A Novel Cecropin-LL37 Hybrid Peptide Protects Mice Against EHEC Infection-Mediated Changes in Gut Microbiota, Intestinal Inflammation, and Impairment of Mucosal Barrier Functions.

Xubiao Wei,Dayong Si,Junyong Wang,Lulu Zhang,Junhao Cheng,Baseer Ahmad,Maierhaba Aihemaiti,Manyi Zhang,Matthew Koci,Rijun Zhang

doi:10.3389/fimmu.2020.01361

Xubiao Wei, Dayong Si + Show 8 more

Open Access

https://doi.org/10.3389/fimmu.2020.01361

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Abstract

Intestinal inflammation can cause impaired epithelial barrier function and disrupt immune homeostasis, which increases the risks of developing many highly fatal diseases. Enterohemorrhagic Escherichia coli (EHEC) O157:H7 causes intestinal infections worldwide and is a major pathogen that induces intestinal inflammation. Various antibacterial peptides have been described as having the potential to suppress and treat pathogen-induced intestinal inflammation. Cecropin A (1–8)-LL37 (17–30) (C-L), a novel hybrid peptide designed in our laboratory that combines the active center of C with the core functional region of L, shows superior antibacterial properties and minimized cytotoxicity compared to its parental peptides. Herein, to examine whether C-L could inhibit pathogen-induced intestinal inflammation, we investigated the anti-inflammatory effects of C-L in EHEC O157:H7-infected mice. C-L treatment improved the microbiota composition and microbial community balance in mouse intestines. The hybrid peptide exhibited improved anti-inflammatory effects than did the antibiotic, enrofloxacin. Hybrid peptide treated infected mice demonstrated reduced clinical signs of inflammation, reduced weight loss, reduced expression of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interferon-gamma (IFN-γ)], reduced apoptosis, and reduced markers of jejunal epithelial barrier function. The peptide also affected the MyD88–nuclear factor κB signaling pathway, thereby modulating inflammatory responses upon EHEC stimulation. Collectively, these findings suggest that the novel hybrid peptide C-L could be developed into a new anti-inflammatory agent for use in animals or humans.

Highlights

Commensal microflora in the intestinal mucosal can promote intestinal stability and prevent pathogens from invading the intestine
We investigated whether the C-L peptide could provide effective therapy against intestinal inflammation and impairment of epithelial barrier function induced by enterohemorrhagic E. coli (EHEC) O157:H7 and explore the underlying mechanisms, using a mouse model of intestinal inflammation
We examined the effects of EHEC infection, with and without C-L and Enro treatment on the microbiota composition in mouse ceca by Illumina sequencing of the 16S rRNA V4 region

Summary

Introduction

Commensal microflora in the intestinal mucosal can promote intestinal stability and prevent pathogens from invading the intestine. The mucosal barrier plays an important role in maintaining physiological homeostasis by physically blocking the passage of harmful foreign antigens, microbes, and their toxins into the host [5, 7]. When this barrier function breaks down the intestinal contents and bacteria can diffuse past the mucosal layer, which can initiate host responses that lead to further break down of the epithelia barrier resulting in activation of the intestinal inflammatory response [5, 7]. Even with treatment EHEC O157:H7 infection can lead to hemolytic-uremic syndrome and permanent kidney damage, especially in young children [8, 9]

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