Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 7, 2021; 27(37): 6248-6261
Published online Oct 7, 2021. doi: 10.3748/wjg.v27.i37.6248
Increased systemic RNA oxidative damage and diagnostic value of RNA oxidative metabolites during Shigella flexneri-induced intestinal infection
Jing-Jing Nie, Ya-Ya Pian, Ji-Hong Hu, Guo-Qing Fan, Lv-Tao Zeng, Qiu-Geng Ouyang, Zhen-Xiang Gao, Zhen Liu, Chen-Chen Wang, Qian Liu, Jian-Ping Cai
Jing-Jing Nie, Ya-Ya Pian, Ji-Hong Hu, Zhen-Xiang Gao, Department of Microbiology, National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
Guo-Qing Fan, Lv-Tao Zeng, Zhen Liu, Qian Liu, Jian-Ping Cai, The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
Qiu-Geng Ouyang, Chen-Chen Wang, Department of Pharmacy, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
Author contributions: Cai JP provided the research concept; Cai JP, Hu JH, and Nie JJ designed the study; Nie JJ and Pian YY performed the majority of the experiments; Fan GQ, Zeng LT, Ouyang QG, Wang CC, Liu Q, Liu Z, and Gao ZX helped to perform part of the experiments; Nie JJ performed the statistical analysis; Nie JJ and Cai JP wrote the manuscript; all authors approved the final version of the article; Nie JJ and Pian YY contributed equally to this work.
Supported by the National Key R&D Program of China, No. 2018YFC2000300; and CAMS Innovation Fund for Medical Sciences, No. 2018-I2M-1-002.
Institutional animal care and use committee statement: This study was approved by the Ethical Committee of the Institute of Medical Biotechnology, Chinese Academy of Medical Sciences (approval number: IMB-201803140206).
Conflict-of-interest statement: The authors declare no conflicts of interest in association with the present study.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jian-Ping Cai, PhD, Professor, The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 Dahua Road, Dongcheng District, Beijing 100730, China. caijp61@vip.sina.com
Received: March 2, 2021
Peer-review started: March 2, 2021
First decision: April 17, 2021
Revised: April 29, 2021
Accepted: August 9, 2021
Article in press: August 9, 2021
Published online: October 7, 2021
Processing time: 211 Days and 1 Hours
ARTICLE HIGHLIGHTS
Research background

Shigella infection is a major public health concern around the world. Shigella flexneri (S. flexneri) is a major pathogen causing acute intestinal infection and is more frequently fatal than other Shigella species. The white blood cell (WBC) count and levels of C-reactive protein (CRP) and cytokines have always been used to evaluate the severity of Shigella-induced infection. Because RNA oxidation plays a substantial role in the progression of multiple diseases, the RNA oxidative product 8-oxo-7,8-dihydroguanosine (8-oxo-Gsn) may be useful as a biomarker for predicting infectious disease progression and severity.

Research motivation

There is no information regarding the diagnostic value of urinary 8-oxo-Gsn and 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxo-dGsn) in intestinal infection induced by S. flexneri. In addition, the correlation of blood inflammatory-related cytokines with RNA oxidative metabolites is unclear. Furthermore, the systematic tissue oxidative damage during Shigella-induced intestinal infection has not been investigated.

Research objectives

To determine the systemic RNA oxidative damage incurred in S. flexneri-induced intestinal infection and to evaluate the diagnostic value of the RNA oxidative metabolites 8-oxo-Gsn in urine.

Research methods

Sprague-Dawley rats were used to establish an acute intestinal infection model by oral gavage of S. flexneri strains. The CRP level was measured by ELISA, and cytokines were detected using the MILLIPLEX MAP Kit according to the manufacturer's protocol. Hematoxylin and eosin staining was performed to detect tissue inflammation. Liquid chromatography with tandem mass spectrometry was used to determine the 8-oxo-dGsn and 8-oxo-Gsn levels in urine. Immunohistochemical staining was performed to detect the expression of 8-oxo-Gsn and 8-oxo-dGsn in the ileum, colon, liver, spleen, and brain.

Research results

Intestinal infection induced by S. flexneri caused an increase in inflammation-related markers in the blood [WBCs, CRP, tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-10, IL-1β, IL-4, and IL-17a] and RNA oxidative damage-related markers in the urine (8-oxo-Gsn). The urinary 8-oxo-Gsn level increased after infection and returned to the baseline level after recovery from infection. A correlation analysis showed that urinary 8-oxo-Gsn was positively correlated with the WBC count and the cytokines IL-6, TNF-α, IL-10, IL-1β, and IL-17α. The evaluation of oxidation in different tissues showed that intestinal infection caused by S. flexneri induced an increase in RNA oxidative damage in various tissues, including the intestine, liver, spleen, and brain.

Research conclusions

This study demonstrated that acute intestinal infection induced by S. flexneri not only causes RNA oxidative damage in the intestine but also other tissues as well (liver, spleen, and brain). Furthermore, the urinary metabolite of RNA oxidation 8-oxo-Gsn was shown to be useful as a diagnostic index to evaluate the infection status.

Research perspectives

Urinary 8-oxo-Gsn can be used as a noninvasive diagnostic biomarker to evaluate the severity and prognosis of infection in clinical practice.