Treatment with Entinostat Heals Experimental Cholera by Affecting Physical and Chemical Barrier Functions of Intestinal Epithelia

Abstract

We have shown previously that oral treatment with sodium butyrate or phenylbutyrate in an experimental model of shigellosis improves clinical outcomes and induces the expression of the antimicrobial peptide CAP-18 in the large intestinal epithelia. In a subsequent study, we found that entinostat, an aroylated phenylenediamine compound, has similar therapeutic potential against shigellosis. In this study, we aimed to evaluate entinostat as a potential candidate for host-directed therapy against cholera in an experimental model. Vibrio cholerae-infected rabbits were treated with two different dose regimens of entinostat: either 0.5 mg twice daily for 2 days or 1 mg once daily for 2 days. The effects of treatment on clinical outcomes and V. cholerae shedding (CFU count in stool) were observed. Immunohistochemical analysis was carried out to assess CAP-18 expression in ileal and jejunal mucosae. The serum zonulin level was measured by an enzyme-linked immunosorbent assay (ELISA) to evaluate gut permeability. Infection of rabbits with V. cholerae downregulated CAP-18 expression in the ileal epithelium; the expression was replenished by oral treatment with entinostat at either dose regimen. The level of zonulin, a marker of gut permeability, in serum was upregulated after infection, and this upregulation was counteracted after treatment with entinostat. Entinostat treatment also led to recovery from cholera and a decline in the V. cholerae count in stool. In conclusion, the improved clinical outcome of cholera for rabbits treated with entinostat is associated with the induction of CAP-18 and the reduction of gut epithelial permeability.

HDAC inhibitors modulate innate immune responses to micro-organisms relevant to chronic mucocutaneous candidiasis

“…The HDACi class I inhibitor entinostat has been reported to reduce inflammation and bone loss in an experimental murine arthritis model []. Additionally, entinostat proved to be effective in mitigating the phenotypes of bacterial infection models with salmonella and Escherichia coli [] and demonstrated beneficial effects in a rabbit in‐vivo model of cholera infection []. Often studied at single loci, indirect enrichment of histone acetylation and concomitant transcriptional activation is the paradigmatic mechanism of action.…”

Novel aroylated phenylenediamine compounds enhance antimicrobial defense and maintain airway epithelial barrier integrity

“…It has been shown that Entinostat stimulates CAMP gene expression via activation of STAT3 and HIF-1α transcription factors in human colonic epithelial cells 29 . Moreover, oral treatment of Shigella - and Vibrio cholera- infected rabbits with Entinostat improved their survival and restored production of the rabbit cathelicidin CAP-18 in gut epithelial surfaces 30,31 . Entinostat is an HDACi undergoing clinical trials as adjunctive cancer therapy 32 .…”

High Throughput Screening for Natural Host Defense Peptide-Inducing Compounds as Novel Alternatives to Antibiotics

“…While HDPs are being directly explored as novel antimicrobials or vaccine adjuvants against drug-resistant infections (Choi et al, 2012 ; Hilchie et al, 2013 ; Mansour et al, 2014 ), modulating the synthesis of endogenous HDPs has shown promise in the treatment of shigellosis, pulmonary tuberculosis, cholera, and enteropathogenic E. coli -induced diarrhea (Raqib et al, 2012 ; Al-Mamun et al, 2013 ; Mily et al, 2015 ; Sarker et al, 2017 ). In fact, a number of small-molecule compounds such as butyrate, vitamin D 3 , bile acids, and histone deacetylase inhibitors have been shown to induce HDP synthesis in humans without provoking inflammation (Campbell et al, 2012 ; Van Der Does et al, 2012 ; Lyu et al, 2015 ; Yedery and Jerse, 2015 ).…”