Abstract
BackgroundTreatment 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.MethodsA 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.ResultsCompared 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.ConclusionAdjunct 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 RegistrationClinicalTrials.gov, NCT00800930.
Highlights
Treatment of shigellosis in rabbits with butyrate reduces clinical severity and counteracts the downregulation of cathelicidin (CAP-18) in the large intestinal epithelia
There were no significant differences in the baseline characteristics and the clinical features between butyrate and placebo treated patients (Table 1)
Routine microscopic examination of stool samples revealed significant reduction in pus cells (p = 0.009) and macrophages (p = 0.043) by day 2 in the Intervention group compared with the Placebo group (Table 2)
Summary
Treatment of shigellosis in rabbits with butyrate reduces clinical severity and counteracts the downregulation of cathelicidin (CAP-18) in the large intestinal epithelia. We aimed to evaluate whether butyrate can be used as an adjunct to antibiotics in the treatment of shigellosis in patients. Antimicrobial peptides (AMPs) are front-line components of innate immunity in multicellular organisms [6]. These peptides constitute an antimicrobial arsenal against a wide range of pathogens at the host-microbe interfaces. Our group and others have previously shown that Shigella spp downregulates the expression of human cathelicidin LL-37 and beta defensins in colonic epithelial cells, one of several mechanisms employed by this pathogen to evade host defenses [7,8]
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