Nutritional Modulation of Host Defense Peptide Synthesis: A Novel Host-Directed Antimicrobial Therapeutic Strategy?

Abstract

The escalating threat of antimicrobial resistance underscores the imperative for innovative therapeutic strategies. Host defense peptides (HDPs), integral components of innate immunity, exhibit profound antimicrobial and immunomodulatory properties. Various dietary compounds, such as short-chain fatty acids, vitamins, minerals, sugars, amino acids, phytochemicals, bile acids, probiotics, and prebiotics have been identified to enhance the synthesis of endogenous HDPs without provoking inflammatory response or compromising barrier integrity. Additionally, different classes of these compounds synergize in augmenting HDP synthesis and disease resistance. Moreover, dietary supplementation of several HDP-inducing compounds or their combinations have demonstrated robust protection in rodents, rabbits, pigs, cattle, and chickens from experimental infections. However, the efficacy of these compounds in inducing HDP synthesis varies considerably among distinct compounds. Additionally, the regulation of HDP genes occurs in a gene-specific, cell type-specific, and species-specific manner. In this comprehensive review, we systematically summarized the modulation of HDP synthesis and the mechanism of action attributed to each major class of dietary compounds, including their synergistic combinations, across a spectrum of animal species including humans. We argue that the ability to enhance innate immunity and barrier function without triggering inflammation or microbial resistance positions the nutritional modulation of endogenous HDP synthesis as a promising host-directed approach for mitigating infectious diseases and antimicrobial resistance. These HDP-inducing compounds, particularly in combinations, harbor substantial clinical potential for further exploration in antimicrobial therapies for both human and other animals.

Keywords: antimicrobial peptides; antimicrobial resistance; host defense peptides; host-directed antimicrobial therapy; nutritional regulation.

FIGURE 1

Classification of dietary compounds with the ability to induce host defense peptides. Key examples are listed in each category.

FIGURE 2

Molecular mechanisms of HDP induction by butyrate, vitamin D-3, bile acids, and lactose. An arrowhead indicates stimulation of a pathway, while a T-bar indicates inhibition of a pathway. See text for details. AC, acetyl group; AP1, activator protein-1; BRG1, Brahma-related gene 1; CDCA, chenodeoxycholic acid; C/EBPα, CCAAT enhancer binding protein α; CRE, cAMP-response element; CREB, cAMP-response element-binding protein; FXR, farnesoid X receptor; GPR, G protein-coupled receptors; HDAC, histone deacetylase; HDP, host defense peptide; LCA, lithocholic acid; MAPK, mitogen-activated protein kinases; mTOR, mammalian target of rapamycin; p50/p65, NF-κB proteins p50 and p65 heterodimer; PU.1, an ETS-family transcription factor; RXR, retinoid X receptor; SRC, steroid receptor coactivator; STAT, signal transducer and activator of transcription; TLR, toll-like receptor; UDCA, ursodeoxycholic acid; VDR; vitamin D receptor.

FIGURE 3

Epigenetic mechanisms of HDP gene induction. See text for details. Ac, acetyl group; C/EBPα, CCAAT enhancer binding protein α; DNMTi, DNA methyltransferase inhibitor; HDACi, histone deacetylase inhibitor; HIF1α, hypoxia-inducible factor-1α; HMTi, histone methyltransferase inhibitor; IKK, Iκ B kinase; P, phosphate group; Me, methyl group; TSA, trichostatin A; p50/p65, NF-κB proteins p50 and p65 heterodimer; STAT, signal transducer and activator of transcription.

FIGURE 4

Molecular mechanisms of HDP gene expression by probiotics. See text for details. Ac, acetyl group; AP1, activator protein-1; HDP, host defense peptide; MAPK, mitogen-activated protein kinases; NF-κB, nuclear factor-kappa B; TLR, toll-like receptor, VDR, vitamin D receptor.