Kok-Ann Gwee, Gleneagles Hospital, Annexe Block 05-37, 6A Napier Road, Singapore 258500, Singapore. Tel: +6564746848. Email:
[email protected] /
[email protected] Financial support: An unrestricted education grant was provided by LF Asia Singapore to support the logistics for the working team meetings. Disclosures: Kok-Ann Gwee, Abbott Laboratories (speaking honorarium, education grant), Eisai (education grant), Janssen Pharmaceuticals (education grant), Menarini Asia-Pacific (advisory board, speakers’ bureau, consultancy), Biocodex (advisory board), Pfizer (advisory board), LF Asia (education grant) and Teva Pharmaceutical (speaking honorarium). Contribution: KAG, WWRL, CJO, KLL, YYD, SHQ planned the meeting, prepared the clinical questions, and reviewed the literature for their respective sections. KAG and WWRL wrote the manuscript. All other faculty members contributed by reviewing and discussing the statements and supporting evidence, voting, reading and approving the manuscript. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/jgh.14268 This article is protected by copyright. All rights reserved.
Consensus and contentious statements on the use of probiotics in clinical practice: a South East Asian Gastro-neuro Motility Association Working Team Report
Abstract: The concept of consuming microorganisms in the treatment of a medical condition and in health maintenance has gained much traction, giving rise to an abundance of medical claims, and of health supplements. We identified relevant clinical questions on the therapeutic use of probiotics and reviewed the literature in irritable bowel syndrome, inflammatory bowel disease, impaired intestinal immunity, liver disease, intestinal infections and common childhood digestive disorders. Statements were developed to address these clinical questions. A panel of experienced clinicians was tasked to critically evaluate and debate the available data. Both consensus and contentious statements are presented to provide to clinicians a perspective on the potential of probiotics, and importantly their limitations.
Keywords: Probiotics, Gastrointestinal, Liver, Obesity, Childhood, Asia Background There is emerging evidence that intervention through manipulation of the individual’s microbiome can lead to medically relevant and meaningful benefit. At the most extreme end of the spectrum, and yet, with one of the strongest evidence of therapeutic efficacy, is the use of fecal microbiota transplant in the treatment of Clostridium difficile infection.1 At the broadest level, the term ‘probiotics’ is used to describe products containing microorganisms purported to have therapeutic benefits for the consumer. Probiotics are a heterogeneous class of products with a wide variability of microbial species and quantity. Probiotics have been proposed for a wide spectrum of conditions in health and disease states. While many of these products are available as health supplements, physicians are frequently asked by patients to make a recommendation. In Canada (http://www.probioticchart.ca/) and in the USA (http://usprobioticguide.com/), there are app tools to guide physicians on the level of evidence supporting the role of probiotics for different health indications. In the absence of a regional food and medicine administration in the Asia-Pacific region, and taking account of differences in product availability, and differences in health and disease priorities in our region, the South East Asian Gastro-neuro Motility Association (SEAGMA) convened a panel of interested clinician scientists and clinicians of various specialties (gastroenterology 15, paediatrics 4, family medicine 3), practicing in academic-tertiary centres (n=12) and private medical centres (n=10), from 5 countries (Singapore, Malaysia, Thailand, Indonesia, Philippines), to develop a set of statements to guide healthcare professionals in evaluating efficacy and safety of probiotic therapy.
Methods We decided at the start to limit our scope to the role of probiotics in digestive health and gastrointestinal disorders comprising irritable bowel syndrome, inflammatory bowel disease, impaired intestinal immunity, liver disease, intestinal infections and common childhood digestive disorders. We adopted the Delphic method beginning with a resource panel of 6 experts (KAG, WWRL, KLL, CJO, SHQ, YYD) (refer to Supplement for full qualifications) in these areas to develop structured questions that reflect clinically relevant issues pertaining to the use of probiotics. (Table 1)
This article is protected by copyright. All rights reserved.
The resource panel then reviewed the questions, rated and rank-ordered in terms of priorities, and after an extensive review of the literature, with justification based on relevance and available evidence, formulated 20 statements addressing these questions.2 These statements, levels of evidence, supporting papers and explanatory notes were then circulated to a wider audience of clinicians in our region. A preliminary voting by email was obtained. A face-toface meeting was held on 3 March 2017 as part of the South-East Asia Gastro-Neuro Motility Association Scientific Meeting in Ipoh, Malaysia. During this meeting, all statements were presented, reviewed, and debated before a final vote was taken. Voting Scheme Participants in both the email consultation process and the face-to-face meeting were asked to vote using the schema of the Canadian Task Force on the Periodic Health Examination.3 (see Table 2) Statements were deemed accepted if at least 80% of the respondents voted either complete acceptance or acceptance with some reservations.
Results The statements receiving consensus support from the group are listed in Table 3, while the statements that did not obtain consensus support are listed in Table 4. Details of the voting and discussions are listed by statements below.
Statement 1: Probiotics are not all the same. Evidence Level 1 Recommendation Grade A Voting a Accept completely b Accept with some reservation c Accept with major reservation d Reject with reservation e Reject completely
100 % 0% 0% 0% 0%
Comments This was the only statement which found unanimous agreement in the first and final votes, indicating that the evidence and recommendation on this were strong. While many different species of microbes may have probiotic property, different outcomes have been observed with different probiotics in different clinical situations. For example in the field of irritable bowel syndrome (IBS), a randomised controlled trial (RCT) found symptom improvement when treated with Bifidobacterium infantis, but not with Lactobacillus salivarius,4 while another RCT with L casei Shirota also failed to show significant improvement in IBS,5 and an RCT with E coli Nissle 1917 essentially failed to show significant advantage over placebo.6 Differences may also exist between adult and paediatric patient populations. In clinical trials of L rhamnosus GG, efficacy was found for childhood IBS7, but not for adult IBS as a single species probiotic treatment,8,9 although multi-species probiotics containing LGG had demonstrated efficacy in adult IBS subjects.10-13 Similarly, in the prevention of antibioticassociated diarrhea, meta-analysis demonstrated efficacy for L rhamnosus GG in children but not in
This article is protected by copyright. All rights reserved.
adults.14 In Clostridium difficile-associated diarrhea, meta-analysis demonstrated significant prevention of recurrence with S boulardii, but not with L rhamnosus GG and L plantarum 299v.15
Statement 2: Appropriate dosing, as guided by clinical evidence is important to achieve intended clinical effect of a probiotic treatment. Evidence Level I Recommendation Grade A Voting a Accept completely b Accept with some reservation c Accept with major reservation d Reject with reservation e Reject completely
88.9 % 11.1 % 0% 0% 0%
Comments The dose used does matter, but more is not always better. An RCT of 3 doses of B infantis in IBS, found improvement in global symptom relief only with the medium dose, but not with the highest and smallest doses.16 Another with multi-species I.31 for the treatment of IBS found significant improvement over placebo, with a trend for greater improvement in the low dose over the high dose.17 In the treatment of mild-moderate ulcerative colitis to achieve remission, an RCT using VSL#3 at a dose of 3.6x1012CFU/day x 8 weeks just failed to show superiority over placebo (remission rates 47.7% vs. 32.4%; p = 0.069),18 while another study using VSL#3 at a higher dose of 7.2x1012CFU/day x 12 weeks, was able to achieve superiority (remission rates 42.9% v 15.7%; p
