Open Access Research article

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

Rubhana Raqib15*, Protim Sarker12, Akhirunnesa Mily1, Nur Haque Alam1, Abu Saleh Mohammed Arifuzzaman1, Rokeya Sultana Rekha12, Jan Andersson3, Gudmundur H Gudmundsson4, Alejandro Cravioto1 and Birgitta Agerberth2

Author Affiliations

1 International Centre for Diarrheal Disease Research, Dhaka, Bangladesh

2 Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

3 Center for Infectious Medicine, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden

4 Institute of Biology, University of Iceland, Reykjavik, Iceland

5 Nutritional Biochemistry Laboratory, Laboratory Sciences Division, International Centre for Diarrheal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka, 1212, Bangladesh

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BMC Infectious Diseases 2012, 12:111  doi:10.1186/1471-2334-12-111

Published: 10 May 2012

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.

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