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

BMC Infectious Diseases

Birgitta Agerberth⁵  Alejandro Cravioto³  Gudmundur H Gudmundsson²  Jan Andersson¹  Rokeya Sultana Rekha⁵  Abu Saleh Mohammed Arifuzzaman³  Nur Haque Alam³  Akhirunnesa Mily³  Protim Sarker⁵  Rubhana Raqib⁴ 

[1] Center for Infectious Medicine, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden;Institute of Biology, University of Iceland, Reykjavik, Iceland;International Centre for Diarrheal Disease Research, Dhaka, Bangladesh;Nutritional Biochemistry Laboratory, Laboratory Sciences Division, International Centre for Diarrheal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka, 1212, Bangladesh;Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

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

Others  :  1175380
DOI  :  10.1186/1471-2334-12-111

 received in 2011-12-15, accepted in 2012-05-02,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Raqib et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Bardhan P, Faruque AS, Naheed A, Sack DA: Decrease in shigellosis-related deaths withoutShigellaspp.-specific interventions, Asia. Emerg Infect Dis 2010, 16(11):1718-1723.
• [2]Sansonetti PJ: Microbes and microbial toxins: paradigms for microbial-mucosal interactions III. Shigellosis: from symptoms to molecular pathogenesis. Am J Physiol Gastrointest Liver Physiol 2001, 280(3):G319-G323.
• [3]Raqib R, Lindberg AA, Wretlind B, Bardhan PK, Andersson U, Andersson J: Persistence of local cytokine production in shigellosis in acute and convalescent stages. Infect Immun 1995, 63(1):289-296.
• [4]Raqib R, Moly PK, Sarker P, Qadri F, Alam NH, Mathan M, Andersson J: Persistence of mucosal mast cells and eosinophils in Shigella-infected children. Infect Immun 2003, 71(5):2684-2692.
• [5]Niyogi SK: Shigellosis. J Microbiol 2005, 43(2):133-143.
• [6]Zasloff M: Antimicrobial peptides of multicellular organisms. Nature 2002, 415(6870):389-395.
• [7]Islam D, Bandholtz L, Nilsson J, Wigzell H, Christensson B, Agerberth B, Gudmundsson G: Downregulation of bactericidal peptides in enteric infections: a novel immune escape mechanism with bacterial DNA as a potential regulator. Nat Med 2001, 7(2):180-185.
• [8]Sperandio B, Regnault B, Guo J, Zhang Z, Stanley SL, Sansonetti PJ, Pedron T: Virulent Shigella flexneri subverts the host innate immune response through manipulation of antimicrobial peptide gene expression. J Exp Med 2008, 205(5):1121-1132.
• [9]Mortensen PB, Clausen MR: Short-chain fatty acids in the human colon: relation to gastrointestinal health and disease. Scand J Gastroenterol Suppl 1996, 216:132-148.
• [10]Rabbani GH, Albert MJ, Hamidur Rahman AS, Moyenul Isalm M, Nasirul Islam KM, Alam K: Short-chain fatty acids improve clinical, pathologic, and microbiologic features of experimental shigellosis. J Infect Dis 1999, 179(2):390-397.
• [11]Raqib R, Sarker P, Bergman P, Ara G, Lindh M, Sack DA, Nasirul Islam KM, Gudmundsson GH, Andersson J, Agerberth B: Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic. Proc Natl Acad Sci U S A 2006, 103(24):9178-9183.
• [12]Rabbani GH, Ahmed S, Hossain I, Islam R, Marni F, Akhtar M, Majid N: Green banana reduces clinical severity of childhood shigellosis: a double-blind, randomized, controlled clinical trial. Pediatr Infect Dis J 2009, 28(5):420-425.
• [13]Jakobovits SL, Travis SP: Management of acute severe colitis. Br Med Bull 2005, 75–76:131-144.
• [14]Raqib R, Reinholt FP, Bardhan PK, Karnell A, Lindberg AA: Immunopathological patterns in the rectal mucosa of patients with shigellosis: expression of HLA-DR antigens and T-lymphocyte subsets. APMIS 1994, 102(5):371-380.
• [15]Cunnane G, Bjork L, Ulfgren AK, Lindblad S, FitzGerald O, Bresnihan B, Andersson U: Quantitative analysis of synovial membrane inflammation: a comparison between automated and conventional microscopic measurements. Ann Rheum Dis 1999, 58(8):493-499.
• [16]Andoh A, Bamba T, Sasaki M: Physiological and anti-inflammatory roles of dietary fiber and butyrate in intestinal functions. JPEN J Parenter Enteral Nutr 1999, 23(5 Suppl):S70-S73.
• [17]Butzner JD, Parmar R, Bell CJ, Dalal V: Butyrate enema therapy stimulates mucosal repair in experimental colitis in the rat. Gut 1996, 38(4):568-573.
• [18]Song M, Xia B, Li J: Effects of topical treatment of sodium butyrate and 5-aminosalicylic acid on expression of trefoil factor 3, interleukin 1β, and nuclear factor κB in trinitrobenzene sulphonic acid induced colitis in rats. Postgrad Med J 2006, 82(964):130-135.
• [19]Canani RB, Costanzo MD, Leone L, Pedata M, Meli R, Calignano A: Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World J Gastroenterol 2011, 17(12):1519-1528.
• [20]Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer RJ: Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther 2008, 27(2):104-119.
• [21]Raqib R, Wretlind B, Andersson J, Lindberg AA: Cytokine secretion in acute shigellosis is correlated to disease activity and directed more to stool than to plasma. J Infect Dis 1995, 171(2):376-384.
• [22]Andoh A, Fujiyama Y, Hata K, Araki Y, Takaya H, Shimada M, Bamba T: Counter-regulatory effect of sodium butyrate on tumour necrosis factor-alpha (TNF-α)-induced complement C3 and factor B biosynthesis in human intestinal epithelial cells. Clin Exp Immunol 1999, 118(1):23-29.
• [23]Inan MS, Rasoulpour RJ, Yin L, Hubbard AK, Rosenberg DW, Giardina C: The luminal short-chain fatty acid butyrate modulates NF-κB activity in a human colonic epithelial cell line. Gastroenterology 2000, 118(4):724-734.
• [24]Place RF, Noonan EJ, Giardina C: HDAC inhibition prevents NF-κB activation by suppressing proteasome activity: down-regulation of proteasome subunit expression stabilizes IκBα. Biochem Pharmacol 2005, 70(3):394-406.
• [25]Luhrs H, Gerke T, Muller JG, Melcher R, Schauber J, Boxberge F, Scheppach W, Menzel T: Butyrate inhibits NF-κB activation in lamina propria macrophages of patients with ulcerative colitis. Scand J Gastroenterol 2002, 37(4):458-466.
• [26]Segain JP, Raingeard de la Bletiere D, Bourreille A, Leray V, Gervois N, Rosales C, Ferrier L, Bonnet C, Blottiere HM, Galmiche JP: Butyrate inhibits inflammatory responses through NFκB inhibition: implications for Crohn's disease. Gut 2000, 47(3):397-403.
• [27]Kinoshita M, Suzuki Y, Saito Y: Butyrate reduces colonic paracellular permeability by enhancing PPARγ activation. Biochem Biophys Res Commun 2002, 293(2):827-831.
• [28]Schwab M, Reynders V, Loitsch S, Steinhilber D, Stein J, Schroder O: Involvement of different nuclear hormone receptors in butyrate-mediated inhibition of inducible NFκB signalling. Mol Immunol 2007, 44(15):3625-3632.
• [29]Klampfer L, Huang J, Sasazuki T, Shirasawa S, Augenlicht L: Inhibition of interferon γ signaling by the short chain fatty acid butyrate. Mol Cancer Res 2003, 1(11):855-862.
• [30]Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS, Mackay F, Artis D, et al.: Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 2009, 461(7268):1282-1286.
• [31]Sarker P, Ahmed S, Tiash S, Rekha RS, Stromberg R, Andersson J, Bergman P, Gudmundsson GH, Agerberth B, Raqib R: Phenylbutyrate counteracts Shigella mediated downregulation of cathelicidin in rabbit lung and intestinal epithelia: a potential therapeutic strategy. PLoS One 2011, 6(6):e20637.
• [32]Vernia P, Monteleone G, Grandinetti G, Villotti G, Di Giulio E, Frieri G, Marcheggiano A, Pallone F, Caprilli R, Torsoli A: Combined oral sodium butyrate and mesalazine treatment compared to oral mesalazine alone in ulcerative colitis: randomized, double-blind, placebo-controlled pilot study. Dig Dis Sci 2000, 45(5):976-981.
• [33]Veiga P, Gallini CA, Beal C, Michaud M, Delaney ML, DuBois A, Khlebnikov A, van Hylckama Vlieg JE, Punit S, Glickman JN, et al.: Bifidobacterium animalis subsp. lactis fermented milk product reduces inflammation by altering a niche for colitogenic microbes. Proc Natl Acad Sci U S A 2010, 107(42):18132-18137.