Efficacy of sodium butyrate adjunct therapy in shigellosis: a randomized, double-blind, placebo-controlled clinical trial

Rubhana Raqib*, Protim Sarker, Akhirunnesa Mily, Nur H. Alam, Abu Saleh M. Arifuzzaman, Rokeya S. Rekha, Jan Andersson, Gudmundur H. Gudmundsson, Alejandro Cravioto, Birgitta Agerberth

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

60 Citations (Scopus)

Abstract

Background: Treatment of shigellosis in rabbits with butyrate reduces clinical severity and counteracts the downregulation of cathelicidin (CAP-18) in the large intestinal epithelia. Here, we aimed to evaluate whether butyrate can be used as an adjunct to antibiotics in the treatment of shigellosis in patients.Methods: A randomized, double-blind, placebo-controlled, parallel-group designed clinical trial was conducted. Eighty adult patients with shigellosis were randomized to either the Intervention group (butyrate, n = 40) or the Placebo group (normal saline, n = 40). The Intervention group was given an enema containing sodium butyrate (80 mM), twice daily for 3 days, while the Placebo group received the same dose of normal saline. The primary endpoint of the trial was to assess the efficacy of butyrate in improving clinical, endoscopic and histological features of shigellosis. The secondary endpoint was to study the effect of butyrate on the induction of antimicrobial peptides in the rectum. Clinical outcomes were assessed and concentrations of antimicrobial peptides (LL-37, human beta defensin1 [HBD-1] and human beta defensin 3 [HBD-3]) and pro-inflammatory cytokines (interleukin-1β [IL-1β] and interleukin-8 [IL-8]) were measured in the stool. Sigmoidoscopic and histopathological analyses, and immunostaining of LL-37 in the rectal mucosa were performed in a subgroup of patients.Results: Compared with placebo, butyrate therapy led to the early reduction of macrophages, pus cells, IL-8 and IL-1β in the stool and improvement in rectal histopathology. Butyrate treatment induced LL-37 expression in the rectal epithelia. Stool concentration of LL-37 remained significantly higher in the Intervention group on days 4 and 7.Conclusion: Adjunct therapy with butyrate during shigellosis led to early reduction of inflammation and enhanced LL-37 expression in the rectal epithelia with prolonged release of LL-37 in the stool.Trial Registration: ClinicalTrials.gov, NCT00800930.

Original languageEnglish
Article number111
JournalBMC Infectious Diseases
Volume12
DOIs
Publication statusPublished - 10 May 2012

Bibliographical note

Funding Information:
The work was supported by “the Swedish Agency for Research Cooperation with Developing Countries (Sida/SAREC Agreement support; grant 384)”; “The Swedish Research Council”; “Swedish Cancer Society”; “The Swedish Strategic Foundation (SSF)”; “Thorsten and Ragnar Söderberg´s Foundations”; “The Swedish Institute”; “Karolinska Institutet”; “icddr,b”; “The Icelandic Centre for Research (RANNIS)” and “University of Iceland research fund”. Icddr,b acknowledges with gratitude the commitment of “Sida/SAREC” to the Centre's research efforts. Icddr,b also gratefully acknowledges the following donors, which provide unrestricted support to the Centre's research efforts: “Australian Agency for International Development (AusAID)”; “Government of the People’s Republic of Bangladesh”; “Canadian International Development Agency (CIDA)”; “Embassy of the Kingdom of the Netherlands (EKN)”; “Swedish International Development Cooperation Agency (Sida)”; “Swiss Agency for Development and Cooperation (SDC)” and “Department for International Development, UK (DFID)”. We acknowledge the patients who generously gave consent to participate in this clinical trial. We thank all individuals who helped us with randomization, blinding, concealing and implementation of interventions and for collection of specimens.

Other keywords

  • Antimicrobial peptides
  • Butyrate
  • Cathelicidin
  • Inflammation
  • Innate immunity
  • LL-37
  • Pro-inflammatory cytokines
  • Rectal mucosa
  • Shigellosis
  • Short chain fatty acids

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