Regulation of intestinal senescence during cholestatic liver disease modulates barrier function and liver disease progression

Moreno-Gonzalez, Mar, Hampton, Katherine, Ruiz, Paula, Beasy, Gemma, Nagies, Falk S. P., Parker, Aimee, Lazenby, James, Bone, Caitlin, Alava-Arteaga, Ane, Patel, Meha, Hellmich, Charlotte, Luri-Martin, Pablo, Silan, Ece, Philo, Mark, Baker, David, Rushbrook, Simon M., Hildebrand, Falk, Rushworth, Stuart A. and Beraza, Naiara (2024) Regulation of intestinal senescence during cholestatic liver disease modulates barrier function and liver disease progression. JHEP Reports, 6 (10). ISSN 2589-5559

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Abstract

Background and Aims: Senescence in cholangiocytes and hepatic stellate cells (HSC) has been described during human and murine cholestatic disease, having differential functions; detrimental in biliary cells and anti-fibrotic in HSC. Cholestatic liver disease associates with loss of intestinal barrier function and changes in the microbiome, the mechanistic cause of which is undetermined. Methods: Intestinal samples were analysed from control and primary sclerosing cholangitis patients (PSC), wildtype (WT) and p16-3MR transgenic mice. Cholestatic liver disease was induced by bile duct ligation (BDL) and feeding with DDC diet. Fexaramine was used as an intestinal-restricted FXR agonist and antibiotics were given to eliminate the intestinal microbiome. Senescent cells were eliminated in p16-3MR mice with Ganciclovir and in WT mice with the senolytic drug ABT-263. In vitro studies were done in intestinal CaCo-2 cells and organoids were generated from intestinal-crypts isolated from mice. Results: Here we show increased senescence in intestinal epithelial cells (IEC) in PSC patients and in mice after BDL and DDC diet. Intestinal senescence responded to reduced exposure to bile acids and increased presence of LPS in vitro and in vivo during cholestatic liver disease. Intestinal senescence associated with lower proliferation while increased intestinal stem cell (ISC) activation, as supported by increased organoid growth from ISC. Elimination of senescent cells with genetic and pharmacological approaches exacerbated liver injury and fibrosis during cholestatic liver disease that associated with increased IEC apoptosis and permeability. Conclusions: Senescence occurs in IEC during cholestatic disease and the elimination of senescent cells has a detrimental impact on the gut-liver axis. Our results point to cell-specific rather than systemic targeting of senescence as a therapeutic approach to treat cholestatic liver disease.

Item Type:	Article
Additional Information:	Data availability statement: The authors declare that all data generated from this study are available within the manuscript and the supplemental material provided. Any additional files or information can be provided upon request to the corresponding authors. Funding information: The authors gratefully acknowledge the support of the Biotechnology and Biological Sciences Research Council (BBSRC) Institute Strategic Programme Gut Health and Food Safety BB/J004529/1, the BBSRC Gut Microbes and Health BBS/E/F/00044509 (to NB), the BBSRC Institute Strategic Programme Gut Microbes and Health BB/R012490/1 and its constituent project BBS/E/F/000PR10355, and the BBSRC Core Capability Grant BB/CCG1860/1 as well as the BBSRC Institute Strategic Programme Food Innovation and Health BB/R012512/1 and its constituent project BBS/E/F/000PR10347. BBSRC Institute Strategic Programme Food Microbiome and Health BB/X011054/1 and its constituent project BBS/E/F/000PR13631 (FH, ES) and BBS/E/F/000PR13632 (NB). FH was supported by European Research Council H2020 StG (erc-stg-948219, EPYC and H2020-EU.3.2.2.3. Grant No. 863059 – www.fns-cloud.eu). FH and FSPN were supported by BBSRC Decoding Biodiversity BB/X011089/1 and its constituent work packages BBS/E/ER/230002A and BBS/E/ER/230002C.
Uncontrolled Keywords:	sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:	Faculty of Science > School of Biological Sciences Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging
Depositing User:	LivePure Connector
Date Deposited:	02 Jul 2024 10:32
Last Modified:	25 Sep 2024 17:55
URI:	https://ueaeprints.uea.ac.uk/id/eprint/95755
DOI:	10.1016/j.jhepr.2024.101159

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