The Effects of Probiotic Supplementation on Experimental Acute Pancreatitis: A Systematic Review and Meta-Analysis Carlijn R. Hooijmans 1 *, Rob B. M. de Vries 1 , Maroeska M. Rovers 2,3 , Hein G. Gooszen 3 , Merel Ritskes- Hoitinga 1 1 Radboud University Nijmegen Medical Centre, SYRCLE at Central Animal Laboratory, Nijmegen, The Netherlands, 2 Radboud University Nijmegen Medical Centre, Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands, 3 Radboud University Nijmegen Medical Centre, Department of Operating Rooms, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands Abstract Background: In February 2008, the results of the PRObiotics in PAncreatitis TRIAl (PROPATRIA) were published. This study investigated the use of probiotics in patients suffering from severe acute pancreatitis. No differences between the groups were found for any of the primary endpoints. However, mortality in the probiotics group was significantly higher than in the placebo group. This result was unexpected in light of the results of the animal studies referred to in the trial protocol. We used the methods of systematic review and meta-analysis to take a closer look at the relation between the animal studies on probiotics and pancreatitis and the PROPATRIA-trial, focussing on indications for harmful effects and efficacy. Methods and results: Both PubMed and Embase were searched for original articles concerning the effects of probiotics in experimental acute pancreatitis, yielding thirteen studies that met the inclusion criteria. Data on mortality, bacterial translocation and histological damage to the pancreas were extracted, as well as study quality indicators. Meta-analysis of the four animal studies published before PROPATRIA showed that probiotic supplementation did not diminish mortality, reduced the overall histopathological score of the pancreas and reduced bacterial translocation to pancreas and mesenteric lymph nodes. Comparable results were found when all relevant studies published so far were taken into account. Conclusions: A more thorough analysis of all relevant animal studies carried out before (and after) the publication of the study protocol of the PROPATRIA trial could not have predicted the harmful effects of probiotics found in the PROPATRIA- trial. Moreover, meta-analysis of the preclinical animal studies did show evidence for efficacy. It may be suggested, however, that the most appropriate animal experiments in relation to the design of the human trial have not yet been conducted, which compromises a fair comparison between the results of the animal studies and the PROPATRIA trial. Citation: Hooijmans CR, de Vries RBM, Rovers MM, Gooszen HG, Ritskes-Hoitinga M (2012) The Effects of Probiotic Supplementation on Experimental Acute Pancreatitis: A Systematic Review and Meta-Analysis. PLoS ONE 7(11): e48811. doi:10.1371/journal.pone.0048811 Editor: Juan Sastre, University of Valencia, Spain Received June 14, 2012; Accepted October 5, 2012; Published November 13, 2012 Copyright: ß 2012 Hooijmans et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The ZonMW program ’Dierproeven begrensd’ in the Netherlands (ZonMW is a scientific organization for health research and development); Grant No. 114000089 and 114000103 funded this project. ZonMW had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: C.Hooijmans@cdl.umcn.nl Introduction In February 2008, Besselink et al. published the results of a randomized clinical trial (RCT) on the use of probiotics in patients suffering from severe acute pancreatitis: the PRObiotics in PAncreatitis TRIAl (PROPATRIA) [1]. A total of 296 patients were enrolled in this study, with 152 in the experimental probiotic group and 144 in the placebo group. The study product, a food supplement called Ecologic 641 (10 10 bacteria) or placebo was administered twice daily and added to the continuously running fibre-enriched tube feeding for a maximum of 28 days. No differences between the groups were found for any of the primary endpoints (infected pancreatic necrosis, bacteraemia, pneumonia, urosepsis or infected ascites). Pathogens cultured from the 87 patients with an infectious complication showed no significant differences between the groups. However, mortality in the probiotics group was significantly higher than in the placebo group (16% vs. 6%, respectively). This result was unexpected in light of the results of the animal studies referred to in the trial protocol (the English protocol [2] cites Mangiante et al. 2001 [3], the Dutch protocol [4] refers to Mangiante et al. 2001 [5] and Lutgendorff et al. 2006 [6]). Lack of correspondence between animal data and results from clinical trials is not uncommon. It has been suggested that in order to increase the potential value of animal studies as a preparation for clinical applications not only the methodological quality of the individual animal studies needs to be improved [7,8,9], but systematic reviews (SRs) should become the standard method for analysing preclinical studies in relation to one another. By means of such reviews (particularly if they include a meta-analysis), information relevant for judging the safety and efficacy of drugs/ PLOS ONE | www.plosone.org 1 November 2012 | Volume 7 | Issue 11 | e48811