Normalization of the α1-Na/K-ATPase/Src Signalosome Restored Microbiota Communities and Rescinded NASH Progression in the Mouse

Mathew Schade; Jacqueline A. Sanabria; Amrita Mallick; Rodrigo Aguilar; Michael Andryka; Daniela Schlatzer; Xiaolin Li; F. E. Hazlett; Maureen Kachman; Aravinda Raskind; Utibe-Abasi Udoh; Pradeep K. Rajan; Juan D. Sanabria; Henri Brunengraber; Komal Sodhi; Sandrine Pierre; Zijian Xie; Joseph I. Shapiro; Juan Sanabria

doi:10.20944/preprints202109.0023.v2

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preprints.org > medicine and pharmacology > gastroenterology and hepatology > doi: 10.20944/preprints202109.0023.v2

Preprint Article Version 2 Preserved in Portico This version is not peer-reviewed

Normalization of the α1-Na/K-ATPase/Src Signalosome Restored Microbiota Communities and Rescinded NASH Progression in the Mouse

Mathew Schade

Jacqueline A. Sanabria

Version 2 : Received: 24 May 2022 / Approved: 25 May 2022 / Online: 25 May 2022 (08:37:22 CEST)

How to cite: Schade, M.; Sanabria, J.A.; Mallick, A.; Aguilar, R.; Andryka, M.; Schlatzer, D.; Li, X.; Hazlett, F.E.; Kachman, M.; Raskind, A.; Udoh, U.; Rajan, P.K.; Sanabria, J.D.; Brunengraber, H.; Sodhi, K.; Pierre, S.; Xie, Z.; Shapiro, J.I.; Sanabria, J. Normalization of the α1-Na/K-ATPase/Src Signalosome Restored Microbiota Communities and Rescinded NASH Progression in the Mouse. Preprints 2021, 2021090023. https://doi.org/10.20944/preprints202109.0023.v2 Schade, M.; Sanabria, J.A.; Mallick, A.; Aguilar, R.; Andryka, M.; Schlatzer, D.; Li, X.; Hazlett, F.E.; Kachman, M.; Raskind, A.; Udoh, U.; Rajan, P.K.; Sanabria, J.D.; Brunengraber, H.; Sodhi, K.; Pierre, S.; Xie, Z.; Shapiro, J.I.; Sanabria, J. Normalization of the α1-Na/K-ATPase/Src Signalosome Restored Microbiota Communities and Rescinded NASH Progression in the Mouse. Preprints 2021, 2021090023. https://doi.org/10.20944/preprints202109.0023.v2

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MDPI and ACS Style

Schade, M.; Sanabria, J.A.; Mallick, A.; Aguilar, R.; Andryka, M.; Schlatzer, D.; Li, X.; Hazlett, F.E.; Kachman, M.; Raskind, A.; Udoh, U.; Rajan, P.K.; Sanabria, J.D.; Brunengraber, H.; Sodhi, K.; Pierre, S.; Xie, Z.; Shapiro, J.I.; Sanabria, J. Normalization of the α1-Na/K-ATPase/Src Signalosome Restored Microbiota Communities and Rescinded NASH Progression in the Mouse. Preprints 2021, 2021090023. https://doi.org/10.20944/preprints202109.0023.v2

APA Style

Schade, M., Sanabria, J.A., Mallick, A., Aguilar, R., Andryka, M., Schlatzer, D., Li, X., Hazlett, F.E., Kachman, M., Raskind, A., Udoh, U., Rajan, P.K., Sanabria, J.D., Brunengraber, H., Sodhi, K., Pierre, S., Xie, Z., Shapiro, J.I., & Sanabria, J. (2022). Normalization of the α1-Na/K-ATPase/Src Signalosome Restored Microbiota Communities and Rescinded NASH Progression in the Mouse. Preprints. https://doi.org/10.20944/preprints202109.0023.v2

Chicago/Turabian Style

Schade, M., Joseph I. Shapiro and Juan Sanabria. 2022 "Normalization of the α1-Na/K-ATPase/Src Signalosome Restored Microbiota Communities and Rescinded NASH Progression in the Mouse" Preprints. https://doi.org/10.20944/preprints202109.0023.v2

Abstract

BACKGROUND. Two sequelae of non-alcoholic steatohepatitis (NASH), ESLD and HCC, have become the leading causes for liver transplantation in the Western. The present study aims to approach the cellular metabolic disturbances involved in NASH progression that are associated with microbiota community changes. METHODS. Metabolic effects and microbiota community changes were explored in the murine with NASH progression by blocking the Na/K-ATPase/Src/reactive oxygen amplification loop using the synthetic targeting peptide pNaKtide. DNA from the terminal ileum microbiota habitat was obtained and amplified by PCR to develop DNA bacterial phylogenic sequence analysis of wild type and treated animals at 12, 24 and 48 weeks. Induced changes by pSrc normalization at 24 weeks were correlated with liver morphological changes, intestinal CD4+/CD8+ ratio, and liver macrophage CD14+ expression. Differences among groups were evaluated by ANOVA/t-test and Principal Component Analysis (PCA). RESULTS. Microbiota communities varied significantly at all time points (12, 24 and 48 weeks), with an increase of Verrucomicrobia and a decrease of Bacteroidetes and Firmicutes in the HFD group. Microbiota community changes regressed to their wild-type state at 24 weeks on treated animals, and those changes were associated with a decrease in liver inflammation and senescence, lower ileum CD4+/CD8+ T cells and higher liver CD14+ cells (p<0.05). Concomitantly, the metabolic disturbances in our diet-induced NASH model were normalized by NKA/Src signaling blockage and exercise with a paucity of apoptotic activity, mitigation of cell senescence, and regression of liver fibrosis (p<0.01). CONCLUSIONS. pSrc inhibition at caveolar α1-Na/K-ATPase rescinded NASH-related metabolic disturbances establishing resident physiological microbiota communities with concomitant paucity on apoptotic activity and regression of liver fibrosis; effects that were associated with both gut and liver T-lymphocyte responses.

Keywords

pSrc; Glutathione; Na/K-ATPase; metabolic prints; metabolomics; NAFLD; NASH; high-fat diet; fibrosis; inflammation

Subject

Medicine and Pharmacology, Gastroenterology and Hepatology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Received: 25 May 2022
Commenter: JUAN SANABRIA
Commenter's Conflict of Interests: Author

Comment: One of our aouthors would like to drop his authorship.

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