Subchronic Microcystin-LR Aggravates Colorectal Inflammatory Response and Barrier Disruption via Raf/ERK Signaling Pathway in Obese Mice

Yue Yang; Shuilin Zheng; Hanyu Chu; Can Du; Mengshi Chen; Mohammed Y Emran; Jihua Chen; Fei Yang; Li Tian

doi:10.3390/toxins15040262

Subchronic Microcystin-LR Aggravates Colorectal Inflammatory Response and Barrier Disruption via Raf/ERK Signaling Pathway in Obese Mice

Toxins (Basel). 2023 Apr 1;15(4):262. doi: 10.3390/toxins15040262.

Authors

Yue Yang¹, Shuilin Zheng^{1

2

3}, Hanyu Chu², Can Du¹, Mengshi Chen¹, Mohammed Y Emran⁴, Jihua Chen¹, Fei Yang^{1

2}, Li Tian⁵

Affiliations

¹ Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410078, China.
² Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, The Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province, Department of Education, Hengyang Medical School, University of South China, Hengyang 421001, China.
³ Changsha Center for Disease Control and Prevention, Changsha 410004, China.
⁴ National Institute for Materials Science (NIMS), 1-2-1 Sengen, Tsukuba 305-0047, Japan.
⁵ Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha 410013, China.

Abstract

Microcystin-LR (MC-LR) is an extremely poisonous cyanotoxin that poses a threat to ecosystems and human health. MC-LR has been reported as an enterotoxin. The objective of this study was to determine the effect and the mechanism of subchronic MC-LR toxicity on preexisting diet-induced colorectal damage. C57BL/6J mice were given either a regular diet or a high-fat diet (HFD) for 8 weeks. After 8 weeks of feeding, animals were supplied with vehicle or 120 μg/L MC-LR via drinking water for another 8 weeks, and their colorectal were stained with H&E to detect microstructural alterations. Compared with the CT group, the HFD and MC-LR + HFD-treatment group induced a significant weight gain in the mice. Histopathological findings showed that the HFD- and MC-LR + HFD-treatment groups caused epithelial barrier disruption and infiltration of inflammatory cells. The HFD- and MC-LR + HFD-treatment groups raised the levels of inflammation mediator factors and decreased the expression of tight junction-related factors compared to the CT group. The expression levels of p-Raf/Raf and p-ERK/ERK in the HFD- and MC-LR + HFD-treatment groups were significantly increased compared with the CT group. Additionally, treated with MC-LR + HFD, the colorectal injury was further aggravated compared with the HFD-treatment group. These findings suggest that by stimulating the Raf/ERK signaling pathway, MC-LR may cause colorectal inflammation and barrier disruption. This study suggests that MC-LR treatment may exacerbate the colorectal toxicity caused by an HFD. These findings offer unique insights into the consequences and harmful mechanisms of MC-LR and provide strategies for preventing and treating intestinal disorders.

Keywords: colorectal injury; high-fat diet; inflammation responses; microcystin-LR; subchronic toxicity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Colorectal Neoplasms*
Ecosystem*
Humans
Inflammation / chemically induced
Mice
Mice, Inbred C57BL
Mice, Obese
Microcystins / toxicity
Signal Transduction

Substances

cyanoginosin LR
Microcystins

Grants and funding

The work was supported by the Key Research and Development Projects in Hunan Province (2022SK2089); the Huxiang Youth Talent Program (2021RC3107); the graduate student independent exploration and innovation project of Central South University (2022ZZTS0246); the Hunan Provincial Innovation Foundation for Postgraduate (CX20220328); and the Hunan Provincial Key Laboratory of Clinical Epidemiology (2021ZNDXLCL005).