Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A reassessment of the PROPATRIA study and its implications for probiotic therapy

Abstract

The PROPATRIA (Probiotics in Pancreatitis Trial) study was a multicenter, double-blind, placebo-controlled clinical trial that aimed to reduce infectious complications in patients with predicted severe acute pancreatitis by the enteral use of a multispecies probiotic preparation. An unprecedented 24 of 152 patients (16%) in the group receiving probiotics died versus 9 of 144 (6%) in the placebo group. This high mortality rate in the probiotic-treated group contrasts strongly with observations from a previous smaller study and from our observations regarding the effects of abundant intestinal lactobacilli in patients with short small bowel (SSB) syndrome. We argue here that a lethal combination of mainly proteolytic pancreas enzymes and probiotic therapy resulted in the high mortality rate of the PROPATRIA trial and that elevated levels of lactic acid produced by bacterial fermentation of carbohydrates were a key contributing factor. We suggest that probiotic therapy may not be counter-indicated for the prevention of secondary infections associated with acute pancreatitis, provided that future clinical studies (i) start probiotic therapy immediately after first onset of disease symptoms, (ii) limit the supply of fermentable carbohydrates, (iii) prevent bacterial (over)growth of patient's own intestinal flora and (iv) massively increase the dose of probiotic bacteria.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: The microbial fermentation process in the small bowel.

References

  1. Working Party of the British Society of Gastroenterology; Association of Surgeons of Great Britain and Ireland; Pancreatic Society of Great Britain and Ireland; Association of Upper GI Surgeons of Great Britain and Ireland. UK guidelines for the management of acute pancreatitis. Gut 54 (suppl. 3), iii 1–9 (2005).

  2. Besselink, M.G.H. et al. Probiotic prophylaxis in patients with predicted severe acute pancreatitis (PROPATRIA): design and rationale of a double-blind, placebo-controlled randomised multicenter trial [ISRCTN38327949]. BMC Surg. 4, 12 (2004).

    Article  Google Scholar 

  3. Besselink, M.G.H. et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 371, 651–659 (2008).

    Article  Google Scholar 

  4. Deitch, E.A. The role of intestinal barrier failure and bacterial translocation in the development of systemic infection and multiple organ failure. Arch. Surg. 125, 403–404 (1990).

    CAS  Article  Google Scholar 

  5. Ammori, B.J. et al. Early increase in intestinal permeability in patients with severe acute pancreatitis: correlation with endotoxemia, organ failure, and mortality. J. Gastrointest. Surg. 3, 252–262 (1999).

    CAS  Article  Google Scholar 

  6. Food and Agriculture Organization of the United Nations/World Health Organization. Health and nutritional properties of probiotics in food including powder milk with live lactic acid bacteria. Joint FAO/WHO Expert Consultation, Cordoba, Argentina, 1–4 October 2001. ftp://ftp.fao.org/es/esn/food/probio_report_en.pdf.

  7. Sneath, P.H.A. (ed.) Bergey's Manual of Systematic Bacteriology. Vol. 2; 1065–1066, 1209–1234, 1418–1434 (Williams & Wilkins, 1986).

    Google Scholar 

  8. Bongaerts, G.P.A. & Severijnen, R.S.V.M. Probiotics: are they incredible panaceas? On the science behind beneficial nonpathogenic microbial agents. Int. J. Probiotics Prebiotics 1, 87–96 (2007).

    Google Scholar 

  9. Oláh, A., Belágyi, T., Issekutz, A., Gamal, M.E. & Bengmark, S. Randomized clinical trial of specific lactobacillus and fibre supplement to early enteral nutrition in patients with acute pancreatitis. Br. J. Surg. 89, 1103–1107 (2002).

    Article  Google Scholar 

  10. Bongaerts, G. et al. D-lactic acidemia and aciduria in pediatric and adult patients with short bowel syndrome. Clin. Chem. 41, 107–110 (1995).

    CAS  Article  Google Scholar 

  11. Bongaerts, G.P.A. et al. Role of bacteria in the pathogenesis of short bowel syndrome-associated D-lactic acidemia. Microb. Pathog. 22, 285–293 (1997).

    CAS  Article  Google Scholar 

  12. Bongaerts, G. et al. Lactobacilli and acidosis in children with short small bowel. J. Pediatr. Gastroenterol. Nutr. 30, 288–293 (2000).

    CAS  Article  Google Scholar 

  13. Martin, F.-P.J. et al. Probiotic modulation of symbiotic gut microbial-host metabolic interactions in a humanized microbiome mouse model. Mol. Syst. Biol. 4, 157 (2008).

    Article  Google Scholar 

  14. Severijnen, R., Naber, T., Tolboom, J. & Bongaerts, G. The role of heterolactic lactobacilli in diarrhoea of short small bowel patients. Microb. Ecol. Health Dis. 17, 88–93 (2005).

    Article  Google Scholar 

  15. Karton, M., Rettmer, R.L. & Lipkin, E.W. Effect of parenteral nutrition and enteral feeding on D-lactic acidosis in a patient with short bowel. J. Parenter. Enteral. Nutr. 11, 586–589 (1987).

    CAS  Article  Google Scholar 

  16. Higuchi, S. et al. Aldehyde dehydrogenase genotypes in Japanese alcoholics. Lancet 343, 741–742 (1994).

    CAS  Article  Google Scholar 

  17. Inspectie voor de Gezondheidszorg, Centrale Commissie Mensgebonden Onderzoek, en Voedsel en Waren Autoriteit. Den Haag/Utrecht. http://www.igz.nl/actueel/nieuws/belangrijketekortkomingenpropatriastudieverbeteringenvoorverantwoordklinischonderzoeknoodzakelijk.aspx (2009).

  18. Gou, S., Yang, Z., Liu, T., Wu, H. & Wang, C. Use of probiotics in the treatment of severe acute pancreatitis: a systematic review and meta-analysis of randomized controlled trials. Crit. Care 18, R57 (2014).

    Article  Google Scholar 

  19. Hooijmans, C.R., De Vries, R.B.M., Rovers, M.M., Gooszen, H.G. & Ritskes-Hoitinga, M. The effects of probiotic supplementation on experimental acute pancreatitis: a systematic review and meta-analysis. PLoS One 7, e48811 (2012).

    CAS  Article  Google Scholar 

  20. van Baal, M.C. et al. Association between probiotics and enteral nutrition in an experimental acute pancreatitis model in rats. Pancreatology 14, 470–477 (2014).

    Article  Google Scholar 

  21. Tangerman, A., Bongaerts, G., Agbeko, R., Semmekrot, B. & Severijnen, R. The origin of hydrogen sulfide in a newborn with sulfhaemoglobin induced cyanosis. J. Clin. Pathol. 55, 631–633 (2002).

    CAS  Article  Google Scholar 

  22. Van Baal, M.C.P.M. Acute pancreatitis; persisting issues from the PROPATRIA and PANTER studies. PhD thesis, Radboud Univ. Medical Centre (2014).

  23. Bongaerts, G.P.A. & Severijnen, R.S.V.M. Preventive and curative effects of probiotics in atopic patients. Med. Hypotheses 64, 1089–1092 (2005).

    CAS  Article  Google Scholar 

  24. Putaala, H. et al. Effect of four probiotic strains and Escherichia coli O157:H7 on tight junction integrity and cyclo-oxygenase expression. Res. Microbiol. 159, 692–698 (2008).

    CAS  Article  Google Scholar 

  25. Bongaerts, G.P.A., Severijnen, R.S.V.M. & Wagener, D.J. Int. J. Probiotics Prebiotics 1, 83–86 (2007).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ger P A Bongaerts.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bongaerts, G., Severijnen, R. A reassessment of the PROPATRIA study and its implications for probiotic therapy. Nat Biotechnol 34, 55–63 (2016). https://doi.org/10.1038/nbt.3436

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nbt.3436

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing