Sex Dimorphic Effects of Bile Acid Metabolism in Liver Cancer in Mice

Golonka, Rachel M.; Yeoh, Beng San; Saha, Piu; Tian, Yuan; Chiang, John Y.L.; Patterson, Andrew D.; Gewirtz, Andrew T.; Joe, Bina; Vijay-Kumar, Matam

doi:10.1016/j.jcmgh.2024.01.011

Cited by 4 publications

(1 citation statement)

References 80 publications

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“…Primary bile acids function as signaling molecules primarily through activating the major bile acid receptor (BAR) called farnesoid X receptor (FXR or NR1H4), a nuclear receptor [2,[5][6][7]. Previous work has suggested an antitumorigenic role for FXR in liver, bladder, and colorectal cancer [8][9][10][11]. Interestingly, we report that BC patients with high FXR expression have greater overall survival uniquely in ER− tumors and the basal-like subtype, but not in the less aggressive luminal A BC subtype or ER+ tumors, suggesting great potential for targeted approaches for subtypes in need of therapeutic advances.…”

Section: Introductionmentioning

confidence: 99%

FXR Agonism with Bile Acid Mimetic Reduces Pre-Clinical Triple-Negative Breast Cancer Burden

Joseph,

Eugin Simon,

Bohm

et al. 2024

Cancers

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Bariatric surgery is associated with improved outcomes for several cancers, including breast cancer (BC), although the mechanisms mediating this protection are unknown. We hypothesized that elevated bile acid pools detected after bariatric surgery may be factors that contribute to improved BC outcomes. Patients with greater expression of the bile acid receptor FXR displayed improved survival in specific aggressive BC subtypes. FXR is a nuclear hormone receptor activated by primary bile acids. Therefore, we posited that activating FXR using an established FDA-approved agonist would induce anticancer effects. Using in vivo and in vitro approaches, we determined the anti-tumor potential of bile acid receptor agonism. Indeed, FXR agonism by the bile acid mimetic known commercially as Ocaliva (“OCA”), or Obeticholic acid (INT-747), significantly reduced BC progression and overall tumor burden in a pre-clinical model. The transcriptomic analysis of tumors in mice subjected to OCA treatment revealed differential gene expression patterns compared to vehicle controls. Notably, there was a significant down-regulation of the oncogenic transcription factor MAX (MYC-associated factor X), which interacts with the oncogene MYC. Gene set enrichment analysis (GSEA) further demonstrated a statistically significant downregulation of the Hallmark MYC-related gene set (MYC Target V1) following OCA treatment. In human and murine BC analyses in vitro, agonism of FXR significantly and dose-dependently inhibited proliferation, migration, and viability. In contrast, the synthetic agonism of another common bile acid receptor, the G protein-coupled bile acid receptor TGR5 (GPBAR1) which is mainly activated by secondary bile acids, failed to significantly alter cancer cell dynamics. In conclusion, agonism of FXR by primary bile acid memetic OCA yields potent anti-tumor effects potentially through inhibition of proliferation and migration and reduced cell viability. These findings suggest that FXR is a tumor suppressor gene with a high potential for use in personalized therapeutic strategies for individuals with BC.

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Section: Introductionmentioning

confidence: 99%

FXR Agonism with Bile Acid Mimetic Reduces Pre-Clinical Triple-Negative Breast Cancer Burden

Joseph,

Eugin Simon,

Bohm

et al. 2024

Cancers

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Sex Matters: From Bile Acid Metabolism to Liver Cancer

Chauhan,

Heinrich

2024

Cellular and Molecular Gastroenterology and Hepatology

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Effect of Sex on Intestinal Microbial Metabolites of Hainan Special Wild Boars

Wang,

Wen,

et al. 2024

Animals

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The intestinal microbiota and its metabolites are essential for the health and growth development of animals. Current research indicates that sex has a certain impact on the structure and function of the intestinal microbiota, but there are few reports on sex differences in intestinal microbiota metabolites, including those of castrated male animals. This study aimed to explore the impact of sex on the intestinal microbial metabolites of Hainan special wild boars (10 entire male pigs, 10 female pigs, and 10 castrated male pigs, denoted EM, FE, and CM, respectively) by employing non-targeted metabolomics and gas chromatography. A total of 1086 metabolites were detected, with the greatest number of differential metabolites observed between EM and FE (54 differential metabolites, including 18 upregulated and 36 downregulated metabolites), the fewest between CM and FE (7 differential metabolites, including 1 upregulated and 6 downregulated metabolites), and an intermediate number between CM and EM (47 differential metabolites, including 35 upregulated and 12 downregulated metabolites). Differential metabolites were involved in more pathways between EM and FE and between CM and EM, including amino acid metabolism and digestive system pathways, whereas differential metabolites were involved in the fewest pathways between CM and FE. Correlation analysis showed Ruminococcaceae UCG-009, uncultured_bacterium_o_SAR324_cladeMarine_group_B, and Candidatus Saccharimonas contributed to the production of metabolites such as trehalose, docosatrienoic acid, D(−)-beta-hydroxy butyric acid, and acetyl-DL-leucine. The levels of acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid were significantly higher in EM than in FE, with CM falling between the two. Streptococcus, Lachnospiraceae_NK4A136_group and Rikenellaceae_RC9_gut_group showed a significant positive correlation with the production of short-chain fatty acids (SCFAs), while [Eubacterium]_coprostanoligenes_group, uncultured_bacterium_f_p–251–o5 and Ruminococcaceae_UCG–005 showed a significant negative correlation with the generation of SCFAs. This study provides foundational data and significant insights into precision feeding strategies for Hainan special wild boars of different sexes, as well as the study of sex differences in intestinal microbial metabolites in animals.

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Sex Dimorphic Effects of Bile Acid Metabolism in Liver Cancer in Mice

Cited by 4 publications

References 80 publications

FXR Agonism with Bile Acid Mimetic Reduces Pre-Clinical Triple-Negative Breast Cancer Burden

FXR Agonism with Bile Acid Mimetic Reduces Pre-Clinical Triple-Negative Breast Cancer Burden

Sex Matters: From Bile Acid Metabolism to Liver Cancer

Effect of Sex on Intestinal Microbial Metabolites of Hainan Special Wild Boars

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