Cathelicidin-WA Protects Against LPS-Induced Gut Damage Through Enhancing Survival and Function of Intestinal Stem Cells.

Sisi Wang,Teresa G Valencak,Luoyi Zhu,Yizhen Wang,Bocheng Xu,Lixia Kai,Nana Chen,Tizhong Shan

doi:10.3389/fcell.2021.685363

Sisi Wang, Teresa G Valencak + Show 6 more

Open Access

https://doi.org/10.3389/fcell.2021.685363

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Abstract

Preservation of intestinal stem cells (ISCs) plays a critical role in initiating epithelial regeneration after intestinal injury. Cathelicidin peptides have been shown to participate in regulating intestinal damage repair. However, it is not known how exactly Cathelicidin-WA (CWA) exert its function after tissue damage. Using a gut injury model in mice involving Lipopolysaccharide (LPS), we observed that CWA administration significantly improved intestinal barrier function, preserved ISCs survival, and augmented ISCs viability within the small intestine (SI) under LPS treatment. In addition, CWA administration effectively prevented proliferation stops and promoted the growth of isolated crypts. Mechanistically, our results show that the appearance of γH2AX was accompanied by weakened expression of SETDB1, a gene that has been reported to safeguard genome stability. Notably, we found that CWA significantly rescued the decreased expression of SETDB1 and reduced DNA damage after LPS treatment. Taken together, CWA could protect against LPS-induced gut damage through enhancing ISCs survival and function. Our results suggest that CWA may become an effective therapeutic regulator to treat intestinal diseases and infections.

Highlights

The intestinal barrier plays an essential role in human and animal health
We found that about seventy percent of mice treated with LPS died whereas only ten percent of LPS-treated mice followed by CWA administration died (Figure 2A)
The expression of tight junction protein ZO-1 (Figures 2D,F) and adherens junction protein E-cad (Figures 2E,F) was markedly enhanced by CWA administration. These results demonstrate that CWA administration notably mitigated LPSinduced gut injury, promoted epithelial differentiation, and increased animal survival

Summary

Introduction

The intestinal barrier plays an essential role in human and animal health. A functional intestinal barrier mediates nutrient absorption and controls toxins and bacteria crossing the intestinal epithelium to maintain the body’s internal milieu. Several gastrointestinal tract diseases such as pathogen infection and inflammatory bowel disease (IBD) always come along with intestinal barrier dysfunction and altered intestinal permeability (Yi et al, 2017; Schoultz and Keita, 2020). Compromised barrier function leads to a systematic influx of microbial products and enhanced enteric infection (Thaiss et al, 2018). For knowing how to regulate the intestinal barrier and function at different conditions, including intestinal diseases and bacterial infection, more and functional studies are required.

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