Smita Ghare, Dennis Warner, Jeffrey Warner, Paula M Chilton, Jiyeon Lee, JingWen Zhang, Min Wang, Josiah Hardesty, Rui Treves, Jon Gabbard, Charles Anderson, Lalit Batra, Chithra Sreenivasan, Jennifer Kraenzle, Matthew McCulley, Stephanie McCoy, Lihua Zhang, Wenke Feng, Dibson Dibe Gondim, Shirish Barve, Jian Zheng, Kenneth Palmer, Craig McClain, Irina Kirpich
{"title":"慢性乙醇摄入和SARS-COV-2对小鼠肝脏和肠道的影响：一项初步剂量反应研究","authors":"Smita Ghare, Dennis Warner, Jeffrey Warner, Paula M Chilton, Jiyeon Lee, JingWen Zhang, Min Wang, Josiah Hardesty, Rui Treves, Jon Gabbard, Charles Anderson, Lalit Batra, Chithra Sreenivasan, Jennifer Kraenzle, Matthew McCulley, Stephanie McCoy, Lihua Zhang, Wenke Feng, Dibson Dibe Gondim, Shirish Barve, Jian Zheng, Kenneth Palmer, Craig McClain, Irina Kirpich","doi":"10.1111/acer.15528","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>During the coronavirus disease 2019 (COVID-19) pandemic, there was a marked increase in alcohol consumption. COVID-19 superimposed on underlying liver disease notably worsens the outcome of many forms of liver injury. The goal of a current pilot study was to test the dual exposure of alcohol and COVID-19 infection in an experimental animal model of alcohol-associated liver disease (ALD).</p><p><strong>Methods: </strong>After 4 weeks of ethanol (EtOH) feeding, C57BL/6 male mice received SARS-CoV-2 (SARS2-N501Y<sub>MA30</sub>) intranasally at 3 × 10<sup>2</sup>, 1 × 10<sup>3</sup>, 3 × 10<sup>3</sup>, and 1 × 10<sup>4</sup> plaque-forming units (PFU). Mice were then weighed/monitored daily for morbidity/mortality for 10 days while continuing EtOH consumption. Markers of liver inflammation, injury, and intestinal barrier integrity were evaluated.</p><p><strong>Results: </strong>A similar gradual weight loss was observed in all inoculated mice (slightly less in the 3 × 10<sup>2</sup> group) up to post-infection day 4. Greater mortality was observed in mice receiving the highest viral dose at days 3 and 4 post-infection. The majority of the surviving mice subjected to EtOH and inoculated with 3 × 10<sup>3</sup> or 1 × 10<sup>4</sup> PFU rapidly lost 25% of their body weight and were euthanized on post-infection day 4. Analysis of liver health in animals that survived to the end of the experiment exhibited no significant changes in hepatic steatosis but had a limited increase in plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at all viral doses versus EtOH alone. However, the 1 × 10<sup>4</sup> PFU viral dose exacerbated EtOH-induced hepatic inflammation characterized by elevated levels of several pro-inflammatory cytokines, including Il-6 and Tnf-α. There was limited effect of viral infection on the intestine.</p><p><strong>Conclusions: </strong>SARS-CoV-2 infection caused a dose-dependent negative impact on body weight and survival in mice fed EtOH. This pilot study suggests that early mortality observed after high-dose SARS-CoV-2 challenge could be due, in part, to hepatic dysfunction following chronic EtOH feeding.</p>","PeriodicalId":72145,"journal":{"name":"Alcohol (Hanover, York County, Pa.)","volume":" ","pages":""},"PeriodicalIF":3.0000,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Impact of chronic ethanol consumption and SARS-COV-2 on the liver and intestine: A pilot dose-response study in mice.\",\"authors\":\"Smita Ghare, Dennis Warner, Jeffrey Warner, Paula M Chilton, Jiyeon Lee, JingWen Zhang, Min Wang, Josiah Hardesty, Rui Treves, Jon Gabbard, Charles Anderson, Lalit Batra, Chithra Sreenivasan, Jennifer Kraenzle, Matthew McCulley, Stephanie McCoy, Lihua Zhang, Wenke Feng, Dibson Dibe Gondim, Shirish Barve, Jian Zheng, Kenneth Palmer, Craig McClain, Irina Kirpich\",\"doi\":\"10.1111/acer.15528\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>During the coronavirus disease 2019 (COVID-19) pandemic, there was a marked increase in alcohol consumption. COVID-19 superimposed on underlying liver disease notably worsens the outcome of many forms of liver injury. The goal of a current pilot study was to test the dual exposure of alcohol and COVID-19 infection in an experimental animal model of alcohol-associated liver disease (ALD).</p><p><strong>Methods: </strong>After 4 weeks of ethanol (EtOH) feeding, C57BL/6 male mice received SARS-CoV-2 (SARS2-N501Y<sub>MA30</sub>) intranasally at 3 × 10<sup>2</sup>, 1 × 10<sup>3</sup>, 3 × 10<sup>3</sup>, and 1 × 10<sup>4</sup> plaque-forming units (PFU). Mice were then weighed/monitored daily for morbidity/mortality for 10 days while continuing EtOH consumption. Markers of liver inflammation, injury, and intestinal barrier integrity were evaluated.</p><p><strong>Results: </strong>A similar gradual weight loss was observed in all inoculated mice (slightly less in the 3 × 10<sup>2</sup> group) up to post-infection day 4. Greater mortality was observed in mice receiving the highest viral dose at days 3 and 4 post-infection. The majority of the surviving mice subjected to EtOH and inoculated with 3 × 10<sup>3</sup> or 1 × 10<sup>4</sup> PFU rapidly lost 25% of their body weight and were euthanized on post-infection day 4. Analysis of liver health in animals that survived to the end of the experiment exhibited no significant changes in hepatic steatosis but had a limited increase in plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at all viral doses versus EtOH alone. However, the 1 × 10<sup>4</sup> PFU viral dose exacerbated EtOH-induced hepatic inflammation characterized by elevated levels of several pro-inflammatory cytokines, including Il-6 and Tnf-α. There was limited effect of viral infection on the intestine.</p><p><strong>Conclusions: </strong>SARS-CoV-2 infection caused a dose-dependent negative impact on body weight and survival in mice fed EtOH. This pilot study suggests that early mortality observed after high-dose SARS-CoV-2 challenge could be due, in part, to hepatic dysfunction following chronic EtOH feeding.</p>\",\"PeriodicalId\":72145,\"journal\":{\"name\":\"Alcohol (Hanover, York County, Pa.)\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.0000,\"publicationDate\":\"2025-01-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Alcohol (Hanover, York County, Pa.)\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1111/acer.15528\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"SUBSTANCE ABUSE\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alcohol (Hanover, York County, Pa.)","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1111/acer.15528","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"SUBSTANCE ABUSE","Score":null,"Total":0}
Impact of chronic ethanol consumption and SARS-COV-2 on the liver and intestine: A pilot dose-response study in mice.
Background: During the coronavirus disease 2019 (COVID-19) pandemic, there was a marked increase in alcohol consumption. COVID-19 superimposed on underlying liver disease notably worsens the outcome of many forms of liver injury. The goal of a current pilot study was to test the dual exposure of alcohol and COVID-19 infection in an experimental animal model of alcohol-associated liver disease (ALD).
Methods: After 4 weeks of ethanol (EtOH) feeding, C57BL/6 male mice received SARS-CoV-2 (SARS2-N501YMA30) intranasally at 3 × 102, 1 × 103, 3 × 103, and 1 × 104 plaque-forming units (PFU). Mice were then weighed/monitored daily for morbidity/mortality for 10 days while continuing EtOH consumption. Markers of liver inflammation, injury, and intestinal barrier integrity were evaluated.
Results: A similar gradual weight loss was observed in all inoculated mice (slightly less in the 3 × 102 group) up to post-infection day 4. Greater mortality was observed in mice receiving the highest viral dose at days 3 and 4 post-infection. The majority of the surviving mice subjected to EtOH and inoculated with 3 × 103 or 1 × 104 PFU rapidly lost 25% of their body weight and were euthanized on post-infection day 4. Analysis of liver health in animals that survived to the end of the experiment exhibited no significant changes in hepatic steatosis but had a limited increase in plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at all viral doses versus EtOH alone. However, the 1 × 104 PFU viral dose exacerbated EtOH-induced hepatic inflammation characterized by elevated levels of several pro-inflammatory cytokines, including Il-6 and Tnf-α. There was limited effect of viral infection on the intestine.
Conclusions: SARS-CoV-2 infection caused a dose-dependent negative impact on body weight and survival in mice fed EtOH. This pilot study suggests that early mortality observed after high-dose SARS-CoV-2 challenge could be due, in part, to hepatic dysfunction following chronic EtOH feeding.
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