Abstract
Host defense peptides (HDPs) are an integral part of the innate immune system with both antimicrobial and immunomodulatory activities. Induction of endogenous HDP synthesis is being actively explored as an antibiotic-alternative approach to disease control and prevention. Butyrate, a short-chain fatty acid, and forskolin, a phytochemical, have been shown separately to induce HDP gene expression in human cells. Here, we investigated the ability of butyrate and forskolin to induce the expressions of chicken HDP genes and the genes involved in barrier function such as mucin 2 and claudin 1 both in vitro and in vivo. We further evaluated their efficacy in protecting chickens from Clostridium perfringens-induced necrotic enteritis. Additionally, we profiled the transcriptome and global phosphorylation of chicken HD11 macrophage cells in response to butyrate and forskolin using RNA sequencing and a kinome peptide array, respectively. Our results showed a strong synergy between butyrate and forskolin in inducing the expressions of several, but not all, HDP genes. Importantly, dietary supplementation of butyrate and a forskolin-containing plant extract resulted in significant alleviation of intestinal lesions and the C. perfringens colonization in a synergistic manner in a chicken model of necrotic enteritis. RNA sequencing revealed a preferential increase in HDP and barrier function genes with no induction of proinflammatory cytokines in response to butyrate and forskolin. The antiinflammatory and barrier protective properties of butyrate and forskolin were further confirmed by the kinome peptide array. Moreover, we demonstrated an involvement of inducible cAMP early repressor (ICER)-mediated negative feedback in HDP induction by butyrate and forskolin. Overall, these results highlight a potential for developing butyrate and forskolin, two natural products, as novel antibiotic alternatives to enhance intestinal health and disease resistance in poultry and other animals.
Highlights
Antimicrobial resistance is a major threat to human health [1]
The chicken genome encodes a total of 14 β-defensins known as avian β-defensin 1–14 (AvBD1–14) and four cathelicidins known as CATH1-3 and CATHB1, with their expression detected throughout the gastrointestinal (GI), respiratory, reproductive, and urogenital tracts as well as in the bone marrow and several types of immune cells [10, 11]
To study whether the synergy occurs with other host defense peptide (HDP) genes as well as two major genes involved in barrier function (MUC2 and CLDN1) [20], we first conducted both dose-response and time-course experiments in chicken HD11 macrophage cells with butyrate and FSK separately, followed by RT-qPCR analysis of gene expression
Summary
Antimicrobial resistance is a major threat to human health [1]. Host-directed therapy has emerged as a promising antibiotic-free strategy for disease control and prevention [2, 3]. Inducing HDP synthesis is a host-directed antimicrobial therapy that is being actively explored for human and livestock applications [2, 6, 7]. HDPs are classified into two major families, namely defensins and cathelicidins, in vertebrate animals [4, 5]. The chicken genome encodes a total of 14 β-defensins known as avian β-defensin 1–14 (AvBD1–14) and four cathelicidins known as CATH1-3 and CATHB1, with their expression detected throughout the gastrointestinal (GI), respiratory, reproductive, and urogenital tracts as well as in the bone marrow and several types of immune cells [10, 11]
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