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Loss of FXR or bile acid-dependent inhibition accelerate carcinogenesis of gastroesophageal adenocarcinoma

Background & Aims - The incidence of Barrett esophagus (BE) and gastroesophageal adenocarcinoma (GEAC) correlates with obesity and a diet rich in fat. Bile acids (BAs) support fat digestion and undergo microbial metabolism in the gut. The farnesoid X receptor (FXR) is an important modulator of t...

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Main Authors: Baumeister, Theresa (Author) , Proaño-Vasco, Andrea (Author) , Metwaly, Amira (Author) , Kleigrewe, Karin (Author) , Kuznetsov, Alexander (Author) , Schömig, Linus R. (Author) , Borgmann, Martin (Author) , Khiat, Mohammed (Author) , Anand, Akanksha (Author) , Strangmann, Julia (Author) , Böttcher, Katrin (Author) , Haller, Dirk (Author) , Dunkel, Andreas (Author) , Somoza, Veronika (Author) , Reiter, Sinah (Author) , Meng, Chen (Author) , Thimme, Robert (Author) , Schmid, Roland M. (Author) , Patil, Deepa T. (Author) , Burgermeister, Elke (Author) , Huang, Yiming (Author) , Sun, Yiwei (Author) , Wang, Harris H. (Author) , Wang, Timothy C. (Author) , Abrams, Julian A. (Author) , Quante, Michael (Author)
Format: Article (Journal)
Language:English
Published: 2025
In: Cellular and Molecular Gastroenterology and Hepatology
Year: 2025, Volume: 19, Issue: 8, Pages: 1-25
ISSN:2352-345X
DOI:10.1016/j.jcmgh.2025.101505
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.jcmgh.2025.101505
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2352345X25000463
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Author Notes:Theresa Baumeister, Andrea Proaño-Vasco, Amira Metwaly, Karin Kleigrewe, Alexander Kuznetsov, Linus R. Schömig, Martin Borgmann, Mohammed Khiat, Akanksha Anand, Julia Strangmann, Katrin Böttcher, Dirk Haller, Andreas Dunkel, Veronika Somoza, Sinah Reiter, Chen Meng, Robert Thimme, Roland M. Schmid, Deepa T. Patil, Elke Burgermeister, Yiming Huang, Yiwei Sun, Harris H. Wang, Timothy C. Wang, Julian A. Abrams, and Michael Quante
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Summary:Background & Aims - The incidence of Barrett esophagus (BE) and gastroesophageal adenocarcinoma (GEAC) correlates with obesity and a diet rich in fat. Bile acids (BAs) support fat digestion and undergo microbial metabolism in the gut. The farnesoid X receptor (FXR) is an important modulator of the BA homeostasis. When activated, FXR can inhibit cancer-related processes, and thus, it is an appealing therapeutic target. Here, we assess the effect of diet on the microbiota-BA axis and evaluate the role of FXR in disease progression. - Methods - L2-IL1B mice (mouse model of BE and GEAC) under different diets, and L2-IL1B-FXR KO-mice were characterized. L2-IL1B-derived organoids were exposed to different BAs and to the FXR agonist obeticholic acid (OCA). The BA profile in serum and stool of healthy controls and patients with BE and GEAC was assessed. - Results - Here we show that a high-fat diet accelerated tumorigenesis in L2-IL1B mice while increasing BA levels and altering the composition of the gut microbiota. Although upregulated in BE, expression of FXR was downregulated in GEAC in mice and humans. In L2-IL1B mice, FXR knockout enhanced the dysplastic phenotype and increased Lgr5 progenitor cell numbers. Treatment of murine BE organoids and L2-IL1B mice with OCA notably ameliorated the phenotype. - Conclusion - GEAC carcinogenesis appears to be partially driven via loss or inhibition of FXR on progenitor cells at the gastroesophageal junction. Considering that the resulting aggravation in the phenotype could be reversed with OCA treatment, we suggest that FXR agonists have great potential as a preventive strategy against GEAC progression.
Item Description:Online verfügbar: 24. März 2025, Artikelversion: 23. Mai 2025
Gesehen am 12.08.2025
Physical Description:Online Resource
ISSN:2352-345X
DOI:10.1016/j.jcmgh.2025.101505

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