Microbial Bile acid metabolite, 3-oxo-LCA, prohibits colorectal cancer progression
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ABSTRACT:
PROVIDER: PRJNA1248922 | ENA |
REPOSITORIES: ENA
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Project description:Objective: Bile acids (BAs) not only influence gut microbiome composition but are also metabolized by gut bacteria to form various microbial BAs. Among these, 3-oxo-lithocholic acid (-oxo-LCA) and isoalloLCA have been reported to modulate host immunity, suppress intestinal pathogens, and provide anti-aging benefits. However, their specific effects on intestinal epithelial cells (IECs) and their role in colorectal cancer (CRC) progression remain unclear. Design: To investigate the impact of 3-oxo-LCA on intestinal tumorigenesis, we examined its effects on the growth of mouse and human CRC cell lines (CT26, MC38, HCT116), as well as on primary mouse intestinal organoids and patient-derived CRC organoids (PDCOs). Additionally, we evaluated its role in vivo using APCMin/+ mice and multiple CRC models, including syngeneic CT26 and MC38 models, as well as HCT116 and PDX-derived xenografts in NSG (immunodeficient) mice. Results: Our findings show that 3-oxo-LCA is a potent FXR agonist that restores FXR signaling both in vitro and in vivo. This results in reduced growth of CRC cell lines and suppression of intestinal stem cell (ISC)’s proliferation in both mouse organoids and PDCOs. In APCMin/+ mice, 3-oxo-LCA reduced BA levels, enhanced gut barrier function, decreased tumor burden, and blocked tumor initiation. Furthermore, it significantly inhibited tumor progression in syngeneic and xenograft mouse models and promoted apoptosis within the tumors, enhancing cancer cell death. Conclusion: These results underscore the therapeutic potential of 3-oxo-LCA as a novel FXR agonist for CRC treatment, with its ability to inhibit tumorigenesis and progression by modulating epithelial cell proliferation and inducing apoptosis.
2025-08-14 | GSE294276 | GEO
Project description:Bariatric surgical procedures such as sleeve gastrectomy (SG) provide effective type 2 diabetes remission in human patients. Previous work demonstrated that gastrointestinal levels of the bacterial metabolite lithocholic acid (LCA) are decreased after SG in mice and humans. Here, we show that LCA worsens glucose tolerance and impairs whole body metabolism. We also show that taurodeoxycholic acid (TDCA), which was the only bile acid whose concentration was increased in the murine small intestine post-SG, suppresses the bacterial bile acid-inducible (bai) operon and production of LCA both in vitro and in vivo. Treatment of diet-induced obese (DIO) mice with TDCA reduces LCA levels and leads to microbiome-dependent improvements in host glucose handling. Moreover, TDCA abundance is decreased in small intestinal tissue from T2D patients. This work has revealed that TDCA is an endogenous inhibitor of LCA production and suggests that TDCA may contribute to the glucoregulatory effects of bariatric surgery.
2024-07-21 | GSE262065 | GEO
Project description:Bacteria that colonize the human gut must withstand a variety of stressors, including detergent-like compounds known as bile acids. Here, we investigated how bile acids found in the human cecum and colon impact the behavior of the probiotic strain Escherichia coli Nissle 1917 (EcN). We found that lithocholic acid (LCA), which is a microbiota-derived secondary bile acid, promotes the formation of a distinctive surface-coating biofilm by EcN, including on an organoid-derived model of the human colonic epithelium. Mechanistic investigations, including RNA-sequencing, revealed that LCA upregulates the production of several components of flagella, which are essential for LCA-induced biofilm formation and form part of the biofilm extracellular matrix.
2025-05-26 | GSE297446 | GEO
Project description:Clostridioides difficile is a Gram-positive anaerobic bacterium that is the leading cause of hospital-acquired gastroenteritis in the US. In the gut milieu, C. difficile encounters microbiota-derived bile acids capable of inhibiting its growth, which are thought to be a mechanism of colonization resistance. While the levels of certain bile acids in the gut correlate with susceptibility to C. difficile infection, their molecular targets in C. difficile remain unknown. In this study, we sought to use chemical proteomics to identify bile acid-interacting proteins in C. difficile. Using photoaffinity bile acid probes and chemical proteomics, we identified a previously uncharacterized MerR family protein, CD3583 (now BapR), as a putative bile acid-sensing transcription regulator. Our data indicate that BapR binds and is stabilized by lithocholic acid (LCA) in C. difficile. Although loss of BapR did not affect C. difficile's sensitivity to LCA, bapR mutant cells elongated more in the presence of LCA than wild-type cells. Transcriptomics revealed that BapR regulates the expression of the gene clusters mdeA-cd3573 and cd0618-cd0616, and cwpV, with the expression of the mdeA-cd3573 locus being specifically de-repressed in the presence of LCA in a BapR-dependent manner. Electrophoretic mobility shift assays revealed that BapR directly binds to the mdeA promoter region. Since mdeA is involved in amino acid-related sulfur metabolism and the mdeA-cd3573 locus encodes putative transporters, we propose that BapR senses a gastrointestinal tract-specific small molecule, LCA, as an environmental cue for metabolic adaptation.
2022-06-03 | GSE205226 | GEO
Project description:TGR5 (Gpbar1) is a G protein-coupled receptor responsive to bile acids (BAs), which is expressed in different non-parenchymal cells of the liver, including biliary epithelial cells, liver-resident macrophages, sinusoidal endothelial cells (LSECs) and activated hepatic stellate cells (HSCs). Mice with targeted deletion of TGR5 are more susceptible towards cholestatic liver injury induced by cholic acid-feeding and bile duct ligation, resulting in a reduced proliferative response and increased liver injury. Conjugated lithocholic acid (LCA) represents the most potent TGR5 BA ligand and LCA-feeding has been used as a model to rapidly induce severe cholestatic liver injury in mice. Thus, TGR5 knockout (KO) mice and wildtype littermates were fed a diet supplemented with 1%LCA for 84 hours. Liver injury and gene expression changes induced by the LCA-diet revealed an enrichment of pathways associated with inflammation, proliferation and matrix remodelling. Knockout of TGR5 in mice caused upregulation of endothelin-1 (ET-1) expression in the livers. Analysis of TGR5-dependent ET-1 signalling in isolated LSECs and HSCs demonstrated that TGR5 activation reduces ET-1 expression and secretion from LSECs and triggers internalization of the ET-1 receptor in HSCs dampening ET-1 responsiveness. Thus, we identified two independent mechanisms by which TGR5 inhibits ET-1 signalling and modulates portal pressure.
2019-11-19 | GSE139075 | GEO
Project description:The microbiota generates structurally diverse small molecules that can regulate host physiology and disease. Of these microbiota metabolites, bile acids have emerged as important modulators of host immunity and microbial pathogenesis. While the modes of action for different bile acids on host pathways are becoming more apparent, the mechanisms by which these prominent microbiota metabolites suppress microbial virulence pathways are less clear. To identify the direct protein targets of bile acids in Salmonella, we have generated three photoaffinity bile acid reporters (alk-X-CDCA, alk-X-UDCA, alk-X-LCA) and performed chemical proteomics. Using a combination of photocrosslinking with bile acid chemical reporters and label-free proteomics, we performed a quantitative analysis of bile acid interacting proteins in Salmonella with or without UV-mediated photocrosslinking. These studies revealed bile acid can interact with many Salmonella proteins, such as extracellular or secreted proteins, T3SS components and motility-related proteins, as predicted by Gene Ontology analysis. In addition, cytoplasmic and membrane proteins including metabolic enzymes are also identified. Notably, HilD, an important transcriptional regulator of S. Typhimurium virulence was also identified by the alk-X-CDCA reporter. This study highlights the utility of chemical proteomics to identify the direct protein targets and mechanisms of action for microbiota metabolites in bacterial pathogens.
2022-09-29 | PXD034373 | Pride
Project description:Primary bile acids are produced in the liver whereas secondary bile acids such as lithocholic acid (LCA) are generated by gut bacteria from primary bile acids that escape the ileal absorption. Besides their well-known function as detergents in lipid digestion, bile acids are important signaling molecules mediating effects on the host’s metabolism. As energy metabolism is closely linked to aging and longevity we supplemented fruit flies (Drosophila melanogaster) with 50 µmol/l LCA either for 30 days or throughout their lifetime. LCA supplementation resulted in a significant induction of the mean (+12 days), median (+10 days) and maximum lifespan (+ 11 days) in comparison to untreated control flies. This lifespan extension was accompanied by an induction of spargel (srl), the fly homolog of mammalian PPARG co-activator 1a(PGC1A. In srl mutant flies, LCA failed to induce longevity emphasizing the essential role of srl in the observed lifespan extension. In addition, the administration of antibiotics to wild type flies abrogated LCA-mediated effects on both lifespan and srl expression, suggesting a substantial contribution of the intestinal microbiota to the LCA-induced longevity. In the present study, we show that the secondary bile acid LCA significantly induced the mean, the median and the maximum survival in Drosophila melanogaster. Our data suggest that besides an up-regulation of the PGC1a-homolog srl unidentified alterations in the structure or metabolism of gut microbiota contribute to the longevity effect of LCA.
2018-08-03 | GSE110367 | GEO
Project description:The gut microbiome can impact brain health and is altered in Parkinson’s disease (PD) patients. The vermiform appendix is a lymphoid tissue implicated in the storage and regulation of the gut microbiome. Here, we investigate changes in the functional microbiome in the appendix of PD patients relative to controls by metatranscriptomic analysis. In the PD appendix, we find microbial dysbiosis affecting lipid metabolism, particularly an upregulation of bacteria responsible for secondary bile acid synthesis. Likewise, proteomic and transcript analysis in the PD gut corroborates a disruption in cholesterol homeostasis and lipid catabolism. Bile acid analysis in the PD appendix reveals an increase in the microbially-derived, toxic secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA). Synucleinopathy in mice induces similar microbiome alterations to those of PD patients and heightens microbial changes to gut inflammation. As observed in PD, the mouse model of synucleinopathy has elevated DCA and LCA. Raised levels of DCA and LCA can lead to liver injury, and an analysis of blood markers of liver dysfunction shows evidence of biliary abnormalities in PD patients, including elevated alkaline phosphatase and bilirubin. Increased bilirubin levels are also evident before PD diagnosis, in individuals at-risk of developing PD. In sum, microbially-derived toxic bile acids are heightened in PD and biliary changes may even precede the onset of overt motor symptoms.
2021-01-28 | PXD020988 | Pride
Project description:The gut microbiome can impact brain health and is altered in Parkinson’s disease (PD) patients. The vermiform appendix is a lymphoid tissue implicated in the storage and regulation of the gut microbiome. Here, we investigate changes in the functional microbiome in the appendix of PD patients relative to controls by metatranscriptomic analysis. In the PD appendix, we find microbial dysbiosis affecting lipid metabolism, particularly an upregulation of bacteria responsible for secondary bile acid synthesis. Likewise, proteomic and transcript analysis in the PD gut corroborates a disruption in cholesterol homeostasis and lipid catabolism. Bile acid analysis in the PD appendix reveals an increase in the microbially-derived, toxic secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA). Synucleinopathy in mice induces similar microbiome alterations to those of PD patients and heightens microbial changes to gut inflammation. As observed in PD, the mouse model of synucleinopathy has elevated DCA and LCA. Raised levels of DCA and LCA can lead to liver injury, and an analysis of blood markers of liver dysfunction shows evidence of biliary abnormalities in PD patients, including elevated alkaline phosphatase and bilirubin. Increased bilirubin levels are also evident before PD diagnosis, in individuals at-risk of developing PD. In sum, microbially-derived toxic bile acids are heightened in PD and biliary changes may even precede the onset of overt motor symptoms.
2021-08-01 | GSE156647 | GEO