Inactivation of glutathione S-transferase alpha 4 blocks Enterococcus faecalis-induced bystander effect by promoting macrophage ferroptosis.

IF 12.2 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut Microbes Pub Date : 2025-12-01 Epub Date: 2025-01-16 DOI:10.1080/19490976.2025.2451090
Yuanyuan Ju, Chunhua Ma, Lin Huang, Yumei Tao, Tianqi Li, Haibo Li, Mark M Huycke, Yonghong Yang, Xingmin Wang
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引用次数: 0

Abstract

Enterococcus faecalis-infected macrophages produce 4-hydroxynonenal (4-HNE) that mediates microbiota-induced bystander effect (MIBE) leading to colorectal cancer (CRC). Glutathione S-transferase alpha 4 (Gsta4), a specific detoxifying enzyme for 4-HNE, is overexpressed in human CRC and E. faecalis-induced murine CRC. However, the roles of Gsta4 in E. faecalis-induced colitis and CRC remain unclear. Herein, we demonstrate that Gsta4 is essential for MIBE by protecting macrophages from E. faecalis-induced ferroptosis. E. faecalis OG1RFSS was used to induce colitis in Gsta4-/- and Il10-/-/Gsta4-/- mice by orogastric gavage. Ferroptosis was assessed in Gsta4-deficient murine macrophages. We found that, unlike Il10-/- mice, Gsta4-/- and Il10-/-/Gsta4-/- mice colonized with E. faecalis failed to develop colitis or CRC. Immunofluorescent staining showed a reduction of macrophages in the lamina propria of E. faecalis-colonized Il10-/-/Gsta4-/- mice, as well as decreased Gpx4 expression, indicating the occurrence of ferroptosis. Ferroptosis was further confirmed in Gsta4-deficient murine macrophages infected with E. faecalis. Moreover, Gsta4 inactivation induced the upregulation of Hmox1 and phosphorylated c-Jun while blocked Nos2 expression, leading to the accumulation of intracellular ferrous iron, lipid peroxidation and, eventually, ferroptosis. Finally, Mapk8, as a ferroptosis driver, was remarkably elevated in E. faecalis-infected Gsta4-deficient macrophages. These results suggest that Gsta4 inactivation blocks MIBE by eliminating macrophages, thereby attenuates E. faecalis-induced colitis and CRC.

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来源期刊
Gut Microbes
Gut Microbes Medicine-Microbiology (medical)
CiteScore
18.20
自引率
3.30%
发文量
196
审稿时长
10 weeks
期刊介绍: The intestinal microbiota plays a crucial role in human physiology, influencing various aspects of health and disease such as nutrition, obesity, brain function, allergic responses, immunity, inflammatory bowel disease, irritable bowel syndrome, cancer development, cardiac disease, liver disease, and more. Gut Microbes serves as a platform for showcasing and discussing state-of-the-art research related to the microorganisms present in the intestine. The journal emphasizes mechanistic and cause-and-effect studies. Additionally, it has a counterpart, Gut Microbes Reports, which places a greater focus on emerging topics and comparative and incremental studies.
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