Omega-3 fatty acids impair miR-1-3p-dependent Notch3 down-regulation and alleviate sepsis-induced intestinal injury

Yin-Jing Xie,You-Lian Chen,Wei-Bu Chen,Wei Wang,Zhen-Mi Liu,Huai-Sheng Chen,Ru Zhang,Xue-Yan Liu,Hong-Xing Ye

doi:10.1186/s10020-021-00425-w

Yin-Jing Xie, You-Lian Chen + Show 7 more

Open Access

https://doi.org/10.1186/s10020-021-00425-w

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Abstract

BackgroundSepsis is a troublesome syndrome that can cause intestinal injury and even high mortality rates. Omega-3 fatty acids (FAs) are known to protect against intestinal damage. Accordingly, the current study set out to explore if omega-3 FAs could affect sepsis-induced intestinal injury with the involvement of the microRNA (miR)-1-3p/Notch3-Smad axis.MethodsFirst, cecal ligation and perforation (CLP) was performed to establish septic mouse models in C57BL/6J mice, and mouse intestinal epithelial MODE-K cells were induced by lipopolysaccharide (LPS) to establish sepsis cell models. The CLP-induced septic mice or LPS-exposed cells were subjected to treatment with Omega-3 FAs and activin (Smad signaling activator), miR-1-3p inhibitor and over-expressed/short hairpin RNA (oe-/sh)-Notch3 to explore their roles in inflammation, intestinal oxidative stress and cell apoptosis. A dual-luciferase reporter gene assay was further performed to verify the regulatory relationship between miR-1-3p and Notch3.ResultsOmega-3 FAs inhibited CLP-induced intestinal injury and ameliorated LPS-induced intestinal epithelial cell injury by down-regulating miR-1-3p, as evidenced by decreased levels of tumor necrosis factor-α, interleukin-1β (IL-1β) and IL-6, in addition to diminished levels of reactive oxygen species, malondialdehyde levels and superoxide dismutase activity. Furthermore, miR-1-3p could down-regulate Notch3, which inactivated the Smad pathway.ConclusionCollectively, our findings indicated that omega-3 FAs elevate the expression of Notch3 by down-regulating miR-1-3p, and then blocking the Smad pathway to alleviate intestinal epithelial inflammation and oxidative stress injury caused by sepsis.

Highlights

Sepsis is a troublesome syndrome that can cause intestinal injury and even high mortality rates
The expression patterns of pro-inflammatory factors tumor necrosis factor-α (TNF-α), IL-1β and interleukin 6 (IL-6) were determined by enzyme-linked immunosorbent assay (ELISA), which were all found to be significantly higher in cecal ligation and perforation (CLP)-induced septic mice relative to sham-operated mice (Additional file 2: Fig. S1D)
The expression patterns of pro-inflammatory factors and oxidative stress markers in the cells of each group were determined after omega-3 fatty acids (FAs) intervention, which revealed that inflammation and oxidative stress response were markedly elevated by LPS intervention, while omega-3 treatment brought about a significant reduction in inflammation and oxidative stress response (Additional file 2: Fig. S1J, K)

Summary

Introduction

Sepsis is a troublesome syndrome that can cause intestinal injury and even high mortality rates. Omega-3 fatty acids (FAs) are known to protect against intestinal damage. Sepsis is a highly-complicated disease of infection-provoked serious systemic inflammation, that can result in organ dysfunction and considerably high mortality (Venet and Monneret 2018; Lelubre and Vincent 2018). Oxidative stress triggered by commonly-occurring inflammatory responses in sepsis is known to precipitate organ damage (Galley 2011). In this context, it would be pragmatic to seek out novel pathways to control the sepsis-induced intestinal injury which is primarily associated with inflammation and oxidative stress

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