Effects of gut microbiota and metabolites on the host defense peptide expression

Abstract

The widespread use of antibiotics has led to the emergence of multidrug-resistant bacteria, which pose significant threats to animal health and food safety. Host defense peptides (HDPs) have emerged as promising alternatives because of their unique antimicrobial properties and minimal resistance induction. However, the high costs associated with HDP production and incorporation into animal management practices hinder their widespread application. Alternatively, promoting endogenous HDP expression has gained attention as a sustainable and cost-effective approach. This study summarizes the latest research findings on the modulation of HDP expression by the gut microbiota and its metabolites. By exploring the intricate relationships among the gut microbiota, metabolites, and HDP expression, this study aims to provide a theoretical foundation for the development of targeted strategies to increase endogenous HDP production, thereby promoting animal health and resistance to infectious diseases. KEY POINTS: • Host defense peptides (HDPs) are expressed via various factors, such as nutrients, the gut microbiota, and microbial metabolites. • Recent trends include mechanisms among the gut microbiota, microbiota metabolites, and the intestine on HDP expression. • A comprehensive overview of mechanisms of HDP expression and gut microbiota-host interaction is provided.

Keywords: Antibiotic alternative; Expression regulation; Gut microbiota; Host defense peptide; Microbial metabolites.

Fig. 1

Probiotics modulate the production of HDPs in the gut. Clostridium butyricum ZJU-F1 enhances HDP expression by the TLR2–MyD88–NF-κB pathways. Lactobacillus plantarum significantly enhances HDP expression and may be mediated by the MAPK signal or AP-1 pathway. But also, there are cases where the expression of HDPs is also downregulated and the exact mechanism is not clear. Lactobacillus royceae can increase the content of butyric acid, and the butyric may enhance HDP expression by GPR41/PPAR-γ pathway. AP-1, activator protein 1; MAPK, mitogen-activated protein kinase; PPAR-γ, peroxisome proliferator–activated receptor gamma; HDPs, host defense peptides; TLR2, toll-like receptor 2; GPR41, G protein–coupled receptor 41

Fig. 2

Microbial metabolites upregulate HDP expression in the gut. Trp may enhance HDP expression by the mTOR/AKT/AMPK/CaSR/AMPK-Sirt1 pathway. Thr significantly enhances HDP expression by enhancing the expression of Sirt1. The BCAAs enhance HDP expression by the Sirt1–ERK1/2–90RSK pathways, and it can also be exerted through Zn²⁺. Arg significantly enhances HDP expression and may be mediated by the MAPK signal or NF-κB and mTOR pathways. The niacin enhances HDP expression by the NF-κB and Sirt1 pathways. SCFAs, MCFAs, and LCFAs can all contribute, and SCFAs affect the HDP expression conducted by directly influencing HDAC/GEFR–phosphorylation/p38-MAPK-JNK signal pathway. AKT, protein kinase B; CaSR, calcium-sensing receptor; BCAA, branched-chain amino acid; HDAC, histone deacetylase; HDP, host defense peptide; 5-HT, 5-hydroxytryptamine; Kyn, kynurenine; ERK, extracellular regulated protein kinase; JNK, c-Jun N-terminal kinase; LCFA, long-chain fatty acid; MAPK, mitogen-activated protein kinase; MCFA, medium-chain fatty acid; mTOR, mammalian target of rapamycin; Sirt1, sirtuin-1; 90RSK, 90-kDa ribosomal S6 kinase

Fig. 3

High-throughput screening process for target metabolites. Predicted defensin promoter sequences were used to construct plasmids, and 14 porcine endogenous immune defense peptide fluorescent reporter cell lines were constructed by transfection, which were verified to be constructed successfully by qPCR technology. Metabolite libraries were constructed using the biosignature method, and the endogenous immune defense peptide fluorescent reporter cell lines were treated with the metabolites, and their expression was shown by qPCR