Bile acid synthesis impedes tumor-specific T cell responses during liver cancer [RNA-seq1]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE279096 | GEO | 2024/10/09
REPOSITORIES: GEO
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Project description:The tumor's metabolic landscape significantly influences anti-tumor immunity, but it remains unclear how metabolic pathways commonly active in the organ of tumor-origin influence immunosurveillance. This study focused on the liver and identified accumulation of primary conjugated and secondary bile acids (BAs) as metabolic features associated with hepatocellular carcinoma and liver cancer models. Inhibiting conjugated BA synthesis through BAAT-deletion in hepatocytes enhanced tumor-specific T cell responses, reduced growth, and sensitized tumors to immune checkpoint blockade. BAs regulated CD8+ T cells differently; primary BAs like TCDCA induced oxidative stress and secondary BAs like LCA impaired T cell function through ER stress, which was countered by UDCA. Indeed, dietary UDCA provision suppressed tumor progression. These findings demonstrate how manipulating organ-specific metabolites affects antitumor immunity and modifying BA synthesis or dietary intake could enhance immunotherapy in liver cancer.
2024-10-09 | GSE279098 | GEO
Project description:The tumor's metabolic landscape significantly influences anti-tumor immunity, but it remains unclear how metabolic pathways commonly active in the organ of tumor-origin influence immunosurveillance. This study focused on the liver and identified accumulation of primary conjugated and secondary bile acids (BAs) as metabolic features associated with hepatocellular carcinoma and liver cancer models. Inhibiting conjugated BA synthesis through BAAT-deletion in hepatocytes enhanced tumor-specific T cell responses, reduced growth, and sensitized tumors to immune checkpoint blockade. BAs regulated CD8+ T cells differently; primary BAs like TCDCA induced oxidative stress and secondary BAs like LCA impaired T cell function through ER stress, which was countered by UDCA. Indeed, dietary UDCA provision suppressed tumor progression. These findings demonstrate how manipulating organ-specific metabolites affects antitumor immunity and modifying BA synthesis or dietary intake could enhance immunotherapy in liver cancer.
2024-10-09 | GSE279097 | GEO
Project description:Background and Aims - Bile acids (BAs) aid intestinal fat absorption and exert systemic actions by receptor-mediated signaling. BA receptors have been identified as drug targets for human diseases, but differences in BA metabolism between humans and mice hamper translation of pre-clinical outcomes. Cyp2c70-ablation in mice prevents synthesis of mouse/rat-specific muricholic acids (MCAs), but potential (patho)physiological consequences of their absence are unknown. We therefore assessed age- and gender-dependent effects of Cyp2c70-deficiency in mice. Methods - BA-related parameters, hepatic and intestinal gene expression patterns, liver morphology and intestinal barrier function were assessed in male and female Cyp2c70-/- mice and WT controls at different ages. Effects of ursodeoxycholic acid (UDCA) treatment were evaluated in young adult female mice. Results – Cyp2c70-/- mice were completely devoid of MCAs and showed high abundances of chenodeoxycholic and lithocholic acids. BA pool size was unaffected in young-adult male but reduced by 40% in female Cyp2c70-/- mice. Interestingly, plasma BAs and transaminases were highest in Cyp2c70-/- mice at weaning and spontaneously decreased with age. Although bile flow and biliary BA secretion were unchanged in young-adult Cyp2c70-/- mice, indicating absence of cholestasis, plasma BA and transaminase levels were still elevated. These young-adult Cyp2c70-/- mice displayed cholangiocyte proliferation, mild portal fibrosis, altered microbiome composition and increased gut permeability. Only the female Cyp2c70-/- mice developed bridging fibrosis with age (7-8 months). UDCA treatment normalized hepatic and intestinal functions and fully restored liver morphology in female Cyp2c70-/- mice. Conclusion – Cyp2c70-/- mice show transient neonatal cholestasis and develop cholangiopathic features which progress to bridging fibrosis in female mice only. These consequences of Cyp2c70-deficiency are fully restored by treatment with UDCA.
2020-12-22 | GSE138779 | GEO
Project description:Bile acids (BAs) are gastrointestinal metabolites that serve dual functions in lipid absorption and cell signaling. BAs circulate actively between the liver and distal small intestine (i.e., ileum), yet the dynamics through which complex BA pools are absorbed in the ileum and interact with intestinal cells in vivo remain ill-defined. Through multi-site sampling of nearly 100 BA species in individual wild type mice, as well as mice lacking the ileal BA transporter, Asbt/Slc10a2, we calculate the ileal BA pool in fasting C57BL/6J mice to be ~0.3 mmoles/g. Asbt-mediated transport accounts for ~80% of this pool and amplifies size, whereas passive absorption explains the remaining ~20%, and generates diversity. Accordingly, ileal BA pools in mice lacking Asbt are ~5-fold smaller than in wild type controls, enriched in secondary BA species normally found in the colon, and elicit unique transcriptional responses in cultured ileal explants. This work quantitatively defines ileal BA pools in mice and reveals how BA dysmetabolism can impinge directly on intestinal physiology.
2024-02-21 | GSE256113 | GEO
Project description:<p><strong>OBJECTIVE:</strong> To characterize the bile acid (BA) metabolomic profile of umbilical cord blood (UCB) and meconium in healthy newborns.</p><p><strong>METHODS:</strong> Fifteen healthy newborns, which born in the Obstetrics Department of the Affiliated Hospital of Southwest Medical University between July 1 and August 31, 2023, were selected as study subjects. UCB and meconium samples were collected, and BA metabolomics were analyzed using ultra-high performance liquid chromatography-tandem mass spectrometry.</p><p><strong>RESULTS:</strong> UCB predominantly contained primary bile acids (PBAs), whereas meconium was rich in secondary bile acids (SBAs). The PBAs/SBAs ratio in UCB was significantly higher than in meconium [2.64 (2.49, 5.70) vs 0.99 (0.37, 1.58), P < 0.001]. Both UCB and meconium were primarily composed of conjugated BAs. However, the ratio of unconjugated to conjugated BAs was notably higher in UCB than in meconium [0.14 (0.07, 0.18) vs 0.01 (0.01, 0.04), P < 0.001]. In terms of individual metabolite, UCB was dominated by taurochenodeoxycholic acid (TCDCA), taurocholic acid (TCA), and glycochenodeoxycholic acid (GCDCA), while meconium was abundant in TCA, taurohyocholic acid, and TCDCA. Conjugated PBAs in UCB primarily originated from chenodeoxycholic acid (CDCA), whereas those in meconium were mainly derived from cholic acid (CA). The CA/CDCA ratio in conjugated PBAs was significantly lower in UCB than in meconium [0.59 (0.19, 0.75) vs 2.21 (1.34, 3.04), P < 0.001]. SBAs in both UCB and meconium were primarily derived from CDCA, but the CA/CDCA ratio was significantly higher in UCB than in meconium [0.42 (0.21, 0.63), vs 0.03 (0.01, 0.05), P < 0.001]. No PBAs in UCB correlated with their counterparts in meconium, and only three PBAs (TCDCA, GCDCA, and glycochenodeoxycholic acid 3-glucoside in UCB) were correlated with their downstream metabolites in meconium [with hyodesoxycholic acid (HDCA) (r = -0.66, P = 0.01), Tauro-ω-muricholic acid (TωMCA) (r = 0.52, P = 0.048) and ursodeoxycholic acid-7S (r = -0.53, P = 0.04), respectively]. In meconium, most of PBAs were correlated with their downstream metabolites (P all < 0.05): CA was positively correlated with 3-dehydrocholic acid (3-DHCA), TCA was positively correlated with TDCA and 3-DHCA, GCA was positively correlated with 3-DHCA, CDCA was positively correlated with GUDCA, taurolithocholic acid (TLCA), and 7-keto Lithocholic acid (7-KetoLCA) and negatively correlated with isolithocholic acid (isoLCA). TCDCA was positively correlated with THDCA, TUDCA, GUDCA, TLCA, TωMCA, and GHDCA, while GCDCA was positively correlated with TUDCA, GUDCA, TLCA, and GHDCA, and negatively correlated with isoLCA.</p><p><strong>CONCLUSION:</strong> The BA metabolites in UCB and meconium differ significantly, and the downstream BA metabolites in meconium are predominantly correlated with their upstream BAs in meconium, but not those BAs in UCB. These findings contribute to a better understanding of BA metabolism in utero and lay the foundation for future research in this topic.</p><p><br></p><p><strong>Umbilical cord blood analysis</strong> is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS10266' rel='noopener noreferrer' target='_blank'><strong>MTBLS10266</strong></a>.</p><p><strong>Meconium analysis</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS10267' rel='noopener noreferrer' target='_blank'><strong>MTBLS10267</strong></a>.</p>
2024-11-28 | MTBLS10266 | MetaboLights
Project description:<p><strong>OBJECTIVE:</strong> To characterize the bile acid (BA) metabolomic profile of umbilical cord blood (UCB) and meconium in healthy newborns.</p><p><strong>METHODS:</strong> Fifteen healthy newborns, which born in the Obstetrics Department of the Affiliated Hospital of Southwest Medical University between July 1 and August 31, 2023, were selected as study subjects. UCB and meconium samples were collected, and BA metabolomics were analyzed using ultra-high performance liquid chromatography-tandem mass spectrometry.</p><p><strong>RESULTS:</strong> UCB predominantly contained primary bile acids (PBAs), whereas meconium was rich in secondary bile acids (SBAs). The PBAs/SBAs ratio in UCB was significantly higher than in meconium [2.64 (2.49, 5.70) vs 0.99 (0.37, 1.58), P < 0.001]. Both UCB and meconium were primarily composed of conjugated BAs. However, the ratio of unconjugated to conjugated BAs was notably higher in UCB than in meconium [0.14 (0.07, 0.18) vs 0.01 (0.01, 0.04), P < 0.001]. In terms of individual metabolite, UCB was dominated by taurochenodeoxycholic acid (TCDCA), taurocholic acid (TCA), and glycochenodeoxycholic acid (GCDCA), while meconium was abundant in TCA, taurohyocholic acid, and TCDCA. Conjugated PBAs in UCB primarily originated from chenodeoxycholic acid (CDCA), whereas those in meconium were mainly derived from cholic acid (CA). The CA/CDCA ratio in conjugated PBAs was significantly lower in UCB than in meconium [0.59 (0.19, 0.75) vs 2.21 (1.34, 3.04), P < 0.001]. SBAs in both UCB and meconium were primarily derived from CDCA, but the CA/CDCA ratio was significantly higher in UCB than in meconium [0.42 (0.21, 0.63), vs 0.03 (0.01, 0.05), P < 0.001]. No PBAs in UCB correlated with their counterparts in meconium, and only three PBAs (TCDCA, GCDCA, and glycochenodeoxycholic acid 3-glucoside in UCB) were correlated with their downstream metabolites in meconium [with hyodesoxycholic acid (HDCA) (r = -0.66, P = 0.01), Tauro-ω-muricholic acid (TωMCA) (r = 0.52, P = 0.048) and ursodeoxycholic acid-7S (r = -0.53, P = 0.04), respectively]. In meconium, most of PBAs were correlated with their downstream metabolites (P all < 0.05): CA was positively correlated with 3-dehydrocholic acid (3-DHCA), TCA was positively correlated with TDCA and 3-DHCA, GCA was positively correlated with 3-DHCA, CDCA was positively correlated with GUDCA, taurolithocholic acid (TLCA), and 7-keto Lithocholic acid (7-KetoLCA) and negatively correlated with isolithocholic acid (isoLCA). TCDCA was positively correlated with THDCA, TUDCA, GUDCA, TLCA, TωMCA, and GHDCA, while GCDCA was positively correlated with TUDCA, GUDCA, TLCA, and GHDCA, and negatively correlated with isoLCA.</p><p><strong>CONCLUSION:</strong> The BA metabolites in UCB and meconium differ significantly, and the downstream BA metabolites in meconium are predominantly correlated with their upstream BAs in meconium, but not those BAs in UCB. These findings contribute to a better understanding of BA metabolism in utero and lay the foundation for future research in this topic.</p><p><br></p><p><strong>Meconium analysis</strong> is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS10267' rel='noopener noreferrer' target='_blank'><strong>MTBLS10267</strong></a>.</p><p><strong>Umbilical cord blood analysis</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS10266' rel='noopener noreferrer' target='_blank'><strong>MTBLS10266</strong></a>.</p>
2024-11-28 | MTBLS10267 | MetaboLights
Project description:Hepatocellular carcinoma (HCC) is a prototypical inflammation-associated cancer and the tumor microenvironment (TME) plays a pivotal role in HCC pathogenesis and response to therapy. The liver is a metabolically active organ, but how liver metabolism impacts TME during HCC development and response to immunotherapy are poorly understood. Here, we show that the metabolic regulator SIRT5 is downregulated in human primary HCC samples, and that Sirt5 deficiency in mice synergizes with oncogenes to increase bile acid (BA) production, which is due to hypersuccinylation and increased BA biosynthesis in the peroxisome. BA acts as a cell-signaling mediator to stimulate its nuclear receptor and promotes M2-like macrophage polarization, thereby creating an immunosuppressive microenvironment favorable for HCC initiating cells. Furthermore, high serum taurocholic acid, a major primary BA, correlates with low SIRT5 expression and increased M2-like tumor-associated macrophages (TAMs) in liver tissue samples from HCC patients. Importantly, administration of cholestyramine, a BA sequestrant and FDA-approved medication for hyperlipemia, reverses the effect of Sirt5 deficiency on promoting M2-like polarized TAMs and liver tumor growth. Our study thus uncovers a novel function of SIRT5 in orchestrating BA metabolism to prevent tumor immune evasion and suppress HCC. These results also suggest a potential strategy using clinically proven bile acid sequestrants for the treatment of HCC patients, especially those with decreased SIRT5 and abnormally high BAs.
2022-01-10 | GSE193213 | GEO
Project description:Cholestasis, a serious complication of liver metastasis (LM), contributes to dismal prognosis in patients with colorectal cancer and LM. However, the mechanism underlying the effect of cholestasis on the development of LM or pre-metastatic microenvironment in the liver remains elusive. In this study, we discovered that cholestasis accelerated the progression of LM and is associated with increased neutrophil infiltration, T-cell exclusion, and exhaustion. Besides, Tβ-MCA and GCA promoted the expression of Arg1 and iNOS in neutrophils via the p38/MAPK signaling pathway. The significant suppression of the activation and cytotoxic effects of CD8+ T cells during co-culture with BA-pretreated neutrophils indicated that BAs directly induce the polarization of immunosuppressive neutrophils. Importantly, targeting BA anabolism with Obeticholic acid effectively suppressed the LM of colorectal cancer in a cholestasis mouse model. Our findings suggest that cholestasis, associated with the failure to achieve drainage of primary BAs, accelerates the progression of LM by remodeling the tumor immune microenvironment. Moreover, targeting BA anabolism with OCA may represent a therapeutic strategy for cholestasis-associated LM of colorectal cancer.
2024-07-10 | GSE209836 | GEO
Project description:Cirrhosis is a late stage of fibrosis impairing liver function. Genetic animal models for cirrhosis are lacking, and molecular mechanisms remain unknown. We report the first murine genetic model recapitulating human cirrhosis induced by hepatocyte-specific elimination of MCRS1, a member of NSL and INO80 chromatin-modifier complexes. MCRS1 loss in hepatocytes modulates the expression of bile acid (BA) transporters, with a pronounced NTCP downregulation, concentrating BAs in liver sinusoids, thereby activating hepatic stellate cell (HSC) via FXR. Consistently, genetic FXR ablation in HSCs suppresses fibrotic marks in mice and in vitro cell culture. Mechanistically, deletion of a putative SANT domain from MCRS1 evicts HDAC1 from its H3 anchoring sites, increasing histone acetylation of BA transporter genes, modulating their expression and perturbing BA flow. Accordingly, human cirrhosis displays loss of nuclear MCRS1 and decreased NTCP expression. Thus, histone acetylation-mediated dysregulation of BA transporters, and consequently FXR activation by BAs in HSCs represent a central and universal signaling event in cirrhosis. The data is from single-nuclei RNA-seq of whole-liver collected during autopsy of 4 individuals with COVID-19 and PMI < 4.5 hours
2023-07-03 | GSE179548 | GEO
Project description:Cholestasis is characterized by hepatic accumulation of cytotoxic bile acids (BAs), which often subsequentlyleads to liver injury, inflammation, fibrosis, and ultimately liver cirrhosis. Fibroblast growth factor 21 (FGF21) is a liver secreted hormone with pleiotropic effects on the homeostasis of glucose, lipid, and energy metabolism. However, whether hepatic FGF21 plays a role in cholestatic liver injury remains elusive. We found that serum and hepatic FGF21 levels were significantly increased in response to cholestatic liver injury. Hepatocyte-specific deletion of Fgf21 exacerbated hepatic accumulation of BAs, further accentuating liver injury. Consistently, administration of rFGF21 ameliorated cholestatic liver injury in α-naphthylisothiocyanate (ANIT)-treated and Mdr2 deficiency mice. Mechanically, FGF21 activated a hepatic FGFR4-JNK signaling pathway to decrease Cyp7a1 expression, thereby reducing hepatic BAs pool. Our study demonstrates that hepatic FGF21 functions as an adaptive stress-responsive signal to downregulate BA biosynthesis, thereby ameliorating cholestatic liver injury, and FGF21 analogs may represent a candidate therapy for cholestatic liver diseases.
2023-08-19 | GSE240733 | GEO