Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic

Abstract

Shigella is a major cause of morbidity, mortality, and growth retardation for children in developing countries. Emergence of antibiotic resistance among Shigellae demands the development of effective medicines. Previous studies found that the endogenous antimicrobial peptide LL-37 is down-regulated in the rectal epithelium of patients during shigellosis and that butyrate upregulates the expression of LL-37 in colonic epithelial cells in vitro and decreases severity of inflammation in experimental shigellosis. In this study, Shigella-infected dysenteric rabbits were treated with butyrate (0.14 mmol͞kg of body weight) twice daily for 3 days, and the expression levels of the rabbit homologue to LL-37, CAP-18, were monitored in the colon. Butyrate treatment resulted in (i) reduced clinical illness, severity of inflammation in the colon, and bacterial load in the stool, (ii) significant up-regulation of CAP-18 in the surface epithelium, and (iii) disappearance of CAP-18-positive cells in lamina propria. The active CAP-18 peptide was released in stool from its proform by butyrate treatment. In healthy controls, CAP-18 expression was localized predominantly to the epithelial surface of the colon. In infected rabbits, CAP-18 expression was localized to immune and inflammatory cells in the colon, whereas the ulcerated epithelium was devoid of CAP-18 expression. The combination of CAP-18 and butyrate was more efficient in killing Shigella in vitro than CAP-18 alone. Our findings indicate that oral butyrate treatment in shigellosis may be of clinical value because of induction of the endogenous cathelicidin CAP-18 in the colonic epithelium, stimulation of the release of the active peptide CAP-18, and promoting elimination of Shigella.antimicrobial peptides ͉ CAP-18 ͉ cathelicidin ͉ colon ͉ Shigella

Histone deacetylase inhibition enhances antimicrobial peptide but not inflammatory cytokine expression upon bacterial challenge

“…However, except for HIV, hepatitis, and malaria infection, the therapeutic potential of HDAC inhibitors for the treatment of infectious diseases has not been largely investigated. One example is the HDAC inhibitor sodium butyrate, which can stimulate expression of the endogenous AMP cathelicidin in the colon and promote the clearance of the enteropathogen Shigella (42). Along the same line, we have demonstrated the property of the HDAC inhibitor TSA to enhance expression of the AMP β-defensin 2 without increasing the level of IL-8 in vitro and ex vivo, using human colonic primary cells.…”

Phenylbutyrate induces LL-37-dependent autophagy and intracellular killing of Mycobacterium tuberculosis in human macrophages

“…15 Our findings have further established that 4-phenylbutyrate (PBA) can induce LL-37 expression at both mRNA and protein levels in a synergistic manner with the active form of vitamin D 3 , 1,25(OH) 2 D 3 , in lung epithelial cells. 16 Accordingly, LL-37 expression is induced in human monocyte derived macrophages (MDMs) upon oral administration of PBA and vitamin D 3 to healthy individuals.…”

Bacteria in the Intestine, Helpful Residents or Enemies from Within?

“…Butyrate is a by-product of bacterial fiber fermentation that is produced by the endogenous intestinal flora, and it is a major trophic factor for colonocytes. A recent compelling study showed that oral butyrate treatment of Shigella-infected dysenteric rabbits led to improvement of clinical symptoms, decreased blood in the stool, and a reduction in the bacterial load in the stool (120). Furthermore, examination of the rectal tissue of butyratetreated rabbits demonstrated that there was upregulation of LL-37 expression.…”