NLRP3 activation maintains intestinal epithelial barrier and reduces liver injury in alcoholic liver disease mice
Abstract Background Alcoholic liver disease (ALD) patients with bacterial infections usually exhibit high mortality rates. Infections frequently involve bacteria such as Vibrio vulnificus and Enterococcus faecalis. Nevertheless, the mechanisms predisposing ALD patients to bacterial infections and th...
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Wiley
2024-12-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.70099 |
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| author | Shi‐Qing Li Ya‐Ru Wang Zhong‐Liang Xie Yan Wang Zi‐Han Feng Jian‐Hao Xu Bing Yuan Yi‐Tong Zhang Guan Yang Jing‐Lin Wang Yuan Yuan |
| author_facet | Shi‐Qing Li Ya‐Ru Wang Zhong‐Liang Xie Yan Wang Zi‐Han Feng Jian‐Hao Xu Bing Yuan Yi‐Tong Zhang Guan Yang Jing‐Lin Wang Yuan Yuan |
| author_sort | Shi‐Qing Li |
| collection | DOAJ |
| description | Abstract Background Alcoholic liver disease (ALD) patients with bacterial infections usually exhibit high mortality rates. Infections frequently involve bacteria such as Vibrio vulnificus and Enterococcus faecalis. Nevertheless, the mechanisms predisposing ALD patients to bacterial infections and the role of the NLRP3 inflammasome in the intestinal epithelial barrier in ALD remain unclear. Methods We established ALD mice models of WT, Nlrp3−/− and Gsdmd−/− through chronic alcohol consumption feeding and acute alcohol induction. We compared alterations in gut microbiota, ileitis, and adhesion protein expression, to analyze the role and potential mechanism of NLRP3 in the early onset of ALD. Concurrently, we examined the changes in inflammation and liver damage in the ileum of ALD and healthy mice following foodborne infection with V. vulnificus. Results Compared with the control group, the expression levels of ZO‐1, Claudin‐1 and E‐cadherin were reduced in the ileum of ALD mice, while those of NLRP3, caspase‐1(p20), GSDMD‐N and IL‐1β were elevated. Nlrp3−/− and Gsdmd−/− ALD mice showed an increased gut bacterial load, decreased ileal expression of E‐cadherin, more severe ileitis, pronounced liver damage, steatosis and higher plasma levels of FITC‐dextran, D‐LA and ZO‐1 compared with WT mice. Notably, Nlrp3−/− ALD mice exhibited a higher presence of Deferribacterota and Enterobacteriaceae. Furthermore, ALD mice infected with V. vulnificus infection exhibited no further activation of NLRP3 in the ileum, leading to increased intestinal permeability and bloodstream infections. Conclusions This study indicated that NLRP3 activation in the ileum of ALD mice stabilizes the inflammation‐related gut microbiota, preserves the intestinal epithelial barrier, and diminishes inflammation and liver injury. Furthermore, the compromised immune defence in ALD mice may contribute to their heightened susceptibility to bacterial pathogens. Key points Activation of the NLRP3‐GSDMD pathway in the ileum of Alcoholic liver disease (ALD) mice. NLRP3 activation maintains homeostasis of gut microbiota and intestinal epithelial barrier in ALD mice. ALD mice infected with V. vulnificus infection exhibited no further activation of NLRP3 in the ileum, leading to increased intestinal permeability and bloodstream infections. |
| format | Article |
| id | doaj-art-bd039f82959d4974bd5f6ad69e3cc3f9 |
| institution | Kabale University |
| issn | 2001-1326 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj-art-bd039f82959d4974bd5f6ad69e3cc3f92025-01-30T03:56:54ZengWileyClinical and Translational Medicine2001-13262024-12-011412n/an/a10.1002/ctm2.70099NLRP3 activation maintains intestinal epithelial barrier and reduces liver injury in alcoholic liver disease miceShi‐Qing Li0Ya‐Ru Wang1Zhong‐Liang Xie2Yan Wang3Zi‐Han Feng4Jian‐Hao Xu5Bing Yuan6Yi‐Tong Zhang7Guan Yang8Jing‐Lin Wang9Yuan Yuan10State Key Laboratory of Pathogen and Biosecurity Academy of Military Medical Sciences (AMMS) Beijing ChinaState Key Laboratory of Pathogen and Biosecurity Academy of Military Medical Sciences (AMMS) Beijing ChinaState Key Laboratory of Pathogen and Biosecurity Academy of Military Medical Sciences (AMMS) Beijing ChinaState Key Laboratory of Pathogen and Biosecurity Academy of Military Medical Sciences (AMMS) Beijing ChinaDepartment of Disease Control and Prevention The No. 96609 Hospital of Chinese People's Liberation Army Yinchuan Ningxia ChinaState Key Laboratory of Pathogen and Biosecurity Academy of Military Medical Sciences (AMMS) Beijing ChinaState Key Laboratory of Pathogen and Biosecurity Academy of Military Medical Sciences (AMMS) Beijing ChinaState Key Laboratory of Pathogen and Biosecurity Academy of Military Medical Sciences (AMMS) Beijing ChinaState Key Laboratory of Proteomics Beijing Proteome Research Center National Center for Protein Sciences (Beijing) Beijing Institute of Lifeomics Beijing ChinaState Key Laboratory of Pathogen and Biosecurity Academy of Military Medical Sciences (AMMS) Beijing ChinaState Key Laboratory of Pathogen and Biosecurity Academy of Military Medical Sciences (AMMS) Beijing ChinaAbstract Background Alcoholic liver disease (ALD) patients with bacterial infections usually exhibit high mortality rates. Infections frequently involve bacteria such as Vibrio vulnificus and Enterococcus faecalis. Nevertheless, the mechanisms predisposing ALD patients to bacterial infections and the role of the NLRP3 inflammasome in the intestinal epithelial barrier in ALD remain unclear. Methods We established ALD mice models of WT, Nlrp3−/− and Gsdmd−/− through chronic alcohol consumption feeding and acute alcohol induction. We compared alterations in gut microbiota, ileitis, and adhesion protein expression, to analyze the role and potential mechanism of NLRP3 in the early onset of ALD. Concurrently, we examined the changes in inflammation and liver damage in the ileum of ALD and healthy mice following foodborne infection with V. vulnificus. Results Compared with the control group, the expression levels of ZO‐1, Claudin‐1 and E‐cadherin were reduced in the ileum of ALD mice, while those of NLRP3, caspase‐1(p20), GSDMD‐N and IL‐1β were elevated. Nlrp3−/− and Gsdmd−/− ALD mice showed an increased gut bacterial load, decreased ileal expression of E‐cadherin, more severe ileitis, pronounced liver damage, steatosis and higher plasma levels of FITC‐dextran, D‐LA and ZO‐1 compared with WT mice. Notably, Nlrp3−/− ALD mice exhibited a higher presence of Deferribacterota and Enterobacteriaceae. Furthermore, ALD mice infected with V. vulnificus infection exhibited no further activation of NLRP3 in the ileum, leading to increased intestinal permeability and bloodstream infections. Conclusions This study indicated that NLRP3 activation in the ileum of ALD mice stabilizes the inflammation‐related gut microbiota, preserves the intestinal epithelial barrier, and diminishes inflammation and liver injury. Furthermore, the compromised immune defence in ALD mice may contribute to their heightened susceptibility to bacterial pathogens. Key points Activation of the NLRP3‐GSDMD pathway in the ileum of Alcoholic liver disease (ALD) mice. NLRP3 activation maintains homeostasis of gut microbiota and intestinal epithelial barrier in ALD mice. ALD mice infected with V. vulnificus infection exhibited no further activation of NLRP3 in the ileum, leading to increased intestinal permeability and bloodstream infections.https://doi.org/10.1002/ctm2.70099alcoholic liver diseaseintestinal epithelial barrierNLRP3 inflammasomeVibrio infection |
| spellingShingle | Shi‐Qing Li Ya‐Ru Wang Zhong‐Liang Xie Yan Wang Zi‐Han Feng Jian‐Hao Xu Bing Yuan Yi‐Tong Zhang Guan Yang Jing‐Lin Wang Yuan Yuan NLRP3 activation maintains intestinal epithelial barrier and reduces liver injury in alcoholic liver disease mice Clinical and Translational Medicine alcoholic liver disease intestinal epithelial barrier NLRP3 inflammasome Vibrio infection |
| title | NLRP3 activation maintains intestinal epithelial barrier and reduces liver injury in alcoholic liver disease mice |
| title_full | NLRP3 activation maintains intestinal epithelial barrier and reduces liver injury in alcoholic liver disease mice |
| title_fullStr | NLRP3 activation maintains intestinal epithelial barrier and reduces liver injury in alcoholic liver disease mice |
| title_full_unstemmed | NLRP3 activation maintains intestinal epithelial barrier and reduces liver injury in alcoholic liver disease mice |
| title_short | NLRP3 activation maintains intestinal epithelial barrier and reduces liver injury in alcoholic liver disease mice |
| title_sort | nlrp3 activation maintains intestinal epithelial barrier and reduces liver injury in alcoholic liver disease mice |
| topic | alcoholic liver disease intestinal epithelial barrier NLRP3 inflammasome Vibrio infection |
| url | https://doi.org/10.1002/ctm2.70099 |
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