Abstract
Antimicrobial resistance is a major concern to public health demanding effective alternative strategies to disease control and prevention. Modulation of endogenous host defense peptide (HDP) synthesis has emerged as a promising antibiotic alternative approach. This study investigated a potential synergy between sugars and butyrate in inducing HDP gene expression in chickens. Our results revealed that sugars differentially regulated HDP expression in both gene- and sugar-specific manners in chicken HD11 macrophage cells. Among eight mono- and disaccharides tested, all were potent inducers of avian β-defensin 9 (AvBD9) gene (p<0.05), but only galactose, trehalose, and lactose obviously upregulated cathelicidin-B1 (CATHB1) gene expression. The expression of AvBD14 gene, on the other hand, was minimally influenced by sugars. Moreover, all sugars exhibited a strong synergy with butyrate in enhancing AvBD9 expression, while only galactose, trehalose, and lactose were synergistic with butyrate in CATHB1 induction. No synergy in AvBD14 induction was observed between sugars and butyrate. Although lactose augmented the expression of nearly all HDP genes, its synergy with butyrate was only seen with several, but not all, HDP genes. Mucin-2 gene was also synergistically induced by a combination of lactose and butyrate. Furthermore, lactose synergized with butyrate to induce AvBD9 expression in chicken jejunal explants (p<0.05). Mechanistically, hyper-acetylation of histones was observed in response to both butyrate and lactose, relative to individual compounds. Mitogen-activated protein kinase, NF-κB, and cyclic adenosine monophosphate signaling pathways were also found to be involved in butyrate- and lactose-mediated synergy in AvBD9 induction. Collectively, a combination of butyrate and a sugar with both HDP-inducing and barrier protective activities holds the promise to be developed as an alternative to antibiotics for disease control and prevention.
Highlights
Routine use of antibiotics at subtherapeutic levels in feed for animal growth promotion and disease prophylaxis has been linked to the emergence of antibiotic-resistant bacteria in humans (Manyi-Loh et al, 2018; Mcewen and Collignon, 2018)
To evaluate whether lactose can activate host defense peptide (HDP) gene expression and whether the synergy exists between lactose and butyrate in chickens, we studied the expression of three representative chicken HDP genes including AvBD9, AvBD14, and CATHB1 in chicken HD11 macrophage cells in response to lactose and butyrate individually and in combination
To determine whether chicken HDP genes are induced by sugars, chicken HD11 macrophages were treated with three monosaccharides, four disaccharides, and a sugar alcohol
Summary
Routine use of antibiotics at subtherapeutic levels in feed for animal growth promotion and disease prophylaxis has been linked to the emergence of antibiotic-resistant bacteria in humans (Manyi-Loh et al, 2018; Mcewen and Collignon, 2018). Dietary modulation of endogenous HDP synthesis has the potential to be developed as a novel antibiotic-free approach to disease control with a minimum risk of triggering antimicrobial resistance (Lyu et al, 2015; Robinson et al, 2018; Bergman et al, 2020; Rodriguez-Carlos et al, 2021). Down-regulation of HDPs is employed by certain pathogens to evade host defense and establish infections, while stimulation of endogenous HDP synthesis has shown potential for antimicrobial therapy (Hancock et al, 2016; Robinson et al, 2018; Bergman et al, 2020; Rodriguez-Carlos et al, 2021). Several classes of compounds such as histone deacetylase inhibitors (HDACi), short-chain fatty acids, and vitamin D3 have been shown to promote HDP synthesis without triggering inflammation (Lyu et al, 2015; Bergman et al, 2020; RodriguezCarlos et al, 2021)
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