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Duodenal-derived organoids from MASH patients exhibit altered digestive homeostasis.

ABSTRACT: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive disease linked to conditions like fibrosis, cirrhosis, and liver cancer, often resulting in higher mortality rates, primarily due to cardiovascular events. While MASH is closely tied to metabolic syndrome, recent research underscores the importance of the gut-liver axis in its pathogenesis, an aspect less explored in human studies. To address this gap, duodenal epithelial organoids were generated from both MASH and healthy (controls) subjects. Organoid formation efficiency was similar between controls derived epithelial organoids (CDEOs) and MASH derived epithelial organoids (MDEOs) groups. Variability in growth patterns was observed, with MDEOs frequently exhibiting cystic spheroid morphology. MASH-derived organoids displayed altered homeostasis and digestive potential in the duodenal epithelium. Despite potential lineage bias, MDEOs retained their lipid metabolic capacity, possibly mediated by lipid oxidation in stem/progenitor cells. Notably, cell adhesion components were misexpressed in MASH-derived organoids, indicating significant intrinsic alterations in cell-cell adhesion potential compared to controls. However, MDEOs maintained transepithelial electric resistance and leak pathway integrity, indicating that the intestinal epithelial barrier remained functionally intact in MDEOs under tested conditions. This study sheds light on the intricate dynamics of duodenal epithelial alterations in MASH, highlighting potential therapeutic avenues for restoring intestinal homeostasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268518 | GEO | 2024/12/13

REPOSITORIES: GEO

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Project description:Metabolic Dysfunction Associated Steatohepatitis (MASH) is characterized by excess circulating toxic lipids, hepatic steatosis, and liver inflammation. Monocyte adhesion to the liver sinusoidal endothelial cells (LSEC) and transendothelial migration (TEM) are crucial in the inflammatory process. LSEC under lipotoxic stress develops a pro-inflammatory phenotype known as endotheliopathy. However, the mediators of endotheliopathy remain obscure. Primary mouse LSEC isolated from C57BL/6J mice on chow or MASH-inducing diets rich in fat, fructose, and cholesterol (FFC) were subjected to multi-omics profiling. Mice with established MASH, due to a choline-deficient high-fat diet (CDHFD) or FFC diet, were treated with two structurally distinct GSK3 inhibitors [LY2090314, elraglusib (9-ING-41)]. Integrated pathway analysis of mouse LSEC proteome and transcriptome indicates that leukocyte TEM and focal adhesion are major pathways altered in MASH. Kinome profiling of the LSEC phospho-proteome identified GSK3β as the major kinase hub in MASH. GSK3β activating phosphorylation was increased in primary human LSEC treated with the toxic lipid palmitate and in human MASH. Palmitate upregulated the expression of C-X-C motif chemokine ligand 2, intracellular adhesion molecule 1, and phosphorylated focal adhesion kinase, via a GSK3-dependant mechanism. Congruently, the adhesive and transendothelial migratory capacities of primary human neutrophils and THP-1 monocytes through LSEC monolayer under lipotoxic stress were reduced by GSK3 inhibition. Treatment with the GSK3 inhibitors LY2090314 and elraglusib ameliorated liver inflammation, injury, and fibrosis in FFC and CDHFD-fed mice, respectively. Immunophenotyping of intrahepatic leukocytes from CDHFD-fed mice treated with elraglusib using cytometry by the time of flight showed reduced proinflammatory monocyte-derived macrophages and monocyte-derived dendritic cells infiltration.GSK3 inhibition attenuates lipotoxicity-induced LSEC endotheliopathy and may serve as a potential therapeutic strategy in human MASH.

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Duodenal-derived organoids from MASH patients exhibit altered digestive homeostasis.

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