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Richtsmeier P, Nedielkov R, Haring M, Yücel O, Elsner L, Lülf RH, Wöhlbrand L, Rabus R, Moeller H, Philipp B, Mueller FM. 7β-Hydroxysteroid dehydratase Hsh3 eliminates the 7-hydroxy group of the bile salt ursodeoxycholate during degradation by Sphingobium sp. strain Chol11 and other Sphingomonadaceae. Appl Environ Microbiol 2025:e0018525. [PMID: 40340444 DOI: 10.1128/aem.00185-25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Accepted: 04/11/2025] [Indexed: 05/10/2025] Open
Abstract
Bile salts are steroids with distinctive hydroxylation patterns that are produced and excreted by vertebrates. In contrast to common human bile salts, ursodeoxycholate (UDCA) has a 7-hydroxy group in β-configuration and is used in large amounts for the treatment of diverse gastrointestinal diseases. We isolated the 7β-hydroxysteroid dehydratase Hsh3 that is involved in UDCA degradation by Sphingobium sp. strain Chol11. Hsh3 eliminates the 7β-hydroxy group as water, leading to a double bond in the B-ring. This is similar to 7α-hydroxysteroid dehydratases in this and other strains, but Hsh3 is evolutionarily different from these. Purified Hsh3 accepted steroids with and without side chains as substrates and had minor activity with 7α-hydroxy groups. The deletion mutant strain Chol11 Δhsh3 had impacted growth with UDCA and accumulated a novel compound. The compound was identified as 3',5-dihydroxy-H-methyl-hexahydro-5-indene-1-one-propanoate, consisting of steroid rings C and D with a C3-side chain carrying the former 7β-hydroxy group, indicating that Hsh3 activity is important especially for the later stages of bile salt degradation. Hsh3 homologs were found in other sphingomonads that were also able to degrade UDCA as well as in environmental metagenomes. Thus, Hsh3 adds to the bacterial enzyme repertoire for degrading a variety of differently hydroxylated bile salts.IMPORTANCEThe bacterial degradation of different bile salts is not only important for the removal of these steroidal compounds from the environment but also harbors interesting enzymes for steroid biotechnology. The 7β-hydroxy bile salt ursodeoxycholate (UDCA) naturally occurs in high concentration in the feces of black bears and has important pharmaceutical relevance for the treatment of different liver-related diseases, for which it is administered in high and increasing amounts. Additionally, it is present in the bile salt pool of humans in trace amounts. While UDCA degradation is environmentally important, the enzyme Hsh3 modifies the hydroxy group that confers the medically relevant properties and thus might be interesting for microbiome analyses and biotechnological applications.
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Affiliation(s)
- Phil Richtsmeier
- Microbial Biotechnology and Ecology, Institute for Molecular Microbiology and Biotechnology, University of Münster, Münster, Germany
| | - Ruslan Nedielkov
- Institute for Chemistry, University of Potsdam, Potsdam, Germany
| | - Malte Haring
- Microbial Biotechnology and Ecology, Institute for Molecular Microbiology and Biotechnology, University of Münster, Münster, Germany
| | - Onur Yücel
- Microbial Biotechnology and Ecology, Institute for Molecular Microbiology and Biotechnology, University of Münster, Münster, Germany
| | - Lea Elsner
- Microbial Biotechnology and Ecology, Institute for Molecular Microbiology and Biotechnology, University of Münster, Münster, Germany
| | - Rebekka Herdis Lülf
- Microbial Biotechnology and Ecology, Institute for Molecular Microbiology and Biotechnology, University of Münster, Münster, Germany
| | - Lars Wöhlbrand
- General and Molecular Microbiology, Institute for Chemistry and Biology of the Marine Environment (ICBM), Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany
| | - Ralf Rabus
- General and Molecular Microbiology, Institute for Chemistry and Biology of the Marine Environment (ICBM), Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany
| | - Heiko Moeller
- Institute for Chemistry, University of Potsdam, Potsdam, Germany
| | - Bodo Philipp
- Microbial Biotechnology and Ecology, Institute for Molecular Microbiology and Biotechnology, University of Münster, Münster, Germany
- Applied Ecology and Bioresources, Fraunhofer-Institute for Molecular and Applied Ecology IME, Schmallenberg, Germany
| | - Franziska Maria Mueller
- Microbial Biotechnology and Ecology, Institute for Molecular Microbiology and Biotechnology, University of Münster, Münster, Germany
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Ionescu VA, Diaconu CC, Gheorghe G, Mihai MM, Diaconu CC, Bostan M, Bleotu C. Gut Microbiota and Colorectal Cancer: A Balance Between Risk and Protection. Int J Mol Sci 2025; 26:3733. [PMID: 40332367 PMCID: PMC12028331 DOI: 10.3390/ijms26083733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Revised: 04/11/2025] [Accepted: 04/14/2025] [Indexed: 05/08/2025] Open
Abstract
The gut microbiome, a complex community of microorganisms residing in the intestinal tract, plays a dual role in colorectal cancer (CRC) development, acting both as a contributing risk factor and as a protective element. This review explores the mechanisms by which gut microbiota contribute to CRC, emphasizing inflammation, oxidative stress, immune evasion, and the production of genotoxins and microbial metabolites. Fusobacterium nucleatum, Escherichia coli (pks+), and Bacteroides fragilis promote tumorigenesis by inducing chronic inflammation, generating reactive oxygen species, and producing virulence factors that damage host DNA. These microorganisms can also evade the antitumor immune response by suppressing cytotoxic T cell activity and increasing regulatory T cell populations. Additionally, microbial-derived metabolites such as secondary bile acids and trimethylamine-N-oxide (TMAO) have been linked to carcinogenic processes. Conversely, protective microbiota, including Lactobacillus, Bifidobacterium, and Faecalibacterium prausnitzii, contribute to intestinal homeostasis by producing short-chain fatty acids (SCFAs) like butyrate, which exhibit anti-inflammatory and anti-carcinogenic properties. These beneficial microbes enhance gut barrier integrity, modulate immune responses, and inhibit tumor cell proliferation. Understanding the dynamic interplay between pathogenic and protective microbiota is essential for developing microbiome-based interventions, such as probiotics, prebiotics, and fecal microbiota transplantation, to prevent or treat CRC. Future research should focus on identifying microbial biomarkers for early CRC detection and exploring personalized microbiome-targeted therapies. A deeper understanding of host-microbiota interactions may lead to innovative strategies for CRC management and improved patient outcomes.
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Affiliation(s)
- Vlad Alexandru Ionescu
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania; (V.A.I.); (G.G.); (M.-M.M.)
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Camelia Cristina Diaconu
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania; (V.A.I.); (G.G.); (M.-M.M.)
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
- Academy of Romanian Scientists, 050085 Bucharest, Romania;
| | - Gina Gheorghe
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania; (V.A.I.); (G.G.); (M.-M.M.)
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Mara-Madalina Mihai
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania; (V.A.I.); (G.G.); (M.-M.M.)
- Department of Oncologic Dermathology, “Elias” University Emergency Hospital, 010024 Bucharest, Romania
| | - Carmen Cristina Diaconu
- Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (C.C.D.); (M.B.)
| | - Marinela Bostan
- Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (C.C.D.); (M.B.)
- Department of Immunology, “Victor Babes” National Institute of Pathology, 050096 Bucharest, Romania
| | - Coralia Bleotu
- Academy of Romanian Scientists, 050085 Bucharest, Romania;
- Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (C.C.D.); (M.B.)
- Research Institute of the University of Bucharest (ICUB), University of Bucharest, 060023 Bucharest, Romania
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3
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Zeng H, Safratowich BD, Cheng WH, Briske-Anderson M. Ursodeoxycholic Acid Exhibits Greater Inhibitory Effects on Cancerous HCT116 Colon Cells than on Noncancerous NCM460 Colon Cells. Nutrients 2025; 17:1072. [PMID: 40292524 PMCID: PMC11944451 DOI: 10.3390/nu17061072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Revised: 03/12/2025] [Accepted: 03/16/2025] [Indexed: 04/30/2025] Open
Abstract
Background/Objectives: Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, exhibits anti-inflammatory effects and attenuates the process of colon carcinogenesis. Certain healthy diets increase colonic UDCA concentrations, but its anticancer mechanistic actions remain largely unknown. We hypothesize that UDCA preferentially inhibits cancerous colon cell proliferation with a minimal effect on noncancerous colon cells. Methods: With human noncancerous NCM460 colon cell and cancerous HCT116 colon cell culture models, we performed biochemical, western blotting, PCR array, cell cycle, apoptosis, and immunofluorescent assays to determine the effects of UDCA treatment on colon cell proliferation and the underlying molecular mechanisms. Results: The inhibitory potential of UDCA against cell proliferation (via cell cycle arrest and apoptosis) was 90% greater in cancerous HCT116 cells than noncancerous NCM460 cells when treated with UDCA (0 to 0.4 mM) for 48 h. In UDCA-treated HCT116 cells, we identified 18 genes with ≥80% change (compared to untreated cells) in mRNA levels out of 93 apoptotic genes which were involved in caspase, death receptor, and NFκB pathways. At the molecular level, 0.4 mM UDCA reduced the protein level of the proto-oncogenic c-Myc gene but increased the putative tumor suppressor p21 gene (≥100%) via the ERK1/2/c-Myc/p21 pathway, which regulates cell cycle and apoptosis. These data are consistent with lower c-Myc but higher p21 expression in normal colon tissues compared to cancerous colon tissues. Conclusions: Collectively, UDCA inhibits cancerous HCT116 colon cells to a higher degree than in noncancerous NCM460 colon cells through cell cycle and apoptosis involving ERK1/2/c-Myc/p21 signaling.
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Affiliation(s)
- Huawei Zeng
- USDA-ARS Grand Forks Human Nutrition Research Center, Grand Forks, ND 58203, USA; (B.D.S.); (M.B.-A.)
| | - Bryan D. Safratowich
- USDA-ARS Grand Forks Human Nutrition Research Center, Grand Forks, ND 58203, USA; (B.D.S.); (M.B.-A.)
| | - Wen-Hsing Cheng
- Department of Nutrition and Food Sciences, Texas Woman’s University, Denton, TX 76209, USA;
| | - Mary Briske-Anderson
- USDA-ARS Grand Forks Human Nutrition Research Center, Grand Forks, ND 58203, USA; (B.D.S.); (M.B.-A.)
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Kovács P, Schwarcz S, Nyerges P, Bíró TI, Ujlaki G, Bai P, Mikó E. Anticarcinogenic effects of ursodeoxycholic acid in pancreatic adenocarcinoma cell models. Front Cell Dev Biol 2024; 12:1487685. [PMID: 39723238 PMCID: PMC11668698 DOI: 10.3389/fcell.2024.1487685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 11/25/2024] [Indexed: 12/28/2024] Open
Abstract
Changes to the composition of the microbiome in neoplasia, is termed oncobiosis, may affect tumor behavior through the changes to the secretion of bacterial metabolites. In this study we show, that ursodeoxycholic acid (UDCA), a bacterial metabolite, has cytostatic properties in pancreatic adenocarcinoma cell (PDAC) models. UDCA in concentrations corresponding to the human serum reference range suppressed PDAC cell proliferation. UDCA inhibited the expression of epithelial mesenchymal transition (EMT)-related markers and invasion capacity of PDAC cells. UDCA treatment increased oxidative/nitrosative stress by reducing the expression of nuclear factor, erythroid 2-like 2 (NRF2), inducing inducible nitric oxide synthase (iNOS) and nitrotyrosine levels and enhancing lipid peroxidation. Furthermore, UDCA reduced the expression of cancer stem cell markers and the proportion of cancer stem cells. Suppression of oxidative stress by antioxidants, blunted the UDCA-induced reduction in cancer stemness. Finally, we showed that UDCA induced mitochondrial oxidative metabolism. UDCA did not modulate the effectiveness of chemotherapy agents used in the chemotherapy treatment of pancreatic adenocarcinoma. The antineoplastic effects of UDCA, observed here, may contribute to the induction of cytostasis in PDAC cell models by providing a more oxidative/nitrosative environment.
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Affiliation(s)
- Patrik Kovács
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Szandra Schwarcz
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Petra Nyerges
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Tímea Ingrid Bíró
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Gyula Ujlaki
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Péter Bai
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- MTA-DE Lendület Laboratory of Cellular Metabolism, University of Debrecen, Debrecen, Hungary
- HUN-REN-UD Cell Biology and Signaling Research Group, Debrecen, Hungary
- Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Edit Mikó
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- MTA-DE Lendület Laboratory of Cellular Metabolism, University of Debrecen, Debrecen, Hungary
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5
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Li Y, Zhao H, Shen Z, Zheng Y, Jiang Y, Song Y, Cai Y. Enhancing DOX efficacy against NSCLC through UDCA-mediated modulation of the TGF-β/MAPK autophagy pathways. Sci Rep 2024; 14:27169. [PMID: 39511265 PMCID: PMC11544154 DOI: 10.1038/s41598-024-73736-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 09/20/2024] [Indexed: 11/15/2024] Open
Abstract
Lung carcinoma, predominantly manifested as non-small cell lung cancer (NSCLC), significantly contributes to oncological mortality, underscoring an imperative for novel therapeutic paradigms. Amidst this context, the present investigation delineates the synergistic potentiation of doxorubicin (DOX)-a canonical chemotherapeutic-by Ursodeoxycholic acid (UDCA), a compound with a historical pedigree in hepatobiliary medicine, now repositioned within oncological pharmacotherapy due to its dichotomous cellular modulation-affording cytoprotection to non-malignant epithelia whilst eliciting apoptotic cascades in neoplastic counterparts. This study, through a rigorous methodological framework, elucidates UDCA's capacity to inhibit NSCLC cellular proliferation and induce apoptosis, thereby significantly amplifying DOX's chemotherapeutic efficacy. Notably, the co-administration of UDCA and DOX was observed to attenuate DOX-induced autophagy via the modulation of the TGF-β/MAPK signaling axis, a pathway pivotal in mediating cellular survival and autophagic mechanisms. Such findings not only underscore the therapeutic potential of UDCA as a chemosensitizer but also illuminate the molecular underpinnings of its modulatory effects, thereby contributing to the corpus of knowledge necessary to surmount chemoresistance in NSCLC. The implications of this research are twofold: firstly, it offers a compelling evidence base for the clinical reevaluation of UDCA in combinatory chemotherapeutic regimens; secondly, it posits a novel mechanistic insight into the modulation of chemotherapeutic efficacy and resistance. Collectively, these insights advocate for the expedited clinical translation of UDCA-DOX synergy, potentially heralding a paradigm shift in the management of NSCLC, thereby addressing a critical lacuna in contemporary oncological therapy.
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Affiliation(s)
- Ying Li
- Department of Nursing, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, 410005, China
- Department of Respiratory Medicine, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, 410005, China
| | - Helian Zhao
- Department of Nursing, School of Medicine, Hunan Normal University, Changsha, 410013, China
| | - Zhoumin Shen
- Department of Nursing, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, 410005, China
| | - Yao Zheng
- Department of Respiratory Medicine, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, 410005, China
| | - Yuanyuan Jiang
- Department of Nursing, School of Medicine, Hunan Normal University, Changsha, 410013, China
| | - Ying Song
- Department of Respiratory Medicine, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, 410005, China.
| | - Yimin Cai
- Department of Nursing, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, 410005, China.
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6
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Fathima A, Jamma T. UDCA ameliorates inflammation driven EMT by inducing TGR5 dependent SOCS1 expression in mouse macrophages. Sci Rep 2024; 14:24285. [PMID: 39414916 PMCID: PMC11484976 DOI: 10.1038/s41598-024-75516-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 10/07/2024] [Indexed: 10/18/2024] Open
Abstract
Long-standing chronic inflammation of the digestive tract leads to Inflammatory Bowel Diseases (IBD), comprising Crohn's Disease (CD) and Ulcerative colitis (UC). The persistent prevalence of these conditions in the gut is a predisposing factor for Colitis-Associated Cancer (CAC), one of the most common sub-types of Colorectal Cancer (CRC), emphasizing the role of inflammation in tumorigenesis. Therefore, targeted intervention of chronic intestinal inflammation is a potential strategy for preclusion and treatment of inflammation-driven malignancies. The association between bile acids (BA) and gut immune homeostasis has been explored in the recent past. However, the exact downstream mechanism by which secondary BA successfully regulating intestinal inflammation and inflammation-dependent CAC is unclear. Our study demonstrated that Ursodeoxycholic acid (UDCA), a secondary bile acid of host gut microbial origin, finetunes the dialogue between activated macrophages and intestinal epithelial cells, modulating inflammation-driven epithelial-mesenchymal transition (EMT), a hallmark of cancer. UDCA treatment and dependency on the TGR5/GPBAR1 receptor significantly upregulated the Suppressor of Cytokine Signaling 1 (SOCS1) expression, contributing to the regulation of pro-inflammatory cytokines in activated macrophages. In this study, we also noticed heightened expression of SOCS1 in UDCA-mitigated CAC in the AOM-DSS mouse model with reduced inflammatory gene expression. Overall, our observations highlight the possible utility of UDCA for inflammation-driven intestinal cancer.
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Affiliation(s)
- Ashna Fathima
- Cell Signaling Laboratory, Department of Biological Sciences, Birla Institute of Technology, and Science-Pilani Hyderabad Campus, Jawahar Nagar, Shameerpet Mandal, Hyderabad, 500078, Telangana , India
| | - Trinath Jamma
- Cell Signaling Laboratory, Department of Biological Sciences, Birla Institute of Technology, and Science-Pilani Hyderabad Campus, Jawahar Nagar, Shameerpet Mandal, Hyderabad, 500078, Telangana , India.
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Li X, Lu C, Mao X, Fan J, Yao J, Jiang J, Wu L, Ren J, Shen J. Bibliometric analysis of research on gut microbiota and bile acids: publication trends and research frontiers. Front Microbiol 2024; 15:1433910. [PMID: 39234549 PMCID: PMC11371755 DOI: 10.3389/fmicb.2024.1433910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 08/07/2024] [Indexed: 09/06/2024] Open
Abstract
The gut microbiota is widely regarded as a "metabolic organ" that could generate myriad metabolites to regulate human metabolism. As the microbiota metabolites, bile acids (BAs) have recently been identified as the critical endocrine molecules that mediate the cross-talk between the host and intestinal microbiota. This study provided a comprehensive insight into the gut microbiota and BA research through bibliometric analysis from 2003 to 2022. The publications on this subject showed a dramatic upward trend. Although the USA and China have produced the most publications, the USA plays a dominant role in this expanding field. Specifically, the University of Copenhagen was the most productive institution. Key research hotspots are the gut-liver axis, short-chain fatty acids (SCFAs), cardiovascular disease (CVD), colorectal cancer (CRC), and the farnesoid x receptor (FXR). The molecular mechanisms and potential applications of the gut microbiota and BAs in cardiometabolic disorders and gastrointestinal cancers have significant potential for further research.
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Affiliation(s)
- Xin Li
- Department of General Medicine and Geriatrics, Linping Campus, The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Department of General Practice, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Can Lu
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xue Mao
- Department of General Medicine and Geriatrics, Linping Campus, The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jiahong Fan
- Department of General Medicine and Geriatrics, Linping Campus, The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jianting Yao
- Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Jingjie Jiang
- Department of General Medicine and Geriatrics, Linping Campus, The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Lele Wu
- Department of General Medicine and Geriatrics, Linping Campus, The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jingjing Ren
- Department of General Practice, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jun Shen
- Department of General Medicine and Geriatrics, Linping Campus, The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
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Hamamah S, Lobiuc A, Covasa M. Antioxidant Role of Probiotics in Inflammation-Induced Colorectal Cancer. Int J Mol Sci 2024; 25:9026. [PMID: 39201713 PMCID: PMC11354872 DOI: 10.3390/ijms25169026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 08/15/2024] [Accepted: 08/16/2024] [Indexed: 09/03/2024] Open
Abstract
Colorectal cancer (CRC) continues to be a significant contributor to global morbidity and mortality. Emerging evidence indicates that disturbances in gut microbial composition, the formation of reactive oxygen species (ROS), and the resulting inflammation can lead to DNA damage, driving the pathogenesis and progression of CRC. Notably, bacterial metabolites can either protect against or contribute to oxidative stress by modulating the activity of antioxidant enzymes and influencing signaling pathways that govern ROS-induced inflammation. Additionally, microbiota byproducts, when supplemented through probiotics, can affect tumor microenvironments to enhance treatment efficacy and selectively mediate the ROS-induced destruction of CRC cells. This review aims to discuss the mechanisms by which taxonomical shifts in gut microbiota and related metabolites such as short-chain fatty acids, secondary bile acids, and trimethylamine-N-oxide influence ROS concentrations to safeguard or promote the onset of inflammation-mediated CRC. Additionally, we focus on the role of probiotic species in modulating ROS-mediated signaling pathways that influence both oxidative status and inflammation, such as Nrf2-Keap1, NF-κB, and NLRP3 to mitigate carcinogenesis. Overall, a deeper understanding of the role of gut microbiota on oxidative stress may aid in delaying or preventing the onset of CRC and offer new avenues for adjunct, CRC-specific therapeutic interventions such as cancer immunotherapy.
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Affiliation(s)
- Sevag Hamamah
- Department of Basic Medical Sciences, College of Osteopathic Medicine, Western University of Health Sciences, Pomona, CA 91766, USA;
- Department of Internal Medicine, Scripps Mercy Hospital, San Diego, CA 92103, USA
| | - Andrei Lobiuc
- Department of Medicine and Biomedical Sciences, College of Medicine and Biological Science, University of Suceava, 7200229 Suceava, Romania;
| | - Mihai Covasa
- Department of Basic Medical Sciences, College of Osteopathic Medicine, Western University of Health Sciences, Pomona, CA 91766, USA;
- Department of Medicine and Biomedical Sciences, College of Medicine and Biological Science, University of Suceava, 7200229 Suceava, Romania;
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9
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Li W, Chen H, Tang J. Interplay between Bile Acids and Intestinal Microbiota: Regulatory Mechanisms and Therapeutic Potential for Infections. Pathogens 2024; 13:702. [PMID: 39204302 PMCID: PMC11356816 DOI: 10.3390/pathogens13080702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/30/2024] [Accepted: 08/14/2024] [Indexed: 09/04/2024] Open
Abstract
Bile acids (BAs) play a crucial role in the human body's defense against infections caused by bacteria, fungi, and viruses. BAs counteract infections not only through interactions with intestinal bacteria exhibiting bile salt hydrolase (BSH) activity but they also directly combat infections. Building upon our research group's previous discoveries highlighting the role of BAs in combating infections, we have initiated an in-depth investigation into the interactions between BAs and intestinal microbiota. Leveraging the existing literature, we offer a comprehensive analysis of the relationships between BAs and 16 key microbiota. This investigation encompasses bacteria (e.g., Clostridioides difficile (C. difficile), Staphylococcus aureus (S. aureus), Escherichia coli, Enterococcus, Pseudomonas aeruginosa, Mycobacterium tuberculosis (M. tuberculosis), Bacteroides, Clostridium scindens (C. scindens), Streptococcus thermophilus, Clostridium butyricum (C. butyricum), and lactic acid bacteria), fungi (e.g., Candida albicans (C. albicans) and Saccharomyces boulardii), and viruses (e.g., coronavirus SARS-CoV-2, influenza virus, and norovirus). Our research found that Bacteroides, C. scindens, Streptococcus thermophilus, Saccharomyces boulardii, C. butyricum, and lactic acid bacteria can regulate the metabolism and function of BSHs and 7α-dehydroxylase. BSHs and 7α-dehydroxylase play crucial roles in the conversion of primary bile acid (PBA) to secondary bile acid (SBA). It is important to note that PBAs generally promote infections, while SBAs often exhibit distinct anti-infection roles. In the antimicrobial action of BAs, SBAs demonstrate antagonistic properties against a wide range of microbiota, with the exception of norovirus. Given the intricate interplay between BAs and intestinal microbiota, and their regulatory effects on infections, we assert that BAs hold significant potential as a novel approach for preventing and treating microbial infections.
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Affiliation(s)
| | - Hui Chen
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People’s Hospital, Fudan University, 128 Ruili Road, Shanghai 200240, China;
| | - Jianguo Tang
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People’s Hospital, Fudan University, 128 Ruili Road, Shanghai 200240, China;
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10
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Di Giorgio C, Morretta E, Lupia A, Bellini R, Massa C, Urbani G, Bordoni M, Marchianò S, Lachi G, Rapacciuolo P, Finamore C, Sepe V, Chiara Monti M, Moraca F, Natalizi N, Graziosi L, Distrutti E, Biagioli M, Catalanotti B, Donini A, Zampella A, Fiorucci S. Bile acids serve as endogenous antagonists of the Leukemia inhibitory factor (LIF) receptor in oncogenesis. Biochem Pharmacol 2024; 223:116134. [PMID: 38494064 DOI: 10.1016/j.bcp.2024.116134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 03/11/2024] [Accepted: 03/14/2024] [Indexed: 03/19/2024]
Abstract
The leukemia inhibitory factor (LIF) is member of interleukin (IL)-6 family of cytokines involved immune regulation, morphogenesis and oncogenesis. In cancer tissues, LIF binds a heterodimeric receptor (LIFR), formed by a LIFRβ subunit and glycoprotein(gp)130, promoting epithelial mesenchymal transition and cell growth. Bile acids are cholesterol metabolites generated at the interface of host metabolism and the intestinal microbiota. Here we demonstrated that bile acids serve as endogenous antagonist to LIFR in oncogenesis. The tissue characterization of bile acids content in non-cancer and cancer biopsy pairs from gastric adenocarcinomas (GC) demonstrated that bile acids accumulate within cancer tissues, with glyco-deoxycholic acid (GDCA) functioning as negative regulator of LIFR expression. In patient-derived organoids (hPDOs) from GC patients, GDCA reverses LIF-induced stemness and proliferation. In summary, we have identified the secondary bile acids as the first endogenous antagonist to LIFR supporting a development of bile acid-based therapies in LIF-mediated oncogenesis.
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Affiliation(s)
| | - Elva Morretta
- University of Salerno, Department of Pharmacy, Salerno, Italy
| | - Antonio Lupia
- University of Cagliari, Department of Life and Environmental Sciences, Cagliari, Italy; Net4Science srl, University "Magna Græcia", Campus Salvatore Venuta, Viale Europa, Catanzaro 88100, Italy
| | - Rachele Bellini
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Carmen Massa
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Ginevra Urbani
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Martina Bordoni
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Silvia Marchianò
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Ginevra Lachi
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | | | - Claudia Finamore
- University of Naples Federico II, Department of Pharmacy, Naples, Italy
| | - Valentina Sepe
- University of Naples Federico II, Department of Pharmacy, Naples, Italy
| | | | - Federica Moraca
- Net4Science srl, University "Magna Græcia", Campus Salvatore Venuta, Viale Europa, Catanzaro 88100, Italy; University of Naples Federico II, Department of Pharmacy, Naples, Italy
| | | | | | | | - Michele Biagioli
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Bruno Catalanotti
- University of Naples Federico II, Department of Pharmacy, Naples, Italy
| | - Annibale Donini
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Angela Zampella
- University of Naples Federico II, Department of Pharmacy, Naples, Italy
| | - Stefano Fiorucci
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy.
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11
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Li W, Zou L, Huang S, Miao H, Liu K, Geng Y, Liu Y, Wu W. The anticancer activity of bile acids in drug discovery and development. Front Pharmacol 2024; 15:1362382. [PMID: 38444942 PMCID: PMC10912613 DOI: 10.3389/fphar.2024.1362382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 01/29/2024] [Indexed: 03/07/2024] Open
Abstract
Bile acids (BAs) constitute essential components of cholesterol metabolites that are synthesized in the liver, stored in the gallbladder, and excreted into the intestine through the biliary system. They play a crucial role in nutrient absorption, lipid and glucose regulation, and the maintenance of metabolic homeostasis. In additional, BAs have demonstrated the ability to attenuate disease progression such as diabetes, metabolic disorders, heart disease, and respiratory ailments. Intriguingly, recent research has offered exciting evidence to unveil their potential antitumor properties against various cancer cell types including tamoxifen-resistant breast cancer, oral squamous cell carcinoma, cholangiocarcinoma, gastric cancer, colon cancer, hepatocellular carcinoma, prostate cancer, gallbladder cancer, neuroblastoma, and others. Up to date, multiple laboratories have synthesized novel BA derivatives to develop potential drug candidates. These derivatives have exhibited the capacity to induce cell death in individual cancer cell types and display promising anti-tumor activities. This review extensively elucidates the anticancer activity of natural BAs and synthetic derivatives in cancer cells, their associated signaling pathways, and therapeutic strategies. Understanding of BAs and their derivatives activities and action mechanisms will evidently assist anticancer drug discovery and devise novel treatment.
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Affiliation(s)
- Weijian Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Lu Zou
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Shuai Huang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huijie Miao
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Ke Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Yajun Geng
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Wenguang Wu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
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12
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Chorawala MR, Postwala H, Prajapati BG, Shah Y, Shah A, Pandya A, Kothari N. Impact of the microbiome on colorectal cancer development. COLORECTAL CANCER 2024:29-72. [DOI: 10.1016/b978-0-443-13870-6.00021-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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13
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Zhou L, Jiang Z, Zhang Z, Xing J, Wang D, Tang D. Progress of gut microbiome and its metabolomics in early screening of colorectal cancer. Clin Transl Oncol 2023; 25:1949-1962. [PMID: 36790675 DOI: 10.1007/s12094-023-03097-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 01/18/2023] [Indexed: 02/16/2023]
Abstract
Gut microbes are widely considered to be closely associated with colorectal cancer (CRC) development. The microbiota is regarded as a potential identifier of CRC, as several studies have found great significant changes in CRC patients' microbiota and metabolic groups. Changes in microbiota, like Fusobacterium nucleatum and Bacteroides fragilis, also alter the metabolic activity of the host, promoting CRC development. In contrast, the metabolome is an intuitive discriminative biomarker as a small molecular bridge to distinguish CRC from healthy individuals due to the direct action of microbes on the host. More diagnostic microbial markers have been found, and the potential discriminatory power of microorganisms in CRC has been investigated through the combined use of biomic genomic metabolomics, bringing new ideas for screening fecal microbial markers. In this paper, we discuss the potential of microorganisms and their metabolites as biomarkers in CRC screening, hoping to provide thoughts and references for non-invasive screening of CRC.
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Affiliation(s)
- Lujia Zhou
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, 225000, People's Republic of China
| | - Zhengting Jiang
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, 225000, People's Republic of China
| | - Zhilin Zhang
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, 225000, People's Republic of China
| | - Juan Xing
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, 225000, People's Republic of China
| | - Daorong Wang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People's Hospital, Clinical Medical College, Yangzhou University, Yangzhou, 225000, People's Republic of China
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People's Hospital, Clinical Medical College, Yangzhou University, Yangzhou, 225000, People's Republic of China.
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14
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Novoa Díaz MB, Carriere P, Gentili C. How the interplay among the tumor microenvironment and the gut microbiota influences the stemness of colorectal cancer cells. World J Stem Cells 2023; 15:281-301. [PMID: 37342226 PMCID: PMC10277969 DOI: 10.4252/wjsc.v15.i5.281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/06/2023] [Accepted: 04/17/2023] [Indexed: 05/26/2023] Open
Abstract
Colorectal cancer (CRC) remains the third most prevalent cancer disease and involves a multi-step process in which intestinal cells acquire malignant characteristics. It is well established that the appearance of distal metastasis in CRC patients is the cause of a poor prognosis and treatment failure. Nevertheless, in the last decades, CRC aggressiveness and progression have been attributed to a specific cell population called CRC stem cells (CCSC) with features like tumor initiation capacity, self-renewal capacity, and acquired multidrug resistance. Emerging data highlight the concept of this cell subtype as a plastic entity that has a dynamic status and can be originated from different types of cells through genetic and epigenetic changes. These alterations are modulated by complex and dynamic crosstalk with environmental factors by paracrine signaling. It is known that in the tumor niche, different cell types, structures, and biomolecules coexist and interact with cancer cells favoring cancer growth and development. Together, these components constitute the tumor microenvironment (TME). Most recently, researchers have also deepened the influence of the complex variety of microorganisms that inhabit the intestinal mucosa, collectively known as gut microbiota, on CRC. Both TME and microorganisms participate in inflammatory processes that can drive the initiation and evolution of CRC. Since in the last decade, crucial advances have been made concerning to the synergistic interaction among the TME and gut microorganisms that condition the identity of CCSC, the data exposed in this review could provide valuable insights into the biology of CRC and the development of new targeted therapies.
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Affiliation(s)
- María Belén Novoa Díaz
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Pedro Carriere
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Claudia Gentili
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
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15
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Wong CC, Yu J. Gut microbiota in colorectal cancer development and therapy. Nat Rev Clin Oncol 2023:10.1038/s41571-023-00766-x. [PMID: 37169888 DOI: 10.1038/s41571-023-00766-x] [Citation(s) in RCA: 225] [Impact Index Per Article: 112.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/13/2023] [Indexed: 05/13/2023]
Abstract
Colorectal cancer (CRC) is one of the commonest cancers globally. A unique aspect of CRC is its intimate association with the gut microbiota, which forms an essential part of the tumour microenvironment. Research over the past decade has established that dysbiosis of gut bacteria, fungi, viruses and Archaea accompanies colorectal tumorigenesis, and these changes might be causative. Data from mechanistic studies demonstrate the ability of the gut microbiota to interact with the colonic epithelia and immune cells of the host via the release of a diverse range of metabolites, proteins and macromolecules that regulate CRC development. Preclinical and some clinical evidence also underscores the role of the gut microbiota in modifying the therapeutic responses of patients with CRC to chemotherapy and immunotherapy. Herein, we summarize our current understanding of the role of gut microbiota in CRC and outline the potential translational and clinical implications for CRC diagnosis, prevention and treatment. Emphasis is placed on how the gut microbiota could now be better harnessed by developing targeted microbial therapeutics as chemopreventive agents against colorectal tumorigenesis, as adjuvants for chemotherapy and immunotherapy to boost drug efficacy and safety, and as non-invasive biomarkers for CRC screening and patient stratification. Finally, we highlight the hurdles and potential solutions to translating our knowledge of the gut microbiota into clinical practice.
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Affiliation(s)
- Chi Chun Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
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16
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Di Giorgio C, Bellini R, Lupia A, Massa C, Bordoni M, Marchianò S, Rosselli R, Sepe V, Rapacciuolo P, Moraca F, Morretta E, Ricci P, Urbani G, Monti MC, Biagioli M, Distrutti E, Catalanotti B, Zampella A, Fiorucci S. Discovery of BAR502, as potent steroidal antagonist of leukemia inhibitory factor receptor for the treatment of pancreatic adenocarcinoma. Front Oncol 2023; 13:1140730. [PMID: 36998446 PMCID: PMC10043345 DOI: 10.3389/fonc.2023.1140730] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 02/20/2023] [Indexed: 03/15/2023] Open
Abstract
IntroductionThe leukemia inhibitory factor (LIF), is a cytokine belonging to IL-6 family, whose overexpression correlate with poor prognosis in cancer patients, including pancreatic ductal adenocarcinoma (PDAC). LIF signaling is mediate by its binding to the heterodimeric LIF receptor (LIFR) complex formed by the LIFR receptor and Gp130, leading to JAK1/STAT3 activation. Bile acids are steroid that modulates the expression/activity of membrane and nuclear receptors, including the Farnesoid-X-Receptor (FXR) and G Protein Bile Acid Activated Receptor (GPBAR1).MethodsHerein we have investigated whether ligands to FXR and GPBAR1 modulate LIF/LIFR pathway in PDAC cells and whether these receptors are expressed in human neoplastic tissues. ResultsThe transcriptome analysis of a cohort of PDCA patients revealed that expression of LIF and LIFR is increased in the neoplastic tissue in comparison to paired non-neoplastic tissues. By in vitro assay we found that both primary and secondary bile acids exert a weak antagonistic effect on LIF/LIFR signaling. In contrast, BAR502 a non-bile acid steroidal dual FXR and GPBAR1 ligand, potently inhibits binding of LIF to LIFR with an IC50 of 3.8 µM.DiscussionBAR502 reverses the pattern LIF-induced in a FXR and GPBAR1 independent manner, suggesting a potential role for BAR502 in the treatment of LIFR overexpressing-PDAC.
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Affiliation(s)
| | - Rachele Bellini
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Antonio Lupia
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
- Net4Science srl, University “Magna Græcia”, Catanzaro, Italy
| | - Carmen Massa
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Martina Bordoni
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Silvia Marchianò
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Valentina Sepe
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | | | - Federica Moraca
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
- Net4Science srl, University “Magna Græcia”, Catanzaro, Italy
| | - Elva Morretta
- Department of Pharmacy, University of Salerno, Salerno, Italy
| | - Patrizia Ricci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Ginevra Urbani
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Michele Biagioli
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Eleonora Distrutti
- Department of Gastroenterology, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Bruno Catalanotti
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
- *Correspondence: Stefano Fiorucci,
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17
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Song D, Wang X, Ma Y, Liu NN, Wang H. Beneficial insights into postbiotics against colorectal cancer. Front Nutr 2023; 10:1111872. [PMID: 36969804 PMCID: PMC10036377 DOI: 10.3389/fnut.2023.1111872] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 02/21/2023] [Indexed: 03/12/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent and life-threatening cancer types with limited therapeutic options worldwide. Gut microbiota has been recognized as the pivotal determinant in maintaining gastrointestinal (GI) tract homeostasis, while dysbiosis of gut microbiota contributes to CRC development. Recently, the beneficial role of postbiotics, a new concept in describing microorganism derived substances, in CRC has been uncovered by various studies. However, a comprehensive characterization of the molecular identity, mechanism of action, or routes of administration of postbiotics, particularly their role in CRC, is still lacking. In this review, we outline the current state of research toward the beneficial effects of gut microbiota derived postbiotics against CRC, which will represent the key elements of future precision-medicine approaches in the development of novel therapeutic strategies targeting gut microbiota to improve treatment outcomes in CRC.
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Affiliation(s)
| | | | | | - Ning-Ning Liu
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Wang
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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18
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Kapoor S, Padwad YS. Phloretin induces G2/M arrest and apoptosis by suppressing the β-catenin signaling pathway in colorectal carcinoma cells. Apoptosis 2023; 28:810-829. [PMID: 36884140 DOI: 10.1007/s10495-023-01826-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/15/2023] [Indexed: 03/09/2023]
Abstract
Colorectal carcinoma (CRC) is the third most prevalent cancer, causing a significant mortality worldwide. Present available therapies are surgery, chemotherapy including radiotherapy, and these are known to be associated with heavy side effects. Therefore, nutritional intervention in the form of natural polyphenols has been well recognised to prevent CRC. Phloretin, a known dihydrochalcone is present in apple, pear and strawberry. This has been proven to induce apoptosis in cancer cells and also exhibited anti-inflammatory activity, thus can be explored as a potential anticancer nutraceutical agent. This study demonstrated phloretin's significant in vitro anticancer activity against CRC. Phloretin suppressed cell proliferation, colony forming ability and cellular migration in human colorectal cancer HCT-116 and SW-480 cells. Results also revealed that phloretin generated reactive oxygen species (ROS) which provoked depolarization of mitochondrial membrane potential (MMP) and further contributed to cytotoxicity in colon cancer cells. Phloretin also modulated the cell cycle regulators including cyclins and cyclin-dependent kinases (CDKs) and halted cell cycle at G2/M phase. Moreover, it also induced apoptosis by regulating the expression of Bax and BCl-2. The Wnt/β-catenin signaling is inactivated by phloretin by targeting the downstream oncogenes namely CyclinD1, c-Myc and Survivin which are involved in the proliferation and apoptosis of colon cancer cells. In our study we showed that lithium chloride (LiCl) induced the expression of β-catenin and its target genes and the co-treatment of phloretin circumvent its effect and downregulated the Wnt/β-catenin signaling. In conclusion, our results strongly suggested that phloretin can be utilized as a nutraceutical anticancer agent for combating CRC.
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Affiliation(s)
- Smita Kapoor
- Pharmacology and Toxicology Lab, Dietetics & Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Himachal Pradesh, Palampur, 176 061, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Yogendra S Padwad
- Pharmacology and Toxicology Lab, Dietetics & Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Himachal Pradesh, Palampur, 176 061, India. .,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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19
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Song P, Zhang X, Feng W, Xu W, Wu C, Xie S, Yu S, Fu R. Biological synthesis of ursodeoxycholic acid. Front Microbiol 2023; 14:1140662. [PMID: 36910199 PMCID: PMC9998936 DOI: 10.3389/fmicb.2023.1140662] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 02/13/2023] [Indexed: 03/14/2023] Open
Abstract
Ursodeoxycholic acid (UDCA) is a fundamental treatment drug for numerous hepatobiliary diseases that also has adjuvant therapeutic effects on certain cancers and neurological diseases. Chemical UDCA synthesis is environmentally unfriendly with low yields. Biological UDCA synthesis by free-enzyme catalysis or whole-cell synthesis using inexpensive and readily available chenodeoxycholic acid (CDCA), cholic acid (CA), or lithocholic acid (LCA) as substrates is being developed. The free enzyme-catalyzed one-pot, one-step/two-step method uses hydroxysteroid dehydrogenase (HSDH); whole-cell synthesis, mainly uses engineered bacteria (mainly Escherichia coli) expressing the relevant HSDHs. To further develop these methods, HSDHs with specific coenzyme dependence, high enzyme activity, good stability, and high substrate loading concentration, P450 monooxygenase with C-7 hydroxylation activity and engineered strain harboring HSDHs must be exploited.
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Affiliation(s)
- Peng Song
- College of Life Sciences, Liaocheng University, Liaocheng, China
- Jiangxi Zymerck Biotechnology Co., Ltd., Nanchang, China
| | - Xue Zhang
- College of Life Sciences, Liaocheng University, Liaocheng, China
| | - Wei Feng
- College of Life Sciences, Liaocheng University, Liaocheng, China
| | - Wei Xu
- College of Life Sciences, Liaocheng University, Liaocheng, China
| | - Chaoyun Wu
- Jiangxi Zymerck Biotechnology Co., Ltd., Nanchang, China
| | - Shaoqing Xie
- Jiangxi Zymerck Biotechnology Co., Ltd., Nanchang, China
| | - Sisi Yu
- Jiangxi Zymerck Biotechnology Co., Ltd., Nanchang, China
| | - Rongzhao Fu
- Jiangxi Zymerck Biotechnology Co., Ltd., Nanchang, China
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20
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He Q, Wu J, Ke J, Zhang Q, Zeng W, Luo Z, Gong J, Chen Y, He Z, Lan P. Therapeutic role of ursodeoxycholic acid in colitis-associated cancer via gut microbiota modulation. Mol Ther 2023; 31:585-598. [PMID: 38556635 PMCID: PMC9931610 DOI: 10.1016/j.ymthe.2022.10.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 09/21/2022] [Accepted: 10/25/2022] [Indexed: 11/09/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a predisposing factor for colitis-associated cancer (CAC). The association between bile acids and the gut microbiota has been demonstrated in colon neoplasia; however, the effect of ursodeoxycholic acid (UDCA) on gut microbiota alteration in development of colitis and CAC is unknown. Our analysis of publicly available datasets demonstrated the association of UDCA treatment and accumulation of Akkermansia. UDCA-mediated alleviation of DSS-induced colitis was microbially dependent. UDCA treatment significantly upregulated Akkermansia colonization in a mouse model. Colonization of Akkermansia was associated with enhancement of the mucus layer upon UDCA treatment as well as activation of bile acid receptors in macrophages. UDCA played a role in CAC prevention and treatment in the AOM-DSS and ApcMin/+-DSS models through downregulation of inflammation and accumulation of Akkermansia. This study suggests that UDCA intervention could reshape intestinal gut homeostasis, facilitating colonization of Akkermansia and preventing and treating colitis and CAC.
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Affiliation(s)
- Qilang He
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, 510655 Guangdong, China
| | - Jinjie Wu
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, 510655 Guangdong, China
| | - Jia Ke
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, 510655 Guangdong, China
| | - Qiang Zhang
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, 510655 Guangdong, China
| | - Wanyi Zeng
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, 510655 Guangdong, China
| | - Zhanhao Luo
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, 510655 Guangdong, China
| | - Junli Gong
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, 510655 Guangdong, China
| | - Yuan Chen
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China
| | - Zhen He
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, 510655 Guangdong, China.
| | - Ping Lan
- The Sixth Affiliated Hospital, School of Medicine, Sun Yat-sen University, Guangzhou, 510655 Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, 510655 Guangdong, China.
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21
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Senchukova MA. Microbiota of the gastrointestinal tract: Friend or foe? World J Gastroenterol 2023; 29:19-42. [PMID: 36683718 PMCID: PMC9850957 DOI: 10.3748/wjg.v29.i1.19] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 11/05/2022] [Accepted: 12/16/2022] [Indexed: 01/04/2023] Open
Abstract
The gut microbiota is currently considered an external organ of the human body that provides important mechanisms of metabolic regulation and protection. The gut microbiota encodes over 3 million genes, which is approximately 150 times more than the total number of genes present in the human genome. Changes in the qualitative and quantitative composition of the microbiome lead to disruption in the synthesis of key bacterial metabolites, changes in intestinal barrier function, and inflammation and can cause the development of a wide variety of diseases, such as diabetes, obesity, gastrointestinal disorders, cardiovascular issues, neurological disorders and oncological concerns. In this review, I consider issues related to the role of the microbiome in the regulation of intestinal barrier function, its influence on physiological and pathological processes occurring in the body, and potential new therapeutic strategies aimed at restoring the gut microbiome. Herewith, it is important to understand that the gut microbiota and human body should be considered as a single biological system, where change of one element will inevitably affect its other components. Thus, the study of the impact of the intestinal microbiota on health should be considered only taking into account numerous factors, the role of which has not yet been fully elucidated.
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Affiliation(s)
- Marina A Senchukova
- Department of Oncology, Orenburg State Medical University, Orenburg 460000, Russia
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22
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Chen L, Li C, Zhong X, Lai C, Zhang B, Luo Y, Guo H, Liang K, Fang J, Zhu X, Zhang J, Guo L. The gut microbiome promotes arsenic metabolism and alleviates the metabolic disorder for their mammal host under arsenic exposure. ENVIRONMENT INTERNATIONAL 2023; 171:107660. [PMID: 36470123 DOI: 10.1016/j.envint.2022.107660] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 10/27/2022] [Accepted: 11/23/2022] [Indexed: 06/17/2023]
Abstract
Gut microbiome can participate in arsenic metabolism. However, its efficacy in the host under arsenic stress is still controversial. To clarify their roles in fecal arsenic excretion, tissue arsenic accumulation, host physiological states and metabolism, in this study, ninety-six C57BL/6 male mice were randomly divided to four groups, groups A and B were given sterile water, and groups C and D were given the third generation of broad-spectrum antibiotic (ceftriaxone) to erase the background gut microbiome. Subsequently, groups B and D were subchronicly exposed to arsenic containing feed prepared by adding arsenical mixture (rice arsenic composition) into control feed. In group D, the fecal total arsenic (CtAs) decreased by 25.5 %, iAsIII composition increased by 46.9 %, unclarified As (uAs) composition decreased by 92.4 %, and the liver CtAs increased by 26.7 %; the fecal CtAs was positively correlated with microbial richness and some metabolites (organic acids, amino acids, carbohydrates, SCFAs, hydrophilic bile acids and their derivatives); and fecal DMA was positively correlated with microbial richness and some metabolites (ferulic acid, benzenepropanoic acid and pentanoic acid); network analysis showed that the numbers of modules, nodes, links were decreased and vulnerability was increased; some SCFAs and hydrophilic bile acid decreased, and hydrophobic bile acids increased (Ps < 0.05). In the tissue samples of group D, Il-18 and Ifn-γ gene expression increased and intestinal barrier-related genes Muc2, Occludin and Zo-1 expression decreased (Ps < 0.05); serum glutathione and urine malondialdehyde significantly increased (Ps < 0.05); urine metabolome significantly changed and the variation was correlated with six SCFAs-producing bacteria, and some SCFAs including isobutyric acid, valeric acid and heptanoic acid decreased (Ps < 0.05). Therefore, the normal gut microbiome increases fecal arsenic excretion and biotransformation, which can maintain a healthier microbiome and metabolic functions, and alleviate the metabolic disorder for their mammal host under arsenic exposure.
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Affiliation(s)
- Linkang Chen
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Chengji Li
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China; Yunfu City Center for Disease Control, Guangdong Province 527300, China
| | - Xiaoting Zhong
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Chengze Lai
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Bin Zhang
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Yu Luo
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Honghui Guo
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Keqing Liang
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Jingwen Fang
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Xuan Zhu
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Jingjing Zhang
- Key Laboratory of Zebrafish Model for Development and Disease & Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China.
| | - Lianxian Guo
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China.
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23
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Thuy PX, Bao TDD, Moon EY. Ursodeoxycholic acid ameliorates cell migration retarded by the SARS-CoV-2 spike protein in BEAS-2B human bronchial epithelial cells. Biomed Pharmacother 2022; 150:113021. [PMID: 35658221 PMCID: PMC9035373 DOI: 10.1016/j.biopha.2022.113021] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/07/2022] [Accepted: 04/20/2022] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) is caused by severe acute -respiratory syndrome coronavirus 2 (SARS- CoV-2) through interaction of the spike protein (SP) with the receptor-binding domain (RBD) and its receptor, angiotensin converting enzyme 2(ACE2). Repair mechanisms induced following virus infection can restore the protective barrier through wound healing. Then, cells from the epithelial basal layer repopulate the damaged area, followed by cell proliferation and differentiation, as well as changes in gene expression. METHODS Using Beas-2B cells and SP, we investigated whether ursodeoxycholic acid (UDCA) contributes to restoration of the bronchial epithelial layer. ACE2 expression was measured by RT-PCR and Western blotting. SP-ACE2 interaction was analyzed by flow cytometry and visualized through immunostaining. Cell migration was assessed using single cell path tracking and wound healing assay. RESULTS Upon ACE2 overexpression in HeLa, HEK293T, and Beas-2B cells following the transfection of pCMV-ACE2 plasmid DNA, SP binding on each cell was increased in the ACE2 overexpression group compared to pCMV-transfected control cells. SP treatment delayed the migration of BEAS-2B cells compared to the control. SP also reduced cell migration, even under ACE2 overexpression; SP binding was greater in ACE2-overexpressed cells than control cells. UDCA interfered significantly with the binding of SP to ACE2 under our experimental conditions. UDCA also restored the inhibitory migration of Beas-2B cells induced by SP treatment. CONCLSION Our data demonstrate that UDCA can contribute to the inhibition of abnormal airway epithelial cell migration. These results suggest that UDCA can enhance the repair mechanism, to prevent damage caused by SP-ACE2 interaction and enhance restoration of the epithelial basal layer.
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Affiliation(s)
- Pham Xuan Thuy
- Department of Integrated Bioscience and Biotechnology, Seoul 05006, Republic of Korea
| | - Tran Duc Duy Bao
- Department of Integrated Bioscience and Biotechnology, Seoul 05006, Republic of Korea
| | - Eun-Yi Moon
- Department of Integrated Bioscience and Biotechnology, Seoul 05006, Republic of Korea.
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24
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Shulpekova Y, Zharkova M, Tkachenko P, Tikhonov I, Stepanov A, Synitsyna A, Izotov A, Butkova T, Shulpekova N, Lapina N, Nechaev V, Kardasheva S, Okhlobystin A, Ivashkin V. The Role of Bile Acids in the Human Body and in the Development of Diseases. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27113401. [PMID: 35684337 PMCID: PMC9182388 DOI: 10.3390/molecules27113401] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/13/2022] [Accepted: 05/23/2022] [Indexed: 11/28/2022]
Abstract
Bile acids are specific and quantitatively important organic components of bile, which are synthesized by hepatocytes from cholesterol and are involved in the osmotic process that ensures the outflow of bile. Bile acids include many varieties of amphipathic acid steroids. These are molecules that play a major role in the digestion of fats and the intestinal absorption of hydrophobic compounds and are also involved in the regulation of many functions of the liver, cholangiocytes, and extrahepatic tissues, acting essentially as hormones. The biological effects are realized through variable membrane or nuclear receptors. Hepatic synthesis, intestinal modifications, intestinal peristalsis and permeability, and receptor activity can affect the quantitative and qualitative bile acids composition significantly leading to extrahepatic pathologies. The complexity of bile acids receptors and the effects of cross-activations makes interpretation of the results of the studies rather difficult. In spite, this is a very perspective direction for pharmacology.
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Affiliation(s)
- Yulia Shulpekova
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Maria Zharkova
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Pyotr Tkachenko
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Igor Tikhonov
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Alexander Stepanov
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 119435 Moscow, Russia; (A.S.); (A.I.); (T.B.)
| | - Alexandra Synitsyna
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 119435 Moscow, Russia; (A.S.); (A.I.); (T.B.)
- Correspondence: ; Tel.: +7-499-764-98-78
| | - Alexander Izotov
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 119435 Moscow, Russia; (A.S.); (A.I.); (T.B.)
| | - Tatyana Butkova
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 119435 Moscow, Russia; (A.S.); (A.I.); (T.B.)
| | | | - Natalia Lapina
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Vladimir Nechaev
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Svetlana Kardasheva
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Alexey Okhlobystin
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Vladimir Ivashkin
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
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25
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Fu J, Yu M, Xu W, Yu S. Research Progress of Bile Acids in Cancer. Front Oncol 2022; 11:778258. [PMID: 35127481 PMCID: PMC8810494 DOI: 10.3389/fonc.2021.778258] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 12/27/2021] [Indexed: 01/09/2023] Open
Abstract
Bile acids (BAs) were originally known as detergents to facilitate the digestion and absorption of lipids. And our current knowledge of BAs has been extended to potential carcinogenic or cancer suppressor factors due to constant research. In fact, BAs were regarded as a tumor promoters as early as the 1940s. Differential bile acid signals emitted by various bile acid profiles can produce distinct pathophysiological traits, thereby participating in the occurrence and development of tumors. Nevertheless, in recent years, more and more studies have noticed the value of BAs as therapeutic targets. And several studies have applied BAs as a therapeutic agent for various diseases including cancer. Based on the above evidence, we acknowledge that the role of BAs in cancer has yet to be exploited, although considerable efforts have been made to probe the functions of BAs. In this review, we describe the characteristics of BAs as a double-edged sword in cancer, hoping to provide references for future cancer treatments.
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Affiliation(s)
- Junhao Fu
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Min Yu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Wenxia Xu
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Shian Yu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
- *Correspondence: Shian Yu,
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26
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Fang Y, Yan C, Zhao Q, Xu J, Liu Z, Gao J, Zhu H, Dai Z, Wang D, Tang D. The roles of microbial products in the development of colorectal cancer: a review. Bioengineered 2021; 12:720-735. [PMID: 33618627 PMCID: PMC8806273 DOI: 10.1080/21655979.2021.1889109] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 02/08/2021] [Indexed: 02/06/2023] Open
Abstract
A large number of microbes exist in the gut and they have the ability to process and utilize ingested food. It has been reported that their products are involved in colorectal cancer development. The molecular mechanisms which underlie the relationship between gut microbial products and CRC are still not fully understood. The role of some microbial products in CRC is particularly controversial. Elucidating the effects of gut microbiota products on CRC and their possible mechanisms is vital for CRC prevention and treatment. In this review, recent studies are examined in order to describe the contribution metabolites and toxicants which are produced by gut microbes make to CRC, primarily focusing on the involved molecular mechanisms.Abbreviations: CRC: colorectal cancer; SCFAs: short chain fatty acids; HDAC: histone deacetylase; TCA cycle: tricarboxylic acid cycle; CoA: cytosolic acyl coenzyme A; SCAD: short chain acyl CoA dehydrogenase; HDAC: histone deacetylase; MiR-92a: microRNA-92a; KLF4: kruppel-like factor; PTEN: phosphatase and tensin homolog; PI3K: phosphoinositide 3-kinase; PIP2: phosphatidylinositol 4, 5-biphosphate; PIP3: phosphatidylinositol-3,4,5-triphosphate; Akt1: protein kinase B subtype α; ERK1/2: extracellular signal-regulated kinases 1/2; EMT: epithelial-to-mesenchymal transition; NEDD9: neural precursor cell expressed developmentally down-regulated9; CAS: Crk-associated substrate; JNK: c-Jun N-terminal kinase; PRMT1: protein arginine methyltransferase 1; UDCA: ursodeoxycholic acid; BA: bile acids; CA: cholic acid; CDCA: chenodeoxycholic acid; DCA: deoxycholic acid; LCA: lithocholic acid; CSCs: cancer stem cells; MHC: major histocompatibility; NF-κB: NF-kappaB; GPR: G protein-coupled receptors; ROS: reactive oxygen species; RNS: reactive nitrogen substances; BER: base excision repair; DNA: deoxyribonucleic acid; EGFR: epidermal growth factor receptor; MAPK: mitogen activated protein kinase; ERKs: extracellular signal regulated kinases; AKT: protein kinase B; PA: phosphatidic acid; TMAO: trimethylamine n-oxide; TMA: trimethylamine; FMO3: flavin-containing monooxygenase 3; H2S: Hydrogen sulfide; SRB: sulfate-reducing bacteria; IBDs: inflammatory bowel diseases; NSAID: non-steroidal anti-inflammatory drugs; BFT: fragile bacteroides toxin; ETBF: enterotoxigenic fragile bacteroides; E-cadherin: extracellular domain of intercellular adhesive protein; CEC: colonic epithelial cells; SMOX: spermine oxidase; SMO: smoothened; Stat3: signal transducer and activator of transcription 3; Th17: T helper cell 17; IL17: interleukin 17; AA: amino acid; TCF: transcription factor; CDT: cytolethal distending toxin; PD-L1: programmed cell death 1 ligand 1.
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Affiliation(s)
- Yongkun Fang
- Department of Clinical Medical College, Dalian Medical University, Dalian, Liaoning, P.R. China
| | - Cheng Yan
- Department of Clinical Medical College, Dalian Medical University, Dalian, Liaoning, P.R. China
| | - Qi Zhao
- Department of Clinical Medical College, Yangzhou University, Yangzhou, P.R. China
| | - Jiaming Xu
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Zhuangzhuang Liu
- Department of Clinical Medical College, Dalian Medical University, Dalian, Liaoning, P.R. China
| | - Jin Gao
- Department of Clinical Medical College, Dalian Medical University, Dalian, Liaoning, P.R. China
| | - Hanjian Zhu
- Department of Clinical Medical College, Yangzhou University, Yangzhou, P.R. China
| | - Zhujiang Dai
- Department of Clinical Medical College, Yangzhou University, Yangzhou, P.R. China
| | - Daorong Wang
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Yangzhou University, Yangzhou, China
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27
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A Comparative Study of the Hepatoprotective Effect of Centella asiatica Extract (CA-HE50) on Lipopolysaccharide/d-galactosamine-Induced Acute Liver Injury in C57BL/6 Mice. Nutrients 2021; 13:nu13114090. [PMID: 34836346 PMCID: PMC8623393 DOI: 10.3390/nu13114090] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/07/2021] [Accepted: 11/14/2021] [Indexed: 01/07/2023] Open
Abstract
Acute liver failure (ALF) refers to the sudden loss of liver function and is accompanied by several complications. In a previous study, we revealed the protective effect of Centella asiatica 50% ethanol extract (CA-HE50) on acetaminophen-induced liver injury. In the present study, we investigate the hepatoprotective effect of CA-HE50 in a lipopolysaccharide/galactosamine (LPS-D-Gal)-induced ALF animal model and compare it to existing therapeutic silymarin, Lentinus edodes mycelia (LEM) extracts, ursodeoxycholic acid (UDCA) and dimethyl diphenyl bicarboxylate (DDB). Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were decreased in the CA-HE50, silymarin, LEM, UDCA and DDB groups compared to the vehicle control group. In particular, AST and ALT levels of the 200 mg/kg CA-HE50 group were significantly decreased compared to positive control groups. Lactate dehydrogenase (LDH) levels were significantly decreased in the CA-HE50, silymarin, LEM, UDCA and DDB groups compared to the vehicle control group and LDH levels of the 200 mg/kg CA-HE50 group were similar to those of the positive control groups. Superoxide dismutase (SOD) activity was significantly increased in the 100 mg/kg CA-HE50, LEM and UDCA groups compared to the vehicle control group and, in particular, the 100 mg/kg CA-HE50 group increased significantly compared to positive control groups. In addition, the histopathological lesion score was significantly decreased in the CA-HE50 and positive control groups compared with the vehicle control group and the histopathological lesion score of the 200 mg/kg CA-HE50 group was similar to that of the positive control groups. These results show that CA-HE50 has antioxidant and hepatoprotective effects at a level similar to that of silymarin, LEM, UDCA and DDB, which are known to have hepatoprotective effects; further, CA-HE50 has potential as a prophylactic and therapeutic agent in ALF.
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28
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Dalal N, Jalandra R, Bayal N, Yadav AK, Harshulika, Sharma M, Makharia GK, Kumar P, Singh R, Solanki PR, Kumar A. Gut microbiota-derived metabolites in CRC progression and causation. J Cancer Res Clin Oncol 2021; 147:3141-3155. [PMID: 34273006 DOI: 10.1007/s00432-021-03729-w] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 07/04/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND Based on recent research reports, dysbiosis and improper concentrations of microbial metabolites in the gut may result into the carcinogenesis of colorectal cancer. Recent advancement also highlights the involvement of bacteria and their secreted metabolites in the cancer causation. Gut microbial metabolites are functional output of the host-microbiota interactions and produced by anaerobic fermentation of food components in the diet. They contribute to influence variety of biological mechanisms including inflammation, cell signaling, cell-cycle disruption which are majorly disrupted in carcinogenic activities. PURPOSE In this review, we intend to discuss recent updates and possible molecular mechanisms to provide the role of bacterial metabolites, gut bacteria and diet in the colorectal carcinogenesis. Recent evidences have proposed the role of bacteria, such as Fusobacterium nucleaturm, Streptococcus bovis, Helicobacter pylori, Bacteroides fragilis and Clostridium septicum, in the carcinogenesis of CRC. Metagenomic study confirmed that these bacteria are in increased abundance in CRC patient as compared to healthy individuals and can cause inflammation and DNA damage which can lead to development of cancer. These bacteria produce metabolites, such as secondary bile salts from primary bile salts, hydrogen sulfide, trimethylamine-N-oxide (TMAO), which are likely to promote inflammation and subsequently cancer development. CONCLUSION Recent studies suggest that gut microbiota-derived metabolites have a role in CRC progression and causation and hence, could be implicated in CRC diagnosis, prognosis and therapy.
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Affiliation(s)
- Nishu Dalal
- Gene Regulation Laboratory, National Institute of Immunology, New Delhi, 110067, India
- Department of Environmental Science, Satyawati College, Delhi University, Delhi, 110052, India
| | - Rekha Jalandra
- Gene Regulation Laboratory, National Institute of Immunology, New Delhi, 110067, India
- Department of Zoology, Maharshi Dayanand University, Rohtak, 124001, India
| | - Nitin Bayal
- Gene Regulation Laboratory, National Institute of Immunology, New Delhi, 110067, India
| | - Amit K Yadav
- Special Centre for Nanoscience, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Harshulika
- Ministry of Environment, Forest and Climate Change, New Delhi, 110003, India
| | - Minakshi Sharma
- Department of Zoology, Maharshi Dayanand University, Rohtak, 124001, India
| | - Govind K Makharia
- Department of Gastroenterology and Human Nutrition, AIIMS, New Delhi, 110029, India
| | - Pramod Kumar
- Sri Aurobindo College, Delhi University, New Delhi, 110067, India
| | - Rajeev Singh
- Department of Environmental Science, Satyawati College, Delhi University, Delhi, 110052, India
| | - Pratima R Solanki
- Special Centre for Nanoscience, Jawaharlal Nehru University, New Delhi, 110067, India.
| | - Anil Kumar
- Gene Regulation Laboratory, National Institute of Immunology, New Delhi, 110067, India.
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Yu S, Shao X, Zhou Y, Yu Y, Kuai X, Zhou C. Bidirectional regulation of bile acid on colorectal cancer through bile acid-gut microbiota interaction. Am J Transl Res 2021; 13:10994-11003. [PMID: 34786038 PMCID: PMC8581861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 06/16/2021] [Indexed: 06/13/2023]
Abstract
Colorectal cancer (CRC) is now the third most common malignancy and the second leading cause of cancer death globally. Bile acid has bidirectional regulatory effects on CRC and influences its progression by interacting with gut microbiota. In this review, we provide evidence for bidirectional regulation of bile acid on CRC at multi-level and discuss the communication of gene, immune, metabolism and diet in the context of CRC with bile acid-gut microbiota interaction. The study on bidirectional regulation of bile acid is helpful to provide a more comprehensive and in-depth understanding of CRC pathogenesis and expect to be a new option for the treatment of CRC.
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Affiliation(s)
- Shunying Yu
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University Suzhou, Jiangsu, China
| | - Xinyu Shao
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University Suzhou, Jiangsu, China
| | - Yuqing Zhou
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University Suzhou, Jiangsu, China
| | - Yang Yu
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University Suzhou, Jiangsu, China
| | - Xiaoyi Kuai
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University Suzhou, Jiangsu, China
| | - Chunli Zhou
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University Suzhou, Jiangsu, China
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Feller FM, Holert J, Yücel O, Philipp B. Degradation of Bile Acids by Soil and Water Bacteria. Microorganisms 2021; 9:1759. [PMID: 34442838 PMCID: PMC8399759 DOI: 10.3390/microorganisms9081759] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/22/2021] [Accepted: 08/12/2021] [Indexed: 02/07/2023] Open
Abstract
Bile acids are surface-active steroid compounds with a C5 carboxylic side chain at the steroid nucleus. They are produced by vertebrates, mainly functioning as emulsifiers for lipophilic nutrients, as signaling compounds, and as an antimicrobial barrier in the duodenum. Upon excretion into soil and water, bile acids serve as carbon- and energy-rich growth substrates for diverse heterotrophic bacteria. Metabolic pathways for the degradation of bile acids are predominantly studied in individual strains of the genera Pseudomonas, Comamonas, Sphingobium, Azoarcus, and Rhodococcus. Bile acid degradation is initiated by oxidative reactions of the steroid skeleton at ring A and degradation of the carboxylic side chain before the steroid nucleus is broken down into central metabolic intermediates for biomass and energy production. This review summarizes the current biochemical and genetic knowledge on aerobic and anaerobic degradation of bile acids by soil and water bacteria. In addition, ecological and applied aspects are addressed, including resistance mechanisms against the toxic effects of bile acids.
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Affiliation(s)
- Franziska Maria Feller
- Institute for Molecular Microbiology and Biotechnology, University of Münster, Corrensstr. 3, 48149 Münster, Germany; (F.M.F.); (J.H.); (O.Y.)
| | - Johannes Holert
- Institute for Molecular Microbiology and Biotechnology, University of Münster, Corrensstr. 3, 48149 Münster, Germany; (F.M.F.); (J.H.); (O.Y.)
| | - Onur Yücel
- Institute for Molecular Microbiology and Biotechnology, University of Münster, Corrensstr. 3, 48149 Münster, Germany; (F.M.F.); (J.H.); (O.Y.)
| | - Bodo Philipp
- Institute for Molecular Microbiology and Biotechnology, University of Münster, Corrensstr. 3, 48149 Münster, Germany; (F.M.F.); (J.H.); (O.Y.)
- Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Auf dem Aberg 1, 57392 Schmallenberg, Germany
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31
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The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer. Nat Rev Gastroenterol Hepatol 2021; 18:335-347. [PMID: 33568795 DOI: 10.1038/s41575-020-00404-2] [Citation(s) in RCA: 234] [Impact Index Per Article: 58.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/14/2020] [Indexed: 01/31/2023]
Abstract
Farnesoid X receptor (FXR) is a ligand-activated transcription factor involved in the control of bile acid (BA) synthesis and enterohepatic circulation. FXR can influence glucose and lipid homeostasis. Hepatic FXR activation by obeticholic acid is currently used to treat primary biliary cholangitis. Late-stage clinical trials investigating the use of obeticholic acid in the treatment of nonalcoholic steatohepatitis are underway. Mouse models of metabolic disease have demonstrated that inhibition of intestinal FXR signalling reduces obesity, insulin resistance and fatty liver disease by modulation of hepatic and gut bacteria-mediated BA metabolism, and intestinal ceramide synthesis. FXR also has a role in the pathogenesis of gastrointestinal and liver cancers. Studies using tissue-specific and global Fxr-null mice have revealed that FXR acts as a suppressor of hepatocellular carcinoma, mainly through regulating BA homeostasis. Loss of whole-body FXR potentiates progression of spontaneous colorectal cancer, and obesity-induced BA imbalance promotes intestinal stem cell proliferation by suppressing intestinal FXR in Apcmin/+ mice. Owing to altered gut microbiota and FXR signalling, changes in overall BA levels and specific BA metabolites probably contribute to enterohepatic tumorigenesis. Modulating intestinal FXR signalling and altering BA metabolites are potential strategies for gastrointestinal and liver cancer prevention and treatment. In this Review, studies on the role of FXR in metabolic diseases and gastrointestinal and liver cancer are discussed, and the potential for development of targeted drugs are summarized.
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32
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Peng Y, Nie Y, Yu J, Wong CC. Microbial Metabolites in Colorectal Cancer: Basic and Clinical Implications. Metabolites 2021; 11:metabo11030159. [PMID: 33802045 PMCID: PMC8001357 DOI: 10.3390/metabo11030159] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/22/2021] [Accepted: 03/05/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading cancers that cause cancer-related deaths worldwide. The gut microbiota has been proved to show relevance with colorectal tumorigenesis through microbial metabolites. By decomposing various dietary residues in the intestinal tract, gut microbiota harvest energy and produce a variety of metabolites to affect the host physiology. However, some of these metabolites are oncogenic factors for CRC. With the advent of metabolomics technology, studies profiling microbiota-derived metabolites have greatly accelerated the progress in our understanding of the host-microbiota metabolism interactions in CRC. In this review, we briefly summarize the present metabolomics techniques in microbial metabolites researches and the mechanisms of microbial metabolites in CRC pathogenesis, furthermore, we discuss the potential clinical applications of microbial metabolites in cancer diagnosis and treatment.
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Affiliation(s)
- Yao Peng
- Department of Gastroenterology, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou 510180, China; (Y.P.); (Y.N.)
| | - Yuqiang Nie
- Department of Gastroenterology, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou 510180, China; (Y.P.); (Y.N.)
- Department of Gastroenterology, The Second Affiliated Hospital, Medical School, South China University of Technology, Guangzhou 510180, China
| | - Jun Yu
- Department of Gastroenterology, The Second Affiliated Hospital, Medical School, South China University of Technology, Guangzhou 510180, China
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Correspondence: (J.Y.); (C.C.W.)
| | - Chi Chun Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Correspondence: (J.Y.); (C.C.W.)
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33
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Gao RY, Shearn CT, Orlicky DJ, Battista KD, Alexeev EE, Cartwright IM, Lanis JM, Kostelecky RE, Ju C, Colgan SP, Fennimore BP. Bile acids modulate colonic MAdCAM-1 expression in a murine model of combined cholestasis and colitis. Mucosal Immunol 2021; 14:479-490. [PMID: 33004979 PMCID: PMC7954872 DOI: 10.1038/s41385-020-00347-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 09/02/2020] [Indexed: 02/07/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a progressive fibrosing cholestatic liver disease that is strongly associated with inflammatory bowel disease (IBD). PSC-associated IBD (PSC-IBD) displays a unique phenotype characterized by right-side predominant colon inflammation and increased risk of colorectal cancer compared to non-PSC-IBD. The frequent association and unique phenotype of PSC-IBD suggest distinctive underlying disease mechanisms from other chronic liver diseases or IBD alone. Multidrug resistance protein 2 knockout (Mdr2-/-) mice develop spontaneous cholestatic liver injury and fibrosis mirroring human PSC. As a novel model of PSC-IBD, we treated Mdr2-/- mice with dextran sulfate sodium (DSS) to chemically induce colitis (Mdr2-/-/DSS). Mdr2-/- mice demonstrate alterations in fecal bile acid composition and enhanced colitis susceptibility with increased colonic adhesion molecule expression, particularly mucosal addressin-cell adhesion molecule 1 (MAdCAM-1). In vitro, ursodeoxycholic acid (UDCA) co-treatment resulted in a dose dependent attenuation of TNF-α-induced endothelial MAdCAM-1 expression. In the combined Mdr2-/-/DSS model, UDCA supplementation attenuated colitis severity and downregulated intestinal MAdCAM-1 expression. These findings suggest a potential mechanistic role for alterations in bile acid signaling in modulating MAdCAM-1 expression and colitis susceptibility in cholestasis-associated colitis. Together, our findings provide a novel model and new insight into the pathogenesis and potential treatment of PSC-IBD.
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Affiliation(s)
- Rachel Y Gao
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Colin T Shearn
- Department of Pediatrics Division of Pediatric Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - David J Orlicky
- Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kayla D Battista
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Erica E Alexeev
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Ian M Cartwright
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA
| | - Jordi M Lanis
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Rachael E Kostelecky
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Cynthia Ju
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Sean P Colgan
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA
| | - Blair P Fennimore
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
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Microbial Hydroxysteroid Dehydrogenases: From Alpha to Omega. Microorganisms 2021; 9:microorganisms9030469. [PMID: 33668351 PMCID: PMC7996314 DOI: 10.3390/microorganisms9030469] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 02/08/2021] [Accepted: 02/18/2021] [Indexed: 12/23/2022] Open
Abstract
Bile acids (BAs) and glucocorticoids are steroid hormones derived from cholesterol that are important signaling molecules in humans and other vertebrates. Hydroxysteroid dehydrogenases (HSDHs) are encoded both by the host and by their resident gut microbiota, and they reversibly convert steroid hydroxyl groups to keto groups. Pairs of HSDHs can reversibly epimerize steroids from α-hydroxy conformations to β-hydroxy, or β-hydroxy to ω-hydroxy in the case of ω-muricholic acid. These reactions often result in products with drastically different physicochemical properties than their precursors, which can result in steroids being activators or inhibitors of host receptors, can affect solubility in fecal water, and can modulate toxicity. Microbial HSDHs modulate sterols associated with diseases such as colorectal cancer, liver cancer, prostate cancer, and polycystic ovary syndrome. Although the role of microbial HSDHs is not yet fully elucidated, they may have therapeutic potential as steroid pool modulators or druggable targets in the future. In this review, we explore metabolism of BAs and glucocorticoids with a focus on biotransformation by microbial HSDHs.
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35
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Loke YL, Chew MT, Ngeow YF, Lim WWD, Peh SC. Colon Carcinogenesis: The Interplay Between Diet and Gut Microbiota. Front Cell Infect Microbiol 2020; 10:603086. [PMID: 33364203 PMCID: PMC7753026 DOI: 10.3389/fcimb.2020.603086] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 10/28/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) incidence increases yearly, and is three to four times higher in developed countries compared to developing countries. The well-known risk factors have been attributed to low physical activity, overweight, obesity, dietary consumption including excessive consumption of red processed meats, alcohol, and low dietary fiber content. There is growing evidence of the interplay between diet and gut microbiota in CRC carcinogenesis. Although there appears to be a direct causal role for gut microbes in the development of CRC in some animal models, the link between diet, gut microbes, and colonic carcinogenesis has been established largely as an association rather than as a cause-and-effect relationship. This is especially true for human studies. As essential dietary factors influence CRC risk, the role of proteins, carbohydrates, fat, and their end products are considered as part of the interplay between diet and gut microbiota. The underlying molecular mechanisms of colon carcinogenesis mediated by gut microbiota are also discussed. Human biological responses such as inflammation, oxidative stress, deoxyribonucleic acid (DNA) damage can all influence dysbiosis and consequently CRC carcinogenesis. Dysbiosis could add to CRC risk by shifting the effect of dietary components toward promoting a colonic neoplasm together with interacting with gut microbiota. It follows that dietary intervention and gut microbiota modulation may play a vital role in reducing CRC risk.
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Affiliation(s)
- Yean Leng Loke
- Centre for Biomedical Physics, School of Healthcare and Medical Sciences, Sunway University, Petaling Jaya, Malaysia
| | - Ming Tsuey Chew
- Centre for Biomedical Physics, School of Healthcare and Medical Sciences, Sunway University, Petaling Jaya, Malaysia
| | - Yun Fong Ngeow
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Kajang, Malaysia.,Centre for Research on Communicable Diseases, Universiti Tunku Abdul Rahman, Kajang, Malaysia
| | - Wendy Wan Dee Lim
- Department of Gastroenterology, Sunway Medical Centre, Petaling Jaya, Malaysia
| | - Suat Cheng Peh
- Ageing Health and Well-Being Research Centre, Sunway University, Petaling Jaya, Malaysia.,Department of Medical Sciences, School of Healthcare and Medical Sciences, Sunway University, Petaling Jaya, Malaysia
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36
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Krumz LM, Gudkova RB, Indejkina LK, Sabelnikova EA, Parfenov AI. [Bile acids are a risk factor for colorectal cancer]. TERAPEVT ARKH 2020; 92:93-96. [PMID: 32598725 DOI: 10.26442/00403660.2020.02.000457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Indexed: 11/22/2022]
Abstract
Bile acids were first considered carcinogenic in 1939. Since then, accumulated data have associated colon cell changes with high levels of bile acids as an important risk factor for developing colorectal cancer, which is more common among people who consume large amounts of dietary fat. Secondary bile acids formed under the influence of the intestinal microbiota can cause the formation of reactive forms of oxygen and nitrogen, disruption of the cell membrane, mitochondria, DNA damage, reduction of apoptosis, increased cell mutation, turning them into cancer cells. High-fat diet, intestinal microflora, bile acids are a risk factors for colorectal cancer.
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Affiliation(s)
- L M Krumz
- Loginov Moscow Clinical Scientific Practical Center
| | - R B Gudkova
- Loginov Moscow Clinical Scientific Practical Center
| | | | | | - A I Parfenov
- Loginov Moscow Clinical Scientific Practical Center
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37
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El-Hamoly T, Abd El-Rahman SS, Al-Abyad M. Potential effects of ursodeoxycholic acid on accelerating cutaneous wound healing. PLoS One 2019; 14:e0226748. [PMID: 31869384 PMCID: PMC6927640 DOI: 10.1371/journal.pone.0226748] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 12/04/2019] [Indexed: 12/12/2022] Open
Abstract
Among the initial responses to skin injury, triggering inflammatory mediators and modifying oxidative status provide the necessary temple for the subsequent output of a new functional barrier, fibroplasia and collagen deposition, modulated by NF-κB and TGF-β1 expressions. Hence, the current study aimed to investigate the effect of local application of ursodeoxycholic acid (UDCA) on cutaneous wound healing induced in Swiss mice. Wound contraction progression was monitored by daily photographing the wounds. Enhanced fibroblast cell migration was observed after incubation with UDCA. Topical application of UDCA (500 μM) cream on excised wounds significantly enhanced wound contraction and improved morphometric scores. In addition, UDCA ameliorated the unbalanced oxidative status of granulated skin tissues. Interestingly, it showed increased expression of TGF-β1 and MMP-2 with decreased expression of NF-κB. On the other hand, UDCA significantly increased collagen fibers deposition and hydroxyproline content and enhanced re-epithelization. UDCA also modified the mitochondrial function throughout the healing process, marked by lower consumption rates of mitochondrial ATP, complex I contents as well as intracellular NAD+ contents accompanied by elevated levels of nicotinamide compared to the untreated controls. In chronic gamma-irradiated (6Gy) model, the illustrated data showed enhanced wound contraction via increased TGF-β1/MMP-2 and collagen deposition incurred by topical application of UDCA without effect on NF-κB level. In sum, the present findings suggest that UDCA may accelerate wound healing by regulating TGF-β1 and MMP-2 and fibroplasia/collagen deposition in either the two wound healing models.
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Affiliation(s)
- Tarek El-Hamoly
- Drug Radiation Research Department, National Center for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt
- Cyclotron Project, Nuclear Research Centre, Atomic Energy Authority, Cairo, Egypt
| | - Sahar S. Abd El-Rahman
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
- * E-mail:
| | - Megahed Al-Abyad
- Cyclotron Project, Nuclear Research Centre, Atomic Energy Authority, Cairo, Egypt
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38
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Current Evidence on miRNAs as Potential Theranostic Markers for Detecting Chemoresistance in Colorectal Cancer: A Systematic Review and Meta-Analysis of Preclinical and Clinical Studies. Mol Diagn Ther 2019; 23:65-82. [PMID: 30726546 DOI: 10.1007/s40291-019-00381-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Findings from observational clinical studies examining the relationship between biomarker expression and theranosis in colorectal cancer (CRC) have been conflicting. OBJECTIVE We conducted this systematic review and meta-analysis to summarise the existing evidence to demonstrate the involvement of microRNAs (miRNAs) in chemoresistance and sensitivity in CRC through drug genetic pathways. METHODS Using PRISMA guidelines, we systematically searched PubMed and Science Direct for relevant studies that took place between 2012 and 2017. A random-effects model of meta-analysis was applied to evaluate the pooled effect size of hazard ratios (HRs) across the included studies. Cochran's Q test and the I2 statistic were used to detect heterogeneity. A funnel plot was used to assess potential publication bias. RESULTS Of the 4700 studies found, 39 studies comprising 2822 patients with CRC met the inclusion criteria. The included studies used one or a combination of 14 chemotherapy drugs, including 5-fluorouracil and oxaliplatin. Of the 60 miRNAs, 28 were associated with chemosensitivity, 20 with chemoresistance, and one with differential expression and radiosensitivity; ten miRNAs were not associated with any impact on chemotherapy. The results outline the importance of 34 drug-regulatory pathways of chemoresistance and sensitivity in CRC. The mean effect size was 0.689 (95% confidence interval 0.428-1.110), indicating that the expression of miRNAs decreased the likelihood of death by about 32%. CONCLUSION Studies have consistently shown that multiple miRNAs could act as clinical predictors of chemoresistance and sensitivity. An inclusion of supplementary miRNA estimation in CRC routine practice needs to be considered to evaluate the efficacy of chemotherapy after confirming our findings with large-scale prospective cohort studies. PROSPERO REGISTRATION NUMBER CRD42017082196.
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39
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Hystrix brachyura Bezoar Characterization, Antioxidant Activity Screening, and Anticancer Activity on Melanoma Cells (A375): A Preliminary Study. Antioxidants (Basel) 2019; 8:antiox8020039. [PMID: 30759849 PMCID: PMC6406421 DOI: 10.3390/antiox8020039] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 01/24/2019] [Accepted: 02/06/2019] [Indexed: 01/28/2023] Open
Abstract
Porcupine bezoars (PBs) are masses of undigested calcareous concretions formed within the gastrointestinal tract. There are undocumented claims that PBs have antioxidant activity and can treat cancers. However, limited scientific study has been carried out to verify these traditional claims. Hence, this study was conducted to characterize the chemical profile and validate the antioxidant and anticancer activity against melanoma cells (A375). PB extract was initially subjected to Fourier-transform infrared spectroscopy (FTIR), gas chromatography⁻mass spectrometry (GCMS), total phenolic content (TPC), and total flavonoid content (TFC) analyses. The bioautography of antioxidant assays, namely 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS), 2,2-diphenyl-1-picrylhydrazy (DPPH), and β-carotene was performed. An in vitro A375 cell viability assay, apoptosis assay, cell cycle arrest assay, and gene expression assay were carried out as well. The experimental finding revealed 5,10-diethoxy-2,3,7,8-tetrahydro-1H,6H-dipyrrolo[1,2-a:1',2'-d]pyrazine, ursodeoxycholic acid, and cholest-5-en-3-ol (3 beta)-, carbonochloridate are major compounds detected in PB extract. PB extract has low phenolic content, viz. 698.7 ± 0.93 (µg GAE/5 mg dry weight). The bioautography antioxidant assays revealed a potent antioxidant effect (ABTS > DPPH > β-carotene), with free radical scavenging activity. Furthermore, PB extract exhibited dose- and time-dependent inhibition of cancer activity on A375 cells due to the exhibition of apoptosis via an intrinsic pathway.
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Zhang J, Pei Y, Yang W, Yang W, Chen B, Zhao X, Long S. Cytoglobin ameliorates the stemness of hepatocellular carcinoma via coupling oxidative-nitrosative stress signals. Mol Carcinog 2018; 58:334-343. [PMID: 30365183 DOI: 10.1002/mc.22931] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 09/22/2018] [Accepted: 10/23/2018] [Indexed: 12/18/2022]
Abstract
Cancer stem cells (CSCs) account for tumor self-renewal and heterogeneity. Oxidative-nitrosative stress (ONS) is an independent etiologic factor throughout tumorigenesis. Emerging evidences indicated that the interaction of ONS with CSCs contributes to tumor progression and resistance to chemoradiotherapy. Cytoglobin (Cygb) is a member of human hexacoordinate hemoglobin family and acts as a dynamic mediator of redox homeostasis. We observed that Cygb is significantly deregulated in human hepatocellular carcinoma (HCC) tissue and its decrease aggravates the growth of liver cancer stem cells (LCSCs) and increases the subpopulation of CD133(+) LCSCs. Cygb restoration inhibits HCC proliferation and LCSC growth, and decreases the subpopulation of CD133 (+) LCSCs in vitro. We found that Cygb absence promotes LCSC phenotypes and PI3 K/AKT activation, whereas Cygb restoration inhibits LCSC phenotypes and PI3 K/AKT activation. Furthermore, exogenous antioxidants can eliminate the inhibitory effect of Cygb to LCSC growth and phenotypes, as well as PI3 K/AKT activation. Collectively, this study demonstrated that cytoglobin functions as a tumor suppressor and targets CSCs at an ONS-dependent manner. Thus, Cygb restoration could be a novel and promising therapeutic strategy against HCC with aberrant ROS/RNS accumulation.
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Affiliation(s)
- Jun Zhang
- Department of Pathology, the Affiliated Hospital of Guizhou Medical University, Guiyang, PR China.,Department of Pathology, Graduate School of Medicine, Guizhou Medical University, Guiyang, PR China.,Key Laboratory of Adult Stem Cell Transformation Research, Chinese Academy of Medical Sciences/Stem Cell and Tissue Engineering Research Center, Guizhou Medical University, Guiyang, PR China
| | - YuanYuan Pei
- Department of Pathology, the Affiliated Hospital of Guizhou Medical University, Guiyang, PR China
| | - Wen Yang
- Department of Pathology, the Affiliated Hospital of Guizhou Medical University, Guiyang, PR China
| | - WenXiu Yang
- Department of Pathology, the Affiliated Hospital of Guizhou Medical University, Guiyang, PR China.,Department of Pathology, Graduate School of Medicine, Guizhou Medical University, Guiyang, PR China
| | - BoXin Chen
- Department of Immunology, Basic School of Medicine, Guizhou Medical University, Guiyang, PR China
| | - Xing Zhao
- Department of Immunology, Basic School of Medicine, Guizhou Medical University, Guiyang, PR China
| | - Shiqi Long
- Department of Immunology, Basic School of Medicine, Guizhou Medical University, Guiyang, PR China
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Nguyen TT, Ung TT, Kim NH, Jung YD. Role of bile acids in colon carcinogenesis. World J Clin Cases 2018; 6:577-588. [PMID: 30430113 PMCID: PMC6232560 DOI: 10.12998/wjcc.v6.i13.577] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 09/15/2018] [Accepted: 10/11/2018] [Indexed: 02/05/2023] Open
Abstract
Bile acids (BAs) are cholesterol derivatives synthesized in the liver and then secreted into the intestine for lipid absorption. There are numerous scientific reports describing BAs, especially secondary BAs, as strong carcinogens or promoters of colon cancers. Firstly, BAs act as strong stimulators of colorectal cancer (CRC) initiation by damaging colonic epithelial cells, and inducing reactive oxygen species production, genomic destabilization, apoptosis resistance, and cancer stem cells-like formation. Consequently, BAs promote CRC progression via multiple mechanisms, including inhibiting apoptosis, enhancing cancer cell proliferation, invasion, and angiogenesis. There are diverse signals involved in the carcinogenesis mechanism of BAs, with a major role of epidermal growth factor receptor, and its down-stream signaling, involving mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt, and nuclear factor kappa-light-chain-enhancer of activated B cells. BAs regulate numerous genes including the human leukocyte antigen class I gene, p53, matrix metalloprotease, urokinase plasminogen activator receptor, Cyclin D1, cyclooxygenase-2, interleukin-8, and miRNAs of CRC cells, leading to CRC promotion. These evidence suggests that targeting BAs is an efficacious strategies for CRC prevention and treatment.
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Affiliation(s)
- Thi Thinh Nguyen
- Department of Biochemistry, Chonnam National University Medical School, Jeonnam 58138, South Korea
| | - Trong Thuan Ung
- Department of Biochemistry, Chonnam National University Medical School, Jeonnam 58138, South Korea
| | - Nam Ho Kim
- Department of Nephrology, Chonnam National University Medical School, Gwangju 501-190, South Korea
| | - Young Do Jung
- Department of Biochemistry, Chonnam National University Medical School, Jeonnam 58138, South Korea
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Gabbia D, Pozzo L, Zigiotto G, Roverso M, Sacchi D, Dalla Pozza A, Carrara M, Bogialli S, Floreani A, Guido M, De Martin S. Dexamethasone counteracts hepatic inflammation and oxidative stress in cholestatic rats via CAR activation. PLoS One 2018; 13:e0204336. [PMID: 30252871 PMCID: PMC6155538 DOI: 10.1371/journal.pone.0204336] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 09/06/2018] [Indexed: 12/19/2022] Open
Abstract
Glucocorticoids (GCs) are currently used for the therapeutic management of cholestatic diseases, but their use and molecular mechanism remain controversial. The aims of this study were 1) to assess the therapeutic effect of a 2-week treatment with the GC dexamethasone on hepatic damage in bile duct-ligated rats; 2) to investigate its effect on the activation of the nuclear receptors (NRs) pregnane X receptor (PXR), constitutive androstane receptor (CAR) and GC receptor (GR), and NF-kB, as well as on oxidative stress and bile acid (BA) hepatic composition. Cholestasis was induced by ligation of bile duct (BDL animals) in 16 male Wistar-Kyoto rats, and eight of them were daily treated by oral gavage with 0.125 mg/ml/kg DEX for 14 days. Eight Sham-operated rats were used as controls. Severity of cholestasis was assessed histologically and on plasma biochemical parameters. The nuclear expression of NF-kB (p65), GR, PXR and CAR was measured in hepatic tissue by Western Blot. Oxidative stress was evaluated by measuring malondialdehyde, carbonylated proteins, GHS and ROS content in rat livers. LC-MS was used to measure the plasma and liver concentration of 7 BAs. Histological findings and a significant drop in several markers of inflammation (p65 nuclear translocation, mRNA expressions of TNF-α, IL-1β, IL-6) showed that DEX treatment reversed cholestasis-induced inflammation, and similar results have been obtained with oxidative stress markers. The nuclear expression of p65 and CAR were inversely correlated, with the latter increasing significantly after DEX treatment (p<0.01 vs vehicle). Hepatic BA levels tended to drop in the untreated cholestatic rats, whereas they were similar to those of healthy rats in DEX-treated animals. Plasma BAs decreased significantly in DEX-treated animals with respect to untreated cholestatic rats. In conclusion, DEX reduces inflammation and oxidative stress in BDL rats, and probably CAR is responsible for this effect. Therefore, this NR represents a promising pharmacological target for managing cholestatic and inflammatory liver diseases.
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Affiliation(s)
- Daniela Gabbia
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Luisa Pozzo
- Institute of Agricultural Biology and Biotechnology, CNR, Pisa, Italy
| | - Giorgia Zigiotto
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Marco Roverso
- Department of Chemical Sciences, University of Padova, Padova, Italy
| | - Diana Sacchi
- Department of Medicine, General Pathology and Cytopathology Unit, University of Padova, Padova, Italy
| | - Arianna Dalla Pozza
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Maria Carrara
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Sara Bogialli
- Department of Chemical Sciences, University of Padova, Padova, Italy
| | - Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Maria Guido
- Department of Medicine, General Pathology and Cytopathology Unit, University of Padova, Padova, Italy
| | - Sara De Martin
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
- * E-mail:
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Metabolism of Oxo-Bile Acids and Characterization of Recombinant 12α-Hydroxysteroid Dehydrogenases from Bile Acid 7α-Dehydroxylating Human Gut Bacteria. Appl Environ Microbiol 2018; 84:AEM.00235-18. [PMID: 29549099 DOI: 10.1128/aem.00235-18] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Accepted: 03/06/2018] [Indexed: 12/31/2022] Open
Abstract
Bile acids are important cholesterol-derived nutrient signaling hormones, synthesized in the liver, that act as detergents to solubilize dietary lipids. Bile acid 7α-dehydroxylating gut bacteria generate the toxic bile acids deoxycholic acid and lithocholic acid from host bile acids. The ability of these bacteria to remove the 7-hydroxyl group is partially dependent on 7α-hydroxysteroid dehydrogenase (HSDH) activity, which reduces 7-oxo-bile acids generated by other gut bacteria. 3α-HSDH has an important enzymatic activity in the bile acid 7α-dehydroxylation pathway. 12α-HSDH activity has been reported for the low-activity bile acid 7α-dehydroxylating bacterium Clostridium leptum; however, this activity has not been reported for high-activity bile acid 7α-dehydroxylating bacteria, such as Clostridium scindens, Clostridium hylemonae, and Clostridium hiranonis Here, we demonstrate that these strains express bile acid 12α-HSDH. The recombinant enzymes were characterized from each species and shown to preferentially reduce 12-oxolithocholic acid to deoxycholic acid, with low activity against 12-oxochenodeoxycholic acid and reduced activity when bile acids were conjugated to taurine or glycine. Phylogenetic analysis suggests that 12α-HSDH is widespread among Firmicutes, Actinobacteria in the Coriobacteriaceae family, and human gut ArchaeaIMPORTANCE 12α-HSDH activity has been established in the medically important bile acid 7α-dehydroxylating bacteria C. scindens, C. hiranonis, and C. hylemonae Experiments with recombinant 12α-HSDHs from these strains are consistent with culture-based experiments that show a robust preference for 12-oxolithocholic acid over 12-oxochenodeoxycholic acid. Phylogenetic analysis identified novel members of the gut microbiome encoding 12α-HSDH. Future reengineering of 12α-HSDH enzymes to preferentially oxidize cholic acid may provide a means to industrially produce the therapeutic bile acid ursodeoxycholic acid. In addition, a cholic acid-specific 12α-HSDH expressed in the gut may be useful for the reduction in deoxycholic acid concentration, a bile acid implicated in cancers of the gastrointestinal (GI) tract.
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