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Pneumosepsis survival in the setting of obesity leads to persistent steatohepatitis and metabolic dysfunction

As critical care practice evolves, the sepsis survivor population continues to expand, often with lingering inflammation in many organs, including the liver. Given the concurrently increasing population of patients with NAFLD, in this study, we aimed to understand the long-term effect of sepsis on p...

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Autores principales: Kumar, Avnee J., Parthasarathy, Chitra, Prescott, Hallie C., Denstaedt, Scott J., Newstead, Michael W., Bridges, Dave, Bustamante, Angela, Singer, Kanakadurga, Singer, Benjamin H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10412436/
https://www.ncbi.nlm.nih.gov/pubmed/37556193
http://dx.doi.org/10.1097/HC9.0000000000000210
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author Kumar, Avnee J.
Parthasarathy, Chitra
Prescott, Hallie C.
Denstaedt, Scott J.
Newstead, Michael W.
Bridges, Dave
Bustamante, Angela
Singer, Kanakadurga
Singer, Benjamin H.
author_facet Kumar, Avnee J.
Parthasarathy, Chitra
Prescott, Hallie C.
Denstaedt, Scott J.
Newstead, Michael W.
Bridges, Dave
Bustamante, Angela
Singer, Kanakadurga
Singer, Benjamin H.
author_sort Kumar, Avnee J.
collection PubMed
description As critical care practice evolves, the sepsis survivor population continues to expand, often with lingering inflammation in many organs, including the liver. Given the concurrently increasing population of patients with NAFLD, in this study, we aimed to understand the long-term effect of sepsis on pre-existing NAFLD and hyperglycemia. METHODS: Male mice were randomized to a high-fat diet or a control diet (CD). After 24 weeks on diet, mice were inoculated with Klebsiella pneumoniae (Kpa). Serial glucose tolerance tests, and insulin and pyruvate challenge tests were performed 1 week before infection and at 2 and 6 weeks after infection. Whole tissue RNA sequencing and histological evaluation of the liver were performed. To test whether persistent inflammation could be reproduced in other abnormal liver environments, mice were also challenged with Kpa after exposure to a methionine-choline–deficient high-fat diet. Finally, a retrospective cohort of 65,139 patients was analyzed to evaluate whether obesity was associated with liver injury after sepsis. RESULTS: After Kpa inoculation, high-fat diet mice had normalized fasting blood glucose without a change in insulin sensitivity but with a notable decrease in pyruvate utilization. Liver examination revealed focal macrophage collections and a unique inflammatory gene signature on RNA analysis. In the clinical cohort, preobesity, and class 1 and class 2 obesity were associated with increased odds of elevated aminotransferase levels 1–2 years after sepsis. CONCLUSIONS: The combination of diet-induced obesity and pneumosepsis survival in a murine model resulted in unique changes in gluconeogenesis and liver inflammation, consistent with the progression of benign steatosis to steatohepatitis. In a cohort study, obese patients had an increased risk of elevated aminotransferase levels 1–2 years following sepsis.
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spelling pubmed-104124362023-08-11 Pneumosepsis survival in the setting of obesity leads to persistent steatohepatitis and metabolic dysfunction Kumar, Avnee J. Parthasarathy, Chitra Prescott, Hallie C. Denstaedt, Scott J. Newstead, Michael W. Bridges, Dave Bustamante, Angela Singer, Kanakadurga Singer, Benjamin H. Hepatol Commun Original Article As critical care practice evolves, the sepsis survivor population continues to expand, often with lingering inflammation in many organs, including the liver. Given the concurrently increasing population of patients with NAFLD, in this study, we aimed to understand the long-term effect of sepsis on pre-existing NAFLD and hyperglycemia. METHODS: Male mice were randomized to a high-fat diet or a control diet (CD). After 24 weeks on diet, mice were inoculated with Klebsiella pneumoniae (Kpa). Serial glucose tolerance tests, and insulin and pyruvate challenge tests were performed 1 week before infection and at 2 and 6 weeks after infection. Whole tissue RNA sequencing and histological evaluation of the liver were performed. To test whether persistent inflammation could be reproduced in other abnormal liver environments, mice were also challenged with Kpa after exposure to a methionine-choline–deficient high-fat diet. Finally, a retrospective cohort of 65,139 patients was analyzed to evaluate whether obesity was associated with liver injury after sepsis. RESULTS: After Kpa inoculation, high-fat diet mice had normalized fasting blood glucose without a change in insulin sensitivity but with a notable decrease in pyruvate utilization. Liver examination revealed focal macrophage collections and a unique inflammatory gene signature on RNA analysis. In the clinical cohort, preobesity, and class 1 and class 2 obesity were associated with increased odds of elevated aminotransferase levels 1–2 years after sepsis. CONCLUSIONS: The combination of diet-induced obesity and pneumosepsis survival in a murine model resulted in unique changes in gluconeogenesis and liver inflammation, consistent with the progression of benign steatosis to steatohepatitis. In a cohort study, obese patients had an increased risk of elevated aminotransferase levels 1–2 years following sepsis. Lippincott Williams & Wilkins 2023-08-09 /pmc/articles/PMC10412436/ /pubmed/37556193 http://dx.doi.org/10.1097/HC9.0000000000000210 Text en Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License 4.0 (https://creativecommons.org/licenses/by/4.0/) (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/)
spellingShingle Original Article
Kumar, Avnee J.
Parthasarathy, Chitra
Prescott, Hallie C.
Denstaedt, Scott J.
Newstead, Michael W.
Bridges, Dave
Bustamante, Angela
Singer, Kanakadurga
Singer, Benjamin H.
Pneumosepsis survival in the setting of obesity leads to persistent steatohepatitis and metabolic dysfunction
title Pneumosepsis survival in the setting of obesity leads to persistent steatohepatitis and metabolic dysfunction
title_full Pneumosepsis survival in the setting of obesity leads to persistent steatohepatitis and metabolic dysfunction
title_fullStr Pneumosepsis survival in the setting of obesity leads to persistent steatohepatitis and metabolic dysfunction
title_full_unstemmed Pneumosepsis survival in the setting of obesity leads to persistent steatohepatitis and metabolic dysfunction
title_short Pneumosepsis survival in the setting of obesity leads to persistent steatohepatitis and metabolic dysfunction
title_sort pneumosepsis survival in the setting of obesity leads to persistent steatohepatitis and metabolic dysfunction
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10412436/
https://www.ncbi.nlm.nih.gov/pubmed/37556193
http://dx.doi.org/10.1097/HC9.0000000000000210
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