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Yang S, Wang Y, Sheng L, Cui W, Ma C. The effect of fecal bile acids on the incidence and risk-stratification of colorectal cancer: an updated systematic review and meta-analysis. Sci Rep 2025; 15:740. [PMID: 39753873 PMCID: PMC11698987 DOI: 10.1038/s41598-024-84801-6] [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: 07/03/2024] [Accepted: 12/27/2024] [Indexed: 01/06/2025] Open
Abstract
Recent studies suggest the role of gut microbes in bile acid metabolism in the development and progression of colorectal cancer. However, the surveys of the association between fecal bile acid concentrations and colorectal cancer (CRC) have been inconsistent. We searched online to identify relevant cross-sectional and case-control studies published online in the major English language databases (Medline, Embase, Web of Science, AMED, and CINAHL) up to January 1, 2024. We selected studies according to inclusion and exclusion criteria and extracted data from them. RevMan 5.3 was used to perform the meta-analyses. In CRC risk meta-analysis, the effect size of CA (cholic acid), CDCA (chenodeoxycholic acid), DCA (deoxycholic acid), and UDCA (ursodeoxycholic acid) were significantly higher (CA: standardized mean difference [SMD] = 0.41, 95% confidence interval [CI]: 0.5-0.76, P = 0.02; CDCA: SMD = 0.35, 95% CI: 0.09-0.62, P = 0.009; DCA: SMD = 0.33,95% CI: 0.03-0.64, P = 0.03; UDCA: SMD = 0.46, 95% CI: 0.14-0.78, P = 0.005), and the combined effect size was significantly higher in the high-risk than the low-risk CRC group (SMD = 0.36, 95% CI: 0.21-0.51, P < 0.00001). In the CRC incidence meta-analysis, the effect sizes of CA and CDCA were significantly higher (CA: SMD = 0.42, 95% CI: 0.04-0.80, P = 0.03; CDCA: SMD = 0.61, 95% CI: 0.26-0.96, P = 0.00079), and their combined effect size was also significantly higher in the high-risk compared to low-risk CRC group (SMD = 0.39, 95% CI: 0.09-0.68, P = 0.01). Only one cross-sectional study suggested a higher concentration of CDCA, DCA, and UDCA in the stool of the CRC high-risk group than the low-risk group. These findings indicate that higher fecal concentrations of bile acid may be associated with a higher risk/incidence of CRC.
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Affiliation(s)
- Shaohui Yang
- Department of Colorectal Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, 315000, China
| | - Yu Wang
- Department of Colorectal Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, 315000, China
| | - Lijuan Sheng
- Gulou Street Community Health Service Center, Ningbo, 315000, China
| | - Wei Cui
- Department of Colorectal Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, 315000, China
| | - Chenyang Ma
- Department of Colorectal Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, 315000, China.
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Cariello M, Zerlotin R, Pasculli E, Piccinin E, Peres C, Porru E, Roda A, Gadaleta RM, Moschetta A. Intestinal FXR Activation via Transgenic Chimera or Chemical Agonism Prevents Colitis-Associated and Genetically-Induced Colon Cancer. Cancers (Basel) 2022; 14:cancers14133081. [PMID: 35804854 PMCID: PMC9265121 DOI: 10.3390/cancers14133081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/20/2022] [Accepted: 06/21/2022] [Indexed: 12/22/2022] Open
Abstract
Simple Summary Disruption of Bile Acids (BA) regulation with increased BA concentration and modulation or their detergent pro-inflammatory activity has been linked to colorectal cancer (CRC). Farnesoid X Receptor (FXR) is the master regulator of BA homeostasis; FXR is a nuclear receptor that transcriptionally modulates their synthesis, transport and metabolism. In this study, we demonstrated that intestinal FXR activation prevented both inflammation- and genetically-driven colorectal tumorigenesis by modulating BA pool size and composition. This could open new avenues for the therapeutic management of intestinal inflammation and tumorigenesis. Abstract The Farnesoid X Receptor (FXR) is the master regulator of Bile Acids (BA) homeostasis orchestrating their synthesis, transport and metabolism. Disruption of BA regulation has been linked to gut-liver axis diseases such as colorectal cancer (CRC). In this study, firstly we examined the role of constitutive activation of intestinal FXR in CRC; then we pre-clinically investigated the therapeutic potential of a diet enriched with a synthetic FXR agonist in two models of CRC (chemically-induced and genetic models). We demonstrated that mice with intestinal constitutive FXR activation are protected from AOM/DSS-induced CRC with a significant reduction of tumor number compared to controls. Furthermore, we evaluated the role of chemical FXR agonism in a DSS model of colitis in wild type (WT) and FXRnull mice. WT mice administered with the FXR activating diet showed less morphological alterations and decreased inflammatory infiltrates compared to controls. The FXR activating diet also protected WT mice from AOM/DSS-induced CRC by reducing tumors’ number and size. Finally, we proved that the FXR activating diet prevented spontaneous CRC in APCMin/+ mice via an FXR-dependent modulation of BA homeostasis. Our results demonstrate that intestinal FXR activation prevented both inflammation- and genetically-driven colorectal tumorigenesis by modulating BA pool size and composition. This could open new avenues for the therapeutic management of intestinal inflammation and tumorigenesis.
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Affiliation(s)
- Marica Cariello
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (M.C.); (R.Z.); (E.P.); (C.P.)
- National Institute of Biostructures and Biosystems (INBB), 00136 Rome, Italy; (E.P.); (A.R.)
| | - Roberta Zerlotin
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (M.C.); (R.Z.); (E.P.); (C.P.)
| | - Emanuela Pasculli
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (M.C.); (R.Z.); (E.P.); (C.P.)
| | - Elena Piccinin
- Department of Basic Medical Science, Neurosciences and Sense Organs, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy;
| | - Claudia Peres
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (M.C.); (R.Z.); (E.P.); (C.P.)
| | - Emanuele Porru
- National Institute of Biostructures and Biosystems (INBB), 00136 Rome, Italy; (E.P.); (A.R.)
- Department of Chemistry “Giacomo Ciamician”, University of Bologna, 40126 Bologna, Italy
| | - Aldo Roda
- National Institute of Biostructures and Biosystems (INBB), 00136 Rome, Italy; (E.P.); (A.R.)
- Department of Chemistry “Giacomo Ciamician”, University of Bologna, 40126 Bologna, Italy
| | - Raffaella Maria Gadaleta
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (M.C.); (R.Z.); (E.P.); (C.P.)
- Correspondence: (R.M.G.); (A.M.); Tel.: +39-3515833893 (R.M.G.); +39-0805593262 (A.M.)
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (M.C.); (R.Z.); (E.P.); (C.P.)
- National Institute of Biostructures and Biosystems (INBB), 00136 Rome, Italy; (E.P.); (A.R.)
- Correspondence: (R.M.G.); (A.M.); Tel.: +39-3515833893 (R.M.G.); +39-0805593262 (A.M.)
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Li N, Zhan S, Tian Z, Liu C, Xie Z, Zhang S, Chen M, Zeng Z, Zhuang X. Alterations in Bile Acid Metabolism Associated With Inflammatory Bowel Disease. Inflamm Bowel Dis 2021; 27:1525-1540. [PMID: 33399195 DOI: 10.1093/ibd/izaa342] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder closely related to gut dysbiosis, which is associated with alterations in an important bacterial metabolite, bile acids (BAs). Although certain findings pertinent to BA changes in IBD vary among studies owing to the differences in sample type, quantitated BA species, study methodology, and patient characteristics, a specific trend concerning variations of BAs in IBD has been identified. In elaborating on this observation, it was noted that primary BAs and conjugated BAs are augmented in fecal samples but there is a reduction in secondary BAs in fecal samples. It is not entirely clear why patients with IBD manifest these changes and what role these changes play in the onset and development of IBD. Previous studies have shown that IBD-associated BA changes may be caused by alterations in BA absorption, synthesis, and bacterial modification. The complex relationship between bacteria and BAs may provide additional and deeper insight into host-gut microbiota interactions in the pathogenesis of IBD. The characteristic BA changes may generate profound effects in patients with IBD by shaping the gut microbiota community, affecting inflammatory processes, causing BA malabsorption associated with diarrhea, and even leading to intestinal dysplasia and cancer. Thus, therapeutic strategies correcting the alterations in the composition of BAs, including the elimination of excess BAs and the supplementation of deficient BAs, may prove promising in IBD.
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Affiliation(s)
- Na Li
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Shukai Zhan
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zhenyi Tian
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Caiguang Liu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zonglin Xie
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Shenghong Zhang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zhirong Zeng
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xiaojun Zhuang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
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Nenkov M, Ma Y, Gaßler N, Chen Y. Metabolic Reprogramming of Colorectal Cancer Cells and the Microenvironment: Implication for Therapy. Int J Mol Sci 2021; 22:6262. [PMID: 34200820 PMCID: PMC8230539 DOI: 10.3390/ijms22126262] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/07/2021] [Accepted: 06/08/2021] [Indexed: 12/20/2022] Open
Abstract
Colorectal carcinoma (CRC) is one of the most frequently diagnosed carcinomas and one of the leading causes of cancer-related death worldwide. Metabolic reprogramming, a hallmark of cancer, is closely related to the initiation and progression of carcinomas, including CRC. Accumulating evidence shows that activation of oncogenic pathways and loss of tumor suppressor genes regulate the metabolic reprogramming that is mainly involved in glycolysis, glutaminolysis, one-carbon metabolism and lipid metabolism. The abnormal metabolic program provides tumor cells with abundant energy, nutrients and redox requirements to support their malignant growth and metastasis, which is accompanied by impaired metabolic flexibility in the tumor microenvironment (TME) and dysbiosis of the gut microbiota. The metabolic crosstalk between the tumor cells, the components of the TME and the intestinal microbiota further facilitates CRC cell proliferation, invasion and metastasis and leads to therapy resistance. Hence, to target the dysregulated tumor metabolism, the TME and the gut microbiota, novel preventive and therapeutic applications are required. In this review, the dysregulation of metabolic programs, molecular pathways, the TME and the intestinal microbiota in CRC is addressed. Possible therapeutic strategies, including metabolic inhibition and immune therapy in CRC, as well as modulation of the aberrant intestinal microbiota, are discussed.
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Affiliation(s)
| | | | | | - Yuan Chen
- Section Pathology of the Institute of Forensic Medicine, University Hospital Jena, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany; (M.N.); (Y.M.); (N.G.)
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5
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Liñares-Blanco J, Munteanu CR, Pazos A, Fernandez-Lozano C. Molecular docking and machine learning analysis of Abemaciclib in colon cancer. BMC Mol Cell Biol 2020; 21:52. [PMID: 32640984 PMCID: PMC7346626 DOI: 10.1186/s12860-020-00295-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 06/24/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The main challenge in cancer research is the identification of different omic variables that present a prognostic value and personalised diagnosis for each tumour. The fact that the diagnosis is personalised opens the doors to the design and discovery of new specific treatments for each patient. In this context, this work offers new ways to reuse existing databases and work to create added value in research. Three published signatures with significante prognostic value in Colon Adenocarcinoma (COAD) were indentified. These signatures were combined in a new meta-signature and validated with main Machine Learning (ML) and conventional statistical techniques. In addition, a drug repurposing experiment was carried out through Molecular Docking (MD) methodology in order to identify new potential treatments in COAD. RESULTS The prognostic potential of the signature was validated by means of ML algorithms and differential gene expression analysis. The results obtained supported the possibility that this meta-signature could harbor genes of interest for the prognosis and treatment of COAD. We studied drug repurposing following a molecular docking (MD) analysis, where the different protein data bank (PDB) structures of the genes of the meta-signature (in total 155) were confronted with 81 anti-cancer drugs approved by the FDA. We observed four interactions of interest: GLTP - Nilotinib, PTPRN - Venetoclax, VEGFA - Venetoclax and FABP6 - Abemaciclib. The FABP6 gene and its role within different metabolic pathways were studied in tumour and normal tissue and we observed the capability of the FABP6 gene to be a therapeutic target. Our in silico results showed a significant specificity of the union of the protein products of the FABP6 gene as well as the known action of Abemaciclib as an inhibitor of the CDK4/6 protein and therefore, of the cell cycle. CONCLUSIONS The results of our ML and differential expression experiments have first shown the FABP6 gene as a possible new cancer biomarker due to its specificity in colonic tumour tissue and no expression in healthy adjacent tissue. Next, the MD analysis showed that the drug Abemaciclib characteristic affinity for the different protein structures of the FABP6 gene. Therefore, in silico experiments have shown a new opportunity that should be validated experimentally, thus helping to reduce the cost and speed of drug screening. For these reasons, we propose the validation of the drug Abemaciclib for the treatment of colon cancer.
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Affiliation(s)
- Jose Liñares-Blanco
- Department of Computer Science and Information Technologies, Faculty of Computer Science, University of A Coruña, CITIC, Campus Elviña s/n, A Coruña, 15071, Spain
| | - Cristian R Munteanu
- Department of Computer Science and Information Technologies, Faculty of Computer Science, University of A Coruña, CITIC, Campus Elviña s/n, A Coruña, 15071, Spain.,Grupo de Redes de Neuronas Artificiales y Sistemas Adaptativos. Imagen Médica y Diagnóstico Radiológico (RNASA-IMEDIR). Instituto de Investigación Biomédica de A Coruña (INIBIC). Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas. Universidade da Coruña (UDC), Xubias de arriba, 84, A Coruña, 15006, Spain
| | - Alejandro Pazos
- Department of Computer Science and Information Technologies, Faculty of Computer Science, University of A Coruña, CITIC, Campus Elviña s/n, A Coruña, 15071, Spain.,Grupo de Redes de Neuronas Artificiales y Sistemas Adaptativos. Imagen Médica y Diagnóstico Radiológico (RNASA-IMEDIR). Instituto de Investigación Biomédica de A Coruña (INIBIC). Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas. Universidade da Coruña (UDC), Xubias de arriba, 84, A Coruña, 15006, Spain
| | - Carlos Fernandez-Lozano
- Department of Computer Science and Information Technologies, Faculty of Computer Science, University of A Coruña, CITIC, Campus Elviña s/n, A Coruña, 15071, Spain. .,Grupo de Redes de Neuronas Artificiales y Sistemas Adaptativos. Imagen Médica y Diagnóstico Radiológico (RNASA-IMEDIR). Instituto de Investigación Biomédica de A Coruña (INIBIC). Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas. Universidade da Coruña (UDC), Xubias de arriba, 84, A Coruña, 15006, Spain.
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6
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Zhang Y, Zhao X, Deng L, Li X, Wang G, Li Y, Chen M. High expression of FABP4 and FABP6 in patients with colorectal cancer. World J Surg Oncol 2019; 17:171. [PMID: 31651326 PMCID: PMC6814121 DOI: 10.1186/s12957-019-1714-5] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 09/24/2019] [Indexed: 12/26/2022] Open
Abstract
Objective To explore the relationship between FABP4 and FABP6 expression and the pathogenesis of colorectal cancer (CRC) and their potential as biomarkers in the diagnosis of CRC. Methods In total, 100 CRC patients and 100 controls were enrolled. The serum levels of FABP4 and FABP6 were detected by enzyme-linked immunosorbent assay (ELISA) before and 2 weeks after radical resection of CRC. The protein expressions of FABP4 and FABP6 were observed in colorectal tumor tissues and adjacent tissues by immunohistochemistry and western blot, respectively. The diagnostic performance of FABP4 and FABP6 in patients with CRC was evaluated by receiver operating characteristic (ROC) curve analysis. Results The serum levels of FABP4 and FABP6 in patients with CRC were higher than the levels in the controls before surgery (P < 0.001), and significantly decreased at 2 weeks after operation (P < 0.001). Immunohistochemistry showed that FABP4 and FABP6 were mainly distributed in the cytoplasm of human colorectal tumor tissues, and only a small amount distributed in adjacent tissues. Western blot revealed that the protein expressions of FABP4 and FABP6 were significantly higher in tumor tissues than in adjacent tissues (P < 0.001, P = 0.002, respectively). Tumors with high and low FABP4 and FABP6 expression have no significant correlation in tumor size, tumor site, distant organ and lymph node metastasis, histologic grade, lymphatic permeation, neurological invasion, vascular invasion, and Duke’s and TNM classification. Multivariate logistic regression analysis showed that FABP4 and FABP6 were independent risk factors for CRC (adjusted odds ratio 1.916; 95%CI 1.340–2.492; P < 0.001; adjusted odds ratio 2.162; 95%CI 1.046, 1.078); P < 0.001, respectively). In discriminating CRC from the normal control, the optimal sensitivity of FABP4 and FABP6 were 93.20% (95%CI 87.8–96.7) and 83.70% (95%CI 76.7–89.3), respectively, while the optimal specificity of FABP4 and FABP6 were 48.8% (95%CI 39.8–57.9) and 58.4% (95%CI 49.2–67.1), respectively. When combined detection of serum carcinoembryonic (CEA) and FABP4 and FABP6, the optimal sensitivity and specificity were 61.33% (95%CI 53.0–69.2) and 79.82% (95%CI 71.3–86.8), respectively. Conclusion Increased expression of FABP4 and FABP6 not only were strong risk factors for the development of CRC but could also represent a potential biomarker for CRC diagnosis in Chinese patients. Combined detection of CEA with FABP4 and FABP6 could improve the diagnostic efficacy of CRC.
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Affiliation(s)
- Yaqin Zhang
- Department of Endocrinology, the First Affiliated Hospital of Anhui Medical University, 210 JiXi Road, Hefei, 230032, People's Republic of China
| | - Xiaotong Zhao
- Department of Endocrinology, the First Affiliated Hospital of Anhui Medical University, 210 JiXi Road, Hefei, 230032, People's Republic of China
| | - Lili Deng
- Department of Endocrinology, the First Affiliated Hospital of Anhui Medical University, 210 JiXi Road, Hefei, 230032, People's Republic of China
| | - Xueting Li
- Department of Endocrinology, the First Affiliated Hospital of Anhui Medical University, 210 JiXi Road, Hefei, 230032, People's Republic of China
| | - Ganbiao Wang
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China
| | - Yongxing Li
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China
| | - Mingwei Chen
- Department of Endocrinology, the First Affiliated Hospital of Anhui Medical University, 210 JiXi Road, Hefei, 230032, People's Republic of China. .,Institute of Diabetes Prevention and Control, Academy of Traditional Chinese Medicine, Hefei, 230032, People's Republic of China.
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7
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Vaughn BP, Kaiser T, Staley C, Hamilton MJ, Reich J, Graiziger C, Singroy S, Kabage AJ, Sadowsky MJ, Khoruts A. A pilot study of fecal bile acid and microbiota profiles in inflammatory bowel disease and primary sclerosing cholangitis. Clin Exp Gastroenterol 2019; 12:9-19. [PMID: 30666146 PMCID: PMC6330977 DOI: 10.2147/ceg.s186097] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Introduction Inflammatory bowel disease (IBD) is thought to arise from an abnormal immune response to the gut microbiota. IBD is associated with altered intestinal microbial community structure and functionality, which may contribute to inflammation and complications such as colon cancer and liver disease. Primary sclerosing cholangitis (PSC) is associated with IBD and markedly increases the risk of colon cancer. We hypothesized that secondary bile acids, which are products of microbial metabolism, are increased in PSC patients. Aim Here, we profiled the fecal bile acid composition and gut microbiota of participants with IBD and PSC, as well as healthy participants. Additionally, we tested the effects of vancomycin, a proposed treatment for PSC, on gut microbiota and fecal bile acid composition in participants with IBD and PSC. Methods Fecal samples were collected from patients with IBD, IBD/PSC and healthy controls and fecal bile acids and DNA for microbiota analysis were extracted. Fecal bile acids were averaged over a seven-day period. For subjects with IBD/PSC, oral vancomycin 500mg twice a day was administered and fecal samples were collected for up to eleven weeks. Results Participants with IBD and PSC had less fecal microbial diversity at baseline relative to controls. While there was some evidence of altered conversion of cholic acid to deoxycholic acid, no substantial differences were found in the fecal bile acid profiles of patients with IBD and PSC (n=7) compared to IBD alone (n=8) or healthy controls (n=8). Oral vancomycin was a potent inhibitor of secondary bile acid production in participants with IBD and PSC, particularly deoxycholic acid, although no changes in liver biochemistry patterns were noted over a two week period. Conclusion In this pilot study, bile acid profiles were overall similar among patients with IBD and PSC, IBD alone, and healthy controls. Microbiota diversity was reduced in those with PSC and IBD compared to IBD alone or healthy controls.
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Affiliation(s)
- Byron P Vaughn
- Inflammatory Bowel Program, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, MN, USA,
| | - Thomas Kaiser
- BioTechnology Institute, University of Minnesota, St Paul, MN, USA.,Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Christopher Staley
- BioTechnology Institute, University of Minnesota, St Paul, MN, USA.,Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | | | - Jon Reich
- Inflammatory Bowel Program, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, MN, USA,
| | - Carolyn Graiziger
- Inflammatory Bowel Program, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, MN, USA,
| | | | - Amanda J Kabage
- Inflammatory Bowel Program, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, MN, USA,
| | - Michael J Sadowsky
- BioTechnology Institute, University of Minnesota, St Paul, MN, USA.,Department of Soil, Water, and Climate, University of Minnesota, St Paul, MN, USA.,Department of Plant and Microbial Biology, University of Minnesota, St Paul, MN, USA
| | - Alexander Khoruts
- Inflammatory Bowel Program, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, MN, USA, .,BioTechnology Institute, University of Minnesota, St Paul, MN, USA
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Pulusu SSR, Lawrance IC. Dysplasia and colorectal cancer surveillance in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2017; 11:711-722. [PMID: 28475382 DOI: 10.1080/17474124.2017.1327347] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease (IBD) patients are at an increased risk of developing colorectal cancer (CRC), a devastating complication of which intestinal dysplasia is the precursor. Considerable progress has been made to determine CRC risk in IBD, identification & management of dysplasia and preventative methods. Traditionally, surveillance colonoscopies with random colonic biopsies was used. However recent data suggests that chromoendoscopy is a better method of surveillance. Using 5-aminosalicylic acid agents primarily for chemoprevention is an ongoing debate however, when prescribed along with other strategies to control inflammation, their use is considered of benefit. This review presents current understanding of risk factors of neoplasia focusing on dysplasia and preventive strategies. Areas covered: PubMed search was done using key words to assess current evidence. Along with genetics, risk factors, strategies that modify the risk of dysplasia, and CRC in IBD are discussed in detail. Expert commentary: The role of our strategies in modifying CRC risk needs further assessment. Future research should aim to fill knowledge gaps such as high quality evidence for Chromoendoscopy and development of molecular markers for dysplasia detection. Our ultimate goal would be to eliminate CRC and is possible by better understanding of key pathogenic mechanisms in IBD.
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Affiliation(s)
- Samba Siva Reddy Pulusu
- a Centre for Inflammatory Bowel Diseases , Saint John of God Hospital , Subiaco , WA , Australia
| | - Ian C Lawrance
- a Centre for Inflammatory Bowel Diseases , Saint John of God Hospital , Subiaco , WA , Australia.,b Harry Perkins Institute of Medical Research, School of Medicine and Pharmacology , University of Western Australia , Murdoch , WA , Australia
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9
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Bile acids and colon cancer: Is FXR the solution of the conundrum? Mol Aspects Med 2017; 56:66-74. [DOI: 10.1016/j.mam.2017.04.002] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Revised: 03/20/2017] [Accepted: 04/07/2017] [Indexed: 02/07/2023]
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10
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Colussi D, Bazzoli F, Ricciardiello L. Chemoprevention of Colorectal Cancer in High-Risk Patients: from Molecular Targets to Clinical Trials. CURRENT COLORECTAL CANCER REPORTS 2017. [DOI: 10.1007/s11888-017-0364-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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11
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Parian A, Lazarev M. Who and how to screen for cancer in at-risk inflammatory bowel disease patients. Expert Rev Gastroenterol Hepatol 2015; 9:731-46. [PMID: 25592672 DOI: 10.1586/17474124.2015.1003208] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel diseases (IBDs) include both Crohn's disease and ulcerative colitis and both diseases are marked by inflammation within the gastrointestinal tract. Due to long-standing inflammation, IBD patients are at increased risk of colorectal cancer, especially patients with chronic inflammation, pancolitis, co-diagnosis of primary sclerosing cholangitis and a longer duration of disease. Small bowel inflammation places Crohn's patients at an increased risk of small bowel cancer. A higher risk of skin cancers, lymphomas and cervical abnormalities is also seen in IBD patients; this is likely related to both disease factors and the presence of immunosuppressive medication. This article reviews which patients are at an increased risk of IBD-associated or IBD treatment-associated cancers, when to begin screening and which screening methods are recommended.
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Affiliation(s)
- Alyssa Parian
- Department of Gastroenterology, Johns Hopkins University, 4940 Eastern Avenue, Building A, Baltimore, MD 21224, USA
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Gadaleta RM, Cariello M, Sabbà C, Moschetta A. Tissue-specific actions of FXR in metabolism and cancer. Biochim Biophys Acta Mol Cell Biol Lipids 2014; 1851:30-9. [PMID: 25139561 DOI: 10.1016/j.bbalip.2014.08.005] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 08/08/2014] [Accepted: 08/11/2014] [Indexed: 12/25/2022]
Abstract
The nuclear Farnesoid X Receptor (FXR) is a transcription factor critically involved in metabolic homeostasis in the gut-liver axis. FXR activity is mediated by hormonal and dietary signals and driven by bile acids (BAs), which are the natural FXR ligands. Given the great physiological importance in BA homeostasis, as well as in the regulation of glucose and lipid metabolism, FXR plays a pivotal role in the pathogenesis of a wide range of disease of the liver, biliary tract and intestine, including hepatic and colorectal cancer. In the last years several studies have shown the relative FXR tissue-specific importance, highlighting synergism and additive effects in the liver and intestine. Gain- and loss-of-FXR-function mouse models have been generated in order to identify the biological processes and the molecular FXR targets. Taking advantage of the knowledge on the structure-activity relationship of BAs for FXR, semi-synthetic and synthetic molecules have been generated to obtain more selective and powerful FXR activators than BAs. This article is part of a Special Issue entitled: Linking transcription to physiology in lipodomics.
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Affiliation(s)
- Raffaella Maria Gadaleta
- Division of Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College London, UK
| | - Marica Cariello
- National Cancer Research Center, IRCCS Istituto Oncologico "Giovanni Paolo II", Bari, Italy
| | - Carlo Sabbà
- Clinica Medica Frugoni, Department of Interdisciplinary Medicine, University of Bari, Italy
| | - Antonio Moschetta
- National Cancer Research Center, IRCCS Istituto Oncologico "Giovanni Paolo II", Bari, Italy; Clinica Medica Frugoni, Department of Interdisciplinary Medicine, University of Bari, Italy.
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Tsaitas C, Semertzidou A, Sinakos E. Update on inflammatory bowel disease in patients with primary sclerosing cholangitis. World J Hepatol 2014; 6:178-187. [PMID: 24799986 PMCID: PMC4009473 DOI: 10.4254/wjh.v6.i4.178] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 03/05/2014] [Accepted: 03/13/2014] [Indexed: 02/06/2023] Open
Abstract
Patients with primary sclerosing cholangitis (PSC) complicated by inflammatory bowel disease (IBD) represent a distinct subset of patients with unique characteristics, which have serious clinical implications. The aim of this literature review was to shed light to the obscure clinical and molecular aspects of the two diseases combined utilizing current data available and putting issues of diagnosis and treatment into perspective. The prevalence of IBD, mainly ulcerative colitis in PSC patients is estimated to be 21%-80%, dependent on screening programs and nationality. PSC-associated colitis is likely to be extensive, characterized by rectal sparing, backwash ileitis, and generally mild symptoms. It is also more likely to progress to colorectal malignancy, making it imperative for clinicians to maintain a high level of suspicion when tackling PSC patients. There is no optimal surveillance strategy but current guidelines advocate that colonoscopy is necessary at the time of PSC diagnosis with annual endoscopic follow-up. Random biopsies have been criticized and a shift towards targeted biopsies using chromoendoscopy, laser endomicroscopy and narrow-band imaging has been noted. Techniques directed towards genetic mutations instead of histological abnormalities hold promise for easier, more accurate diagnosis of dysplastic lesions. Chemopreventive measures against colorectal cancer have been sought in these patients. Ursodeoxycholic acid seemed promising at first but subsequent studies yielded conflicting results showing anticarcinogenic effects in low doses (8-15 mg/kg per day) and carcinogenic properties in high doses (15-30 mg/kg per day).
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Affiliation(s)
- Christos Tsaitas
- Christos Tsaitas, Anysia Semertzidou, Emmanouil Sinakos, 4 Internal Medicine Unit, University Hospital of Thessaloniki, Thessaloniki 54642, Greece
| | - Anysia Semertzidou
- Christos Tsaitas, Anysia Semertzidou, Emmanouil Sinakos, 4 Internal Medicine Unit, University Hospital of Thessaloniki, Thessaloniki 54642, Greece
| | - Emmanouil Sinakos
- Christos Tsaitas, Anysia Semertzidou, Emmanouil Sinakos, 4 Internal Medicine Unit, University Hospital of Thessaloniki, Thessaloniki 54642, Greece
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Farnesoid X receptor expression is decreased in colonic mucosa of patients with primary sclerosing cholangitis and colitis-associated neoplasia. Inflamm Bowel Dis 2013; 19:275-82. [PMID: 23348121 DOI: 10.1097/mib.0b013e318286ff2e] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The expression and distribution of farnesoid X receptor (FXR) in colitis and colitis-associated neoplasia (CAN) is unknown. We investigated FXR expression in neoplastic and nonneoplastic tissue from ulcerative colitis (UC) patients, with or without primary sclerosing cholangitis (PSC), as well as the role of DNA methylation in FXR expression in colorectal cancer (CRC) cell lines. METHODS Samples from the right (RC) and left (LC) colon of patients with UC, with and without PSC, and with or without CAN, were stained by immunohistochemistry and scored semiquantitatively for nuclear FXR expression. FXR expression was analyzed by western blot and polymerase chain reaction (PCR) in nine different CRC cell lines before and after demethylation with 5-azacytidine. RESULTS In nondysplastic samples, FXR expression demonstrated a diminishing expression from proximal to distal colon (strong FXR expression: 39% RC samples vs. 14% LC samples; P = 0.007). With moderate-to-severe inflammation, FXR expression was almost always absent or weak in both UC and PSC-UC, regardless of location. With quiescent/mild inflammation, 56% of UC samples in the RC retained strong FXR expression versus 24% of PSC-UC samples (P= 0.017). FXR was absent in 72% of the neoplastic samples, with an inverse association with the grade of dysplasia. FXR expression was absent in all CRC cell lines, in some cases due to DNA methylation. CONCLUSIONS FXR expression is inversely correlated with neoplastic progression and severity of inflammation in UC. Patients with PSC-UC have diminished FXR expression in the proximal colon compared to UC patients. This finding could contribute to the higher risk of proximal neoplasia in PSC patients.
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Trivedi PJ, Chapman RW. PSC, AIH and overlap syndrome in inflammatory bowel disease. Clin Res Hepatol Gastroenterol 2012; 36:420-36. [PMID: 22306055 DOI: 10.1016/j.clinre.2011.10.007] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2011] [Revised: 10/08/2011] [Accepted: 10/14/2011] [Indexed: 02/07/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a progressive, cholestatic disorder characterised by chronic inflammation and stricture formation of the biliary tree. Symptoms include pruritus, fatigue and in advanced cases ascending cholangitis, cirrhosis and end-stage hepatic failure. Patients are at an increased risk of malignancy arising from the bile ducts, gallbladder, liver and colon. The majority (>80%) of Northern European patients with PSC also have inflammatory bowel disease (IBD), usually ulcerative colitis (UC). IBD commonly presents before the onset of PSC, although the opposite can occur and the onset of both conditions can be separated by many years. The colitis associated with PSC is characteristically mild although frequently involves the whole colon. Despite the majority of patients having relatively inactive colonic disease, paradoxically the risk of colorectal malignancy is substantially increased. Patients may also develop dominant, stenotic lesions of the biliary tree which may be difficult to differentiate from cholangiocarcinoma and the coexistence of IBD may influence the development of this complication. Ursodeoxycholic acid may offer a chemoprotective effect against colorectal malignancy and improve liver biochemical indices. Evidence of any beneficial effect on histological progression of hepatobiliary disease is less clear. High doses (∼25-30 mg/kg/d) may be harmful and should be avoided. Autoimmune hepatitis (AIH) is less common in patients with IBD than PSC, however, an association has been observed. A small subgroup may have an overlap syndrome between AIH and PSC and management should be individualised dependant on liver histology, serum immunoglobulin levels, autoantibodies, degree of biochemical cholestasis and cholangiography.
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Affiliation(s)
- P J Trivedi
- Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, Wolfson Drive, Edgbaston, Birmingham, B15 2TT United Kingdom.
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Abstract
Colorectal cancer is the third and second most common cancer among men and women, respectively, in France. Interest in the chemoprevention of colorectal cancer has increased over the last two decades. Experimental data strongly suggest that ursodeoxycholic acid (UDCA) may have chemopreventative actions in colorectal cancer. UDCA is able to inhibit tumor development in azoxymethane and in dextran-related colitis models. In high-risk populations such as subjects with previous colorectal adenoma removal or inflammatory bowel disease, five out of 10 published studies suggested beneficial effects with UDCA on colonic carcinogenesis. In the azoxymethane model, UDCA inhibited tumor development by counteracting the tumor-promoting effects of secondary bile acids such as deoxycholic acid (DCA). The opposing effects of UDCA and DCA on lipid raft composition may be central to their effects on colonic tumorigenesis. Differential effects of DCA and UDCA on growth factor and inflammatory signals involved in colorectal carcinogenesis, such as epidermal growth factor receptor (EGFR) signaling and COX-2 expression, very likely mediate their opposing effects on colonic tumor promotion and tumor inhibition, respectively.
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Affiliation(s)
- Lawrence Serfaty
- Service d'Hépatologie, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France.
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Braden B, Halliday J, Aryasingha S, Sharifi Y, Checchin D, Warren BF, Kitiyakara T, Travis SPL, Chapman RW. Risk for colorectal neoplasia in patients with colonic Crohn's disease and concomitant primary sclerosing cholangitis. Clin Gastroenterol Hepatol 2012; 10:303-308. [PMID: 22037429 DOI: 10.1016/j.cgh.2011.10.020] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2011] [Revised: 10/05/2011] [Accepted: 10/17/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Patients with ulcerative colitis and concomitant primary sclerosing cholangitis (PSC) have a greater risk of developing colorectal dysplasia or invasive cancer than patients with only ulcerative colitis. Therefore, annual surveillance colonoscopies are recommended. We investigated whether primary sclerosing cholangitis is also a risk factor for colorectal dysplasia or cancer in patients with Crohn's disease of the colon. METHODS We performed a retrospective review of data from a tertiary care hospital on 166 patients with PSC and inflammatory bowel disease; 120 had concomitant ulcerative colitis, 35 had Crohn's disease, and 11 had indeterminate colitis. The controls comprised 114 patients with colonic involvement of Crohn's disease and 102 patients with ulcerative colitis. The main outcome parameter was the development of colorectal cancer or intraepithelial neoplasia. RESULTS Only 1 patient with colonic Crohn's disease and concomitant PSC developed dysplasia in an adenomatous polyp during a median follow-up of 10 years (range, 7-16 years). In contrast, 2 cancers and 8 cases of colorectal dysplasia were diagnosed in patients with ulcerative colitis and PSC during a median follow up of 11 years (range, 8-16 years); the crude annual incidence of dysplasia or colorectal cancer was 1 in 150 patients with ulcerative colitis. Among patients with colonic Crohn's disease without PSC, 2 developed colorectal cancer during follow-up. The presence of PSC did not increase the risk of developing colorectal dysplasia in patients with Crohn's disease (P = 1.00). CONCLUSIONS PSC does not seem to increase the risk for dysplasia of the colon in patients with colonic Crohn's disease.
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Affiliation(s)
- Barbara Braden
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, United Kingdom
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Hanouneh IA, Macaron C, Lopez R, Zein NN, Lashner BA. Risk of colonic neoplasia after liver transplantation for primary sclerosing cholangitis. Inflamm Bowel Dis 2012; 18:269-74. [PMID: 21425212 DOI: 10.1002/ibd.21692] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2011] [Accepted: 01/25/2011] [Indexed: 12/20/2022]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) confers an increased risk of colon cancer in patients with inflammatory bowel disease (IBD). However, there is a scarcity of data to determine whether the rate of colon cancer changes after liver transplantation (LT) in IBD patients with PSC. The aims were 1) to estimate the risk of colon neoplasia after LT in IBD patients with PSC; 2) to identify the factors associated with colon neoplasia after LT in IBD patients with PSC. METHODS We identified patients with IBD/PSC who underwent LT from 1998-2005 (n = 43). Two control groups were identified. Control 1 was IBD/PSC who did not undergo LT, matched 1:1 for age, gender, and type of IBD. Control 2 was patients with chronic liver disease other than PSC who underwent LT, matched 1:1 for age, gender, and follow-up time since LT. All patients were monitored by serial colonoscopy. Logistic regression analysis was used. RESULTS During a mean follow-up of 54.7 ± 47.7 months, patients with IBD/PSC who underwent LT had similar rate of colon neoplasia compared to those who did not have LT (34% versus 30%, P = 0.24). The rate of colon neoplasia in LT recipients was higher in PSC patients compared to those with other forms of chronic liver disease (34% versus 0%, P = 0.018). Post-LT cytomegalovirus infection was associated with higher likelihood of colon neoplasia post-LT in IBD/PSC patients (hazard ratio = 4.4, P = 0.024). There was no significant difference in survival outcome between the three study groups. CONCLUSIONS IBD/PSC patients remain at an increased risk of colon neoplasia after LT.
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Affiliation(s)
- Ibrahim A Hanouneh
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio 44195, USA
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Shen B, Bennett AE, Navaneethan U, Lian L, Shao Z, Kiran RP, Fazio VW, Remzi FH. Primary sclerosing cholangitis is associated with endoscopic and histologic inflammation of the distal afferent limb in patients with ileal pouch-anal anastomosis. Inflamm Bowel Dis 2011; 17:1890-900. [PMID: 21830267 DOI: 10.1002/ibd.21594] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2010] [Accepted: 11/03/2010] [Indexed: 12/16/2022]
Abstract
BACKGROUND We hypothesized that patients with primary sclerosing cholangitis (PSC) may have a higher risk for prepouch ileitis in the setting of ileal pouch-anal anastomosis (IPAA). The aim of this study was to compare endoscopic and histologic inflammation in the afferent limb (prepouch ileum) and pouch between IPAA patients with and without PSC. METHODS In all, 39 consecutive inflammatory bowel disease (IBD) and IPAA patients with PSC (study group) were identified and 91 IBD and IPAA patients without PSC (control group) were randomly selected with a 1:2 ratio. Demographic, clinical, endoscopic, and histologic variables were analyzed. RESULTS There were no significant differences in age, gender, and nonsteroidal antiinflammatory drug use between the study and control groups. Twelve (30.8%) patients in the IPAA-PSC group had coexisting autoimmune disorders, in contrast to five (5.5%) patients in the IPAA control group (P < 0.001). More patients in the study group had endoscopic inflammation as demonstrated by the higher Pouchitis Disease Activity Index (PDAI) endoscopic scores of the afferent limb and pouch body than those in the control group (P = 0.02 and P < 0.001, respectively). In addition, more patients with PSC had higher PDAI histologic scores of the afferent limb than those without PSC (P < 0.001). Multivariate analysis showed higher PDAI endoscopy and histology subscores were associated with risk for PSC, with odds ratio 1.34 (95% confidence interval [CI]: 1.34, 3.79) and 1.61 (95% CI: 1.00, 2.58), respectively. CONCLUSIONS Concurrent PSC appears to be associated with a significant prepouch ileitis on endoscopy and histology in patients with IPAA. Pouch patients with long segment of ileitis should be evaluated for PSC.
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Affiliation(s)
- Bo Shen
- Department of Gastroenterology, the Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
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Torres J, Pineton de Chambrun G, Itzkowitz S, Sachar DB, Colombel JF. Review article: colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease. Aliment Pharmacol Ther 2011; 34:497-508. [PMID: 21692821 DOI: 10.1111/j.1365-2036.2011.04753.x] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease strongly associated with inflammatory bowel disease (IBD). IBD patients diagnosed with PSC have an increased risk of colorectal dysplasia and cancer. AIMS To review the available evidence regarding colorectal neoplasia epidemiology, preventive strategies and outcomes in patients with PSC and IBD, and to advance some hypotheses regarding possible mechanisms involved in cancer pathogenesis in these patients. METHODS A PubMed search was conducted for the English language publications with predetermined search criteria. Reference lists from studies selected were manually searched to identify further relevant reports. Relevant manuscripts considering colorectal neoplasia in patients with PSC-IBD were selected. RESULTS Primary sclerosing cholangitis increases the risk of colorectal neoplasia in patients with ulcerative colitis; fewer data are available for Crohn's disease. PSC-IBD patients tend to be younger at diagnosis of IBD and at diagnosis of colorectal cancer. Colorectal cancer in PSC-IBD patients predominates in the right colon. The increased risk of neoplasia is maintained after liver transplant and proctocolectomy. The role of ursodeoxycholic acid as a chemopreventive agent is controversial. The mechanisms underlying increased risk of colorectal neoplasia in these patients remain unknown. CONCLUSIONS A more comprehensive understanding of the mechanisms involved in colorectal neoplasia development in PSC-IBD patients is needed. Until then, early cancer detection through enrolment in surveillance programmes is the only available strategy to decrease cancer risk.
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Affiliation(s)
- J Torres
- The Dr. Henry D. Janowitz Division of Gastroenterology, Mount Sinai School of Medicine, New York, NY, USA
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Subramanian V, Logan RF. Chemoprevention of colorectal cancer in inflammatory bowel disease. Best Pract Res Clin Gastroenterol 2011; 25:593-606. [PMID: 22122774 DOI: 10.1016/j.bpg.2011.09.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Accepted: 09/11/2011] [Indexed: 02/07/2023]
Abstract
The risk of developing colorectal cancer is increased in patients with inflammatory bowel disease (IBD). Surveillance colonoscopy has not been shown to prolong survival and rates of interval cancer are reported to be high. Various chemopreventive agents have been clearly shown to reduce the risk of colorectal adenoma and cancer in the general population and the problems associated with colonoscopic surveillance have led to increasing interest in utilising chemopreventive strategies to reduce the risk of colorectal cancer in patients with inflammatory bowel disease as well. Continuing colonic inflammation has been shown to be important in the development of colorectal cancer and therefore anti-inflammatory agents have been considered potential chemopreventive agents. As present no agents have been shown to have indisputable chemopreventive activity in IBD but 5-ASAs and thiopurine analogues by reducing inflammation are likely to have some chemopreventive activity and will often be indicated for disease control. More studies are needed using agents such as aspirin and calcium which have been shown to be chemopreventive in sporadic colorectal neoplasia.
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Serfaty L, Bissonnette M, Poupon R. Ursodeoxycholic acid and chemoprevention of colorectal cancer. ACTA ACUST UNITED AC 2010; 34:516-22. [PMID: 20609543 DOI: 10.1016/j.gcb.2010.05.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2010] [Revised: 05/20/2010] [Accepted: 05/20/2010] [Indexed: 01/12/2023]
Abstract
Colorectal cancer is respectively the third and second most common cancer among men and women in France. Interest in chemoprevention for colorectal cancer has increased over the last two decades. Beside non-steroidal anti-inflammatory drugs, ursodeoxycholic acid (UDCA) may have chemopreventive action in colorectal cancer with a likely better tolerance. In high-risk populations such as patients with inflammatory bowel disease or prior colorectal adenoma or carcinoma, retrospective and prospective studies have suggested a beneficial effect of UDCA. In azoxymethane model, UDCA inhibits tumor development by countering the tumor-promoting effects of secondary bile acids, such as deoxycholic acid (DCA). The opposing effects of UDCA and DCA on lipid raft composition may be central to their effects on colonic tumorigenesis. Differential effects of DCA and UDCA on growth factor and inflammatory signals involved in colorectal carcinogenesis, such as epidermal growth factor receptors (EGFR) signaling and Cox-2 expression, likely mediate their opposing effects on colonic tumor promotion and tumor inhibition, respectively.
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Affiliation(s)
- L Serfaty
- Service d'hépatologie, hôpital Saint-Antoine, Assistance publique-Hôpitaux de Paris, université Pierre-et-Marie-Curie, 184 rue du Faubourg-Saint-Antoine, Paris cedex 12, France.
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Byrne AM, Foran E, Sharma R, Davies A, Mahon C, O’Sullivan J, O’Donoghue D, Kelleher D, Long A. Bile acids modulate the Golgi membrane fission process via a protein kinase Cη and protein kinase D-dependent pathway in colonic epithelial cells. Carcinogenesis 2010; 31:737-44. [DOI: 10.1093/carcin/bgq011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Claessen MMH, Lutgens MWMD, van Buuren HR, Oldenburg B, Stokkers PCF, van der Woude CJ, Hommes DW, de Jong DJ, Dijkstra G, van Bodegraven AA, Siersema PD, Vleggaar FP. More right-sided IBD-associated colorectal cancer in patients with primary sclerosing cholangitis. Inflamm Bowel Dis 2009; 15:1331-6. [PMID: 19229982 DOI: 10.1002/ibd.20886] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Patients with inflammatory bowel disease (IBD) and concurrent primary sclerosing cholangitis (PSC) have a higher risk of developing colorectal cancer (CRC) than IBD patients without PSC. The aim of this study was to investigate potential clinical differences between patients with CRC in IBD and those with CRC in IBD and PSC, as this may lead to improved knowledge of underlying pathophysiological mechanisms of CRC development. METHODS The retrospective study from 1980-2006 involved 7 Dutch university medical centers. Clinical data were retrieved from cases identified using the national pathology database (PALGA). RESULTS In total, 27 IBD-CRC patients with PSC (70% male) and 127 IBD-CRC patients without PSC (59% male) were included. CRC-related mortality was not different between groups (30% versus 19%, P = 0.32); however, survival for cases with PSC after diagnosing CRC was lower (5-year survival: 40% versus 75% P = 0.001). Right-sided tumors were more prevalent in the PSC group (67% versus 36%, P = 0.006); adjusted for age, sex, and extent of IBD, this difference remained significant (odds ratio: 4.8, 95% confidence interval [CI] 2.0-11.8). In addition, tumors in individuals with PSC were significantly more advanced. CONCLUSIONS The right colon is the predilection site for development of colonic malignancies in patients with PSC and IBD. When such patients are diagnosed with cancer they tend to have more advanced tumors than patients with IBD without concurrent PSC, and the overall prognosis is worse. Furthermore, the higher frequency of right-sided tumors in patients with PSC suggests a different pathogenesis between patients with PSC and IBD and those with IBD alone.
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Affiliation(s)
- M M H Claessen
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, The Netherlands
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Ejderhamn J, Hedenborg G, Strandvik B. Long-term double-blind study on the influence of dietary fibres on faecal bile acid excretion in juvenile ulcerative colitis. Scandinavian Journal of Clinical and Laboratory Investigation 2009; 52:697-706. [PMID: 1360699 DOI: 10.3109/00365519209115515] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
A double-blind cross-over long-term trial (18 months) with randomized supplementation with wheat fibre or ispaghula for two periods of six months, separated by a six-month wash-out period with placebo, was performed in ten patients with juvenile ulcerative colitis to study the effect on faecal bile acid (BA) excretion. All patients were in remission since 0.5-2 years and orally treated with sulphasalazine. The average intake of either fibres was 16 g day-1. Faecal samples were collected (72 h) before and after each fibre period. Faecal water were prepared by centrifugation of faeces at 15,000 g for 2 h. BA in faeces and faecal water were studied using capillary column gas-liquid chromatography-mass spectrometry. Faecal excretion of total BA were not significantly changed by the two fibres. Supplementation with wheat fibre, but not with ispaghula, decreased the faecal concentration of total BA by 43% (p < 0.05), unconjugated BA by 41% (p < 0.01), and taurine conjugated BA by 58% (p < 0.05). Addition of wheat fibre decreased the concentration of chenodeoxycholic acid by 66% (p < 0.05) and isomers of cholic acid by 51% (p < 0.05) in faeces. The mean faecal water concentration of taurine-conjugated BA decreased by 55% when wheat fibre was added (p < 0.05) and the concentration of isomers of deoxycholic acid increased by 39% when ispaghula was supplemented (p < 0.05). The ratio isomeric deoxycholic acid to deoxycholic acid in faecal water increased significantly when wheat fibre was added (p < 0.05). The percentage distribution of secondary and ketonic BA was not influenced by the dietary fibre supplementation. The concentration of BA in faeces and faecal water decreased only by wheat fibre, suggesting that it is superior in obtaining an affect on faecal BA concentration.
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Affiliation(s)
- J Ejderhamn
- Department of Paediatrics, Karolinska Institutet, Huddinge Hospital, Sweden
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Tong JL, Ran ZH, Shen J, Fan GQ, Xiao SD. Association between fecal bile acids and colorectal cancer: a meta-analysis of observational studies. Yonsei Med J 2008; 49:792-803. [PMID: 18972600 PMCID: PMC2615380 DOI: 10.3349/ymj.2008.49.5.792] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
PURPOSE To provide a systematic review with meta-analysis for addressing the relationship between fecal bile acids (FBAs) and colorectal cancer. MATERIALS AND METHODS Electronic databases were searched for all observational studies that examined the relationship between FBAs and colorectal cancer or adenoma, and calculated weighted mean difference (WMD) and 95% confidence interval (CI). Publication bias was assessed with funnel plot. RESULTS Twenty case-control or cohort studies were identified. All studies were pooled to assess the relationship between total FBAs and cancer/adenoma of the large bowel, however, no association was seen (WMD 0.61mg/g freeze-dried feces; 95% CI: -0.35-1.57). Significantly increased concentration of chenodeoxycholic acid (CDCA) was seen while pooling to assess the relationship between CDCA and cancer/adenoma of the large bowel (WMD 0.13 mg/g freeze-dried feces; 95% CI: 0.01-0.25), especially for colorectal cancer (WMD 0.28mg/g freeze-dried feces; 95% CI: 0.10-0.46). However, no significant differences in deoxycholic acid (DCA), lithocholic acid (LCA), and primary and secondary bile acids, were seen between patients with cancer and patients with matched controls regardless of fixed and random effects models. CONCLUSION CDCA might play a role in the etiology of colorectal cancer.
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Affiliation(s)
- Jin Lu Tong
- Department of Gastroenterology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Zhi Hua Ran
- Department of Gastroenterology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Jun Shen
- Department of Gastroenterology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Guo Quan Fan
- Department of Immunology, Shanxi Medical University, Taiyuan, China
| | - Shu Dong Xiao
- Department of Gastroenterology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Disease, Shanghai, China
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Livesey G. Health potential of polyols as sugar replacers, with emphasis on low glycaemic properties. Nutr Res Rev 2007; 16:163-91. [DOI: 10.1079/nrr200371] [Citation(s) in RCA: 212] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Abstract Polyols are hydrogenated carbohydrates used as sugar replacers. Interest now arises because of their multiple potential health benefits. They are non-cariogenic (sugar-free tooth-friendly), low-glycaemic (potentially helpful in diabetes and cardiovascular disease), low-energy and low-insulinaemic (potentially helpful in obesity), low-digestible (potentially helpful in the colon), osmotic (colon-hydrating, laxative and purifying) carbohydrates. Such potential health benefits are reviewed. A major focus here is the glycaemic index (GI) of polyols as regards the health implications of low-GI foods. The literature on glycaemia and insulinaemia after polyol ingestion was analysed and expressed in the GI and insulinaemic index (II) modes, which yielded the values: erythritol 0, 2; xylitol 13, 11; sorbitol 9, 11; mannitol 0, 0; maltitol 35, 27; isomalt 9, 6; lactitol 6, 4; polyglycitol 39, 23. These values are all much lower than sucrose 65, 43 or glucose 100, 100. GI values on replacing sucrose were independent of both intake (up to 50 g) and the state of carbohydrate metabolism (normal, type 1 with artificial pancreas and type 2 diabetes mellitus). The assignment of foods and polyols to GI bands is considered, these being: high (> 70), intermediate (> 55–70), low (> 40–55), and very low (< 40) including non-glycaemic; the last aims to target particularly low-GI-carbohydrate-based foods. Polyols ranged from low to very low GI. An examination was made of the dietary factors affecting the GI of polyols and foods. Polyol and other food GI values could be used to estimate the GI of food mixtures containing polyols without underestimation. Among foods and polyols a departure of II from GI was observed due to fat elevating II and reducing GI. Fat exerted an additional negative influence on GI, presumed due to reduced rates of gastric emptying. Among the foods examined, the interaction was prominent with snack foods; this potentially damaging insulinaemia could be reduced using polyols. Improved glycated haemoglobin as a marker of glycaemic control was found in a 12-week study of type 2 diabetes mellitus patients consuming polyol, adding to other studies showing improved glucose control on ingestion of low-GI carbohydrate. In general some improvement in long-term glycaemic control was discernible on reducing the glycaemic load via GI by as little as 15–20 g daily. Similar amounts of polyols are normally acceptable. Although polyols are not essential nutrients, they contribute to clinically recognised maintenance of a healthy colonic environment and function. A role for polyols and polyol foods to hydrate the colonic contents and aid laxation is now recognised by physicians. Polyols favour saccharolytic anaerobes and aciduric organisms in the colon, purifying the colon of endotoxic, putrefying and pathological organisms, which has clinical relevance. Polyols also contribute towards short-chain organic acid formation for a healthy colonic epithelium. Polyol tooth-friendliness and reduced energy values are affirmed and add to the potential benefits. In regard to gastrointestinal tolerance, food scientists and nutritionists, physicians, and dentists have in their independent professional capacities each now described sensible approaches to the use and consumption of polyols.
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Ohmachi T, Inoue H, Mimori K, Tanaka F, Sasaki A, Kanda T, Fujii H, Yanaga K, Mori M. Fatty acid binding protein 6 is overexpressed in colorectal cancer. Clin Cancer Res 2007; 12:5090-5. [PMID: 16951225 DOI: 10.1158/1078-0432.ccr-05-2045] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Fatty acid binding protein 6 (FABP6) is a cancer-related protein that acts as an intracellular transporter of bile acid in the ileal epithelium. Because bile acids are implicated in the carcinogenesis of colorectal cancer, we evaluated FABP6 expression in colorectal cancer. EXPERIMENTAL DESIGN The expression of FABP6 mRNA was evaluated in 78 paired samples of cancer/normal tissue representing colorectal cancer cases, plus 16 adenomas, and 16 metastatic lymph nodes. An immunohistochemical study was conducted with paraffin sections. In vitro transfection was done to determine FABP6's biological roles. RESULTS The expression of FABP6 mRNA was significantly higher in cancer (75 of 78, 96.2%) than in normal tissue (P<0.001). The expression of mRNA was increased in cancer compared with adenoma, but was dramatically decreased in node metastases. Tumors with high FABP6 expression were smaller in size (P<0.01), more often in the left colon (P<0.05), and had shallower invasion into the bowel wall (P<0.05) compared with those with low expression. There was no significant difference between high- and low-expression tumors regarding clinicopathologic variables such as histologic type, lymph node, or liver metastasis, Dukes' classification, and prognosis. Immunohistochemical study revealed that FABP6 expression was primarily observed in cancer cells. In vitro transfection revealed that transfectants showed weaker invasiveness (P<0.05), more dominant proliferation (P<0.001), and less apoptosis than mock cells. CONCLUSIONS The expression of FABP6 was higher in primary colorectal cancers and adenomas than in normal epithelium, but was dramatically decreased in lymph node metastases, suggesting that FABP6 may play an important role in early carcinogenesis.
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Affiliation(s)
- Takahiro Ohmachi
- Department of Surgery and Molecular Oncology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
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Smith T, Befeler AS. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Curr Gastroenterol Rep 2007; 9:54-9. [PMID: 17335678 DOI: 10.1007/s11894-008-0021-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a cholestatic liver disease that results in progressive fibrosis of intrahepatic and extrahepatic bile ducts. No effective therapy currently exists for this disease. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, is the most promising treatment option because of its benign side effect profile and documented benefit in the treatment of other cholestatic liver diseases, including primary biliary cirrhosis. Multiple studies using standard-dosage (8-15 mg/kg/d) and high-dosage (20-30 mg/kg/d) UDCA generally show improvement in liver chemistries in PSC patients, and several show improvement in liver histology. However, the majority of trials using UDCA in PSC are underpowered and fail to show improvements in clinically relevant endpoints, such as delayed progression to cirrhosis, portal hypertension, liver transplantation, development of cholangiocarcinoma, or death.
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Affiliation(s)
- Timothy Smith
- Division of Gastroenterology and Hepatology, Saint Louis University, 3635 Vista at Grand Boulevard, St. Louis, MO 63110, USA.
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30
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Chan EP, Lichtenstein GR. Chemoprevention: risk reduction with medical therapy of inflammatory bowel disease. Gastroenterol Clin North Am 2006; 35:675-712. [PMID: 16952746 DOI: 10.1016/j.gtc.2006.07.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
The ideal chemopreventative agent, in addition to being efficacious in the prevention of cancer, must be easily administered, affordable, safe, and well tolerated, with minimal side effects. In the past decade, a growing body of literature has emerged on the prevention of CRC in patients with long-standing CD and UC. The data are not definitive and consist almost exclusively of retrospective case-control and cohort studies rather than the more rigorous prospective RCTs. 5-ASA compounds have been most thoroughly studied, and most of the existing data support the use of 5-ASA in the prevention of CRC. Although the precise dose and duration are unclear, studies suggest that chronic systemic administration of 5-ASA at a dose of at least 1.2 g/d is most likely to be effective. A beneficial effect of folate, albeit not statistically significant, has been consistently shown in every study performed for this purpose. Folate supplementation, which is safe and affordable, should also be recommended for all patients with IBD, especially those taking sulfasalazine. UDCA has been shown to exert a protective effect in most studies on patients with UC and concomitant PSC. Because this patient population is at particularly high risk for CRC, it is advisable to consider UDCA in all patients with colitis complicated by PSC. For patients without PSC, sufficient data do not exist to recommend it for the purpose of cancer prevention. Five of the six corticosteroid studies have found a beneficial effect of systemic steroids, although most did not reach statistical significance. Regardless, given the frequent and serious adverse effects associated with chronic steroid use, systemic corticosteroids should not be prescribed for this indication. Budesonide, an oral corticosteroid with minimal systemic absorption, is a potential alternative, although it has not yet been studied as a chemopreventative agent. Similarly, until the long-term safety of chronic NSAID use can be demonstrated in patients with IBD, the role of NSAIDs in chemoprevention remains undefined. Although the data are conflicting, immune-modulating medications, such as AZA, do not seem to confer any reduction in the risk of dysplasia or CRC. The data on calcium supplementation and statin use are still too limited to endorse their use for the prevention of colitis-related CRC. Chemoprevention is an area that holds great promise in the reduction of morbidity and mortality associated with IBD. Further studies, including prospective trials when possible and cost-effectiveness analyses, need to be performed to develop an optimal strategy for the reduction of cancer risk in patients with IBD.
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Affiliation(s)
- Erick P Chan
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283, USA
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Abstract
The management of primary sclerosing cholangitis (PSC) is hindered by incomplete understanding of the pathogenesis of the disease and the lack of good prognostic models. Few large randomized controlled trials of drug therapy have been published. Best practice in the management of PSC is currently based therefore on careful interpretation of the available evidence, close observation of individual patients and clinical experience of the disease. Drug therapy is useful for alleviating symptoms. Ursodeoxycholic acid may slow progression of the disease and reduce the frequency of complications. Consensus is emerging on the issues of screening for the malignant complications of PSC and the indications for liver transplantation are becoming broader and encompassing the earliest stages of cholangiocarcinoma. In view of the rarity of the disease in the general population, large international collaborations to study PSC are necessary to provide clearer answers in areas of uncertainty, and these are now beginning to emerge.
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Affiliation(s)
- S N Cullen
- John Radcliffe Hospital, Oxford OX3 9DU, UK.
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32
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Portincasa P, Vacca M, Moschetta A, Petruzzelli M, Palasciano G, van Erpecum KJ, van Berge-Henegouwen GP. Primary sclerosing cholangitis: updates in diagnosis and therapy. World J Gastroenterol 2005; 11:7-16. [PMID: 15609388 PMCID: PMC4205387 DOI: 10.3748/wjg.v11.i1.7] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2004] [Revised: 05/28/2004] [Accepted: 07/17/2004] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic syndrome of unknown origin mostly found in males, and characterized by diffuse inflammation and fibrosis of both intra- and extra-hepatic bile ducts. So far, PSC is considered as an autoimmune hepatobiliary disease. In most cases the progression of PSC towards liver cirrhosis and liver failure is slow but irreversible, and liver transplantation is currently the only definitive treatment. In recent years, PSC has been an area of active research worldwide with great interest in etiology, pathogenesis, diagnosis, and therapeutic options such as hydrophilic ursodeoxycholic acid and immunosuppressive agent tacrolimus. Recent updates on clinical and therapeutic aspects of PSC are discussed in the present review.
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Affiliation(s)
- Piero Portincasa
- Section of Internal Medicine, Department of Internal and Public Medicine (DIMIMP), University Medical School, Bari, Italy.
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Abstract
Colorectal cancer is a disease with a high mortality at present, due to the late stage at which many cases present. Attention is therefore focusing on preventative strategies for colorectal cancer given that polyps appear to be identifiable and treatable precursor lesions of this disease. Endoscopic polypectomy has been shown to reduce the incidence of colorectal cancer and there is a good case for endoscopic screening of the general population. However, this will require a large amount of manpower and resources and its success will also depend on the overall compliance of the population. Epidemiological studies have shown that individuals reporting a regular intake of aspirin and other non-steroidal anti-inflammatory drugs have a reduced risk of developing colorectal polyps and cancer. Similarly, a number of natural substances, such as calcium and folate, when supplemented regularly in the diet, have also been linked to a possible decreased incidence of colorectal cancer. This has led to the concept of using such agents to reduce the number of cases of colorectal cancer. In this article, we review the current evidence for the use of these and other agents for the chemoprevention of colorectal cancer, together with theories as to their possible mechanisms of action.
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Affiliation(s)
- E D J Courtney
- Gastroenterology Medicine Division, St George's Hospital Medical School, London, UK.
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34
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Croog VJ, Ullman TA, Itzkowitz SH. Chemoprevention of colorectal cancer in ulcerative colitis. Int J Colorectal Dis 2003; 18:392-400. [PMID: 12904996 DOI: 10.1007/s00384-002-0476-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/12/2002] [Indexed: 02/06/2023]
Abstract
BACKGROUND Patients with ulcerative colitis (UC) are at greater risk of developing colorectal cancer (CRC) than the general population. Both duration and extent of UC are important risk factors for CRC, as is the presence of primary sclerosing cholangitis, family history of CRC, and (in some studies) early age at diagnosis of UC. Efforts to reduce this risk have focused on colonoscopic surveillance as the best alternative to the more definitive, but less appealing, approach of prophylactic colectomy. However, spurred on by findings in the sporadic CRC literature, there has been a growing interest in a possible role for chemoprevention of CRC in patients with UC. EMPIRICAL STUDIES Published evidence to date indicates that 5-aminosalicylic acid agents are protective against the development of dysplasia and CRC. Oral, but not topical, steroids also appear to be chemoprotective, but their chronic use cannot be recommended for this indication. Ursodeoxycholic acid has been shown to reduce the risk of neoplasia in UC patients with primary sclerosing cholangitis. Evidence suggests, but does not prove, that folic acid is chemopreventive in patients with UC. Further studies are needed to fully define the chemoprotective role of these and other agents.
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Affiliation(s)
- Victoria J Croog
- Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029, USA
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Pardi DS, Loftus EV, Kremers WK, Keach J, Lindor KD. Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology 2003; 124:889-93. [PMID: 12671884 DOI: 10.1053/gast.2003.50156] [Citation(s) in RCA: 355] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Ursodeoxycholic acid (UDCA) has shown effectiveness as a colon cancer chemopreventive agent in preclinical studies. In addition, a recent report suggests that it also may decrease the risk for developing colorectal dysplasia in patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC). We sought to evaluate the effect of UDCA on colorectal neoplasia in a group of patients with UC and PSC enrolled in a randomized, placebo-controlled trial. METHODS From a prior, randomized, placebo-controlled trial of UDCA therapy in PSC at our center, we followed-up patients with concomitant UC to assess the effect of UDCA on the development of colorectal dysplasia and cancer as compared with placebo. RESULTS Fifty-two subjects were followed-up for a total of 355 person-years. Those originally assigned to receive UDCA had a relative risk of 0.26 for developing colorectal dysplasia or cancer (95% confidence interval, 0.06-0.92; P = 0.034). Many of the patients originally assigned to the placebo group eventually received open-label UDCA. Assigning these patients to the UDCA group from the time they began active therapy did not change the magnitude of the protective effect (relative risk, 0.26; 95% confidence interval, 0.07-0.99; P = 0.049). CONCLUSIONS UDCA significantly decreases the risk for developing colorectal dysplasia or cancer in patients with UC and PSC.
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Affiliation(s)
- Darrell S Pardi
- Division of Gastroenterology and Hepatology and Division of Biostatistics, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
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Lindberg BU, Broomé U, Persson B. Proximal colorectal dysplasia or cancer in ulcerative colitis. The impact of primary sclerosing cholangitis and sulfasalazine: results from a 20-year surveillance study. Dis Colon Rectum 2001; 44:77-85. [PMID: 11805567 DOI: 10.1007/bf02234825] [Citation(s) in RCA: 90] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE Known risk factors for the development of colorectal dysplasia or cancer in ulcerative colitis are total colonic involvement and long duration of the disease. It has recently been suggested that presence of primary sclerosing cholangitis is another independent risk factor-especially for proximal colorectal dysplasia or cancer-and that treatment with sulfasalazine might reduce the frequency of colorectal cancer in ulcerative colitis; the present study was undertaken to shed light on the validity of these theories. METHODS A total of 143 patients with ulcerative colitis underwent regular colonoscopies and multiple biopsies in a 20-year surveillance program for studies of long-standing total ulcerative colitis. Fifty-one of the patients developed colorectal dysplasia or cancer. Patient records were scrutinized retrospectively for information of presence of primary sclerosing cholangitis, site of the colorectal malignancy, and results of sulfasalazine treatment. RESULTS Nineteen of the patients had primary sclerosing cholangitis; these ran a significantly higher risk of developing colorectal dysplasia or cancer than patients with ulcerative colitis only. All colorectal cancers (n = 3) and 75 percent of all colorectal dysplasias or cancers among patients with primary sclerosing cholangitis were located in the proximal part of the colon, whereas 36 percent were found in that same region among the patients with ulcerative colitis without primary sclerosing cholangitis (P = 0.02). Sulfasalazine treatment showed no significant protective effect on the development of colorectal dysplasia or cancer in patients with ulcerative colitis. CONCLUSION The risk evaluation, as assessed by multivariate analysis, shows that primary sclerosing cholangitis proves to be an additional and independent risk factor for the development of colorectal dysplasia or cancer in patients with ulcerative colitis-particularly in the proximal part of the colon. The findings do not support the theory that sulfasalazine treatment exerts a protective effect against colorectal dysplasia or cancer.
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Affiliation(s)
- B U Lindberg
- Department of Diagnostic Radiology, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden
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Haines A, Hill MJ, Thompson MH, Owen RW, Williams RE, Meade TW, Wilkes H, Griffin M. A prospective study of faecal bile acids and colorectal cancer. Eur J Cancer Prev 2000; 9:317-23. [PMID: 11075884 DOI: 10.1097/00008469-200010000-00005] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
A prospective study of 7079 people aged 45-74 recruited through general practices in South Wales, Herefordshire and Edinburgh, Scotland was undertaken to test the hypothesis that faecal bile acids are implicated in the causation of large bowel cancer. The population was recruited between 1974 and 1980 and the response rate for stool collection was 67%. Bile acid analyses were performed on those cases that presented by 1990. It was decided in advance to examine the hypothesis separately for left- and right-sided bowel cancer because of known epidemiological differences between the two sites and to exclude the cases presenting within 2 years of the stool sample from the analyses because the cancer could have been present at recruitment and might have possibly affected faecal bile acid concentrations. Each case (n = 51 left-sided and 8 right-sided) was matched with three controls by age (within 5 years), sex, place of residence and time of providing the stool sample (within 3 months). Statistical analyses using conditional logistic regression showed no significant differences between the left-sided cases and controls for any of the concentrations of individual bile acids, total bile acid concentrations, faecal neutral steroids, percentage bacterial conversion and the ratio of lithocholic acid to deoxycholic acid concentrations. There was a statistically significant (P = 0.021) association of the presence of chenodeoxycholic acid (5/8 samples) in the right-sided cases compared with the controls (3/23), odds ratio 6.26 (95% confidence interval 1.19, 32.84). A high proportion of primary bile acids has also been found in other studies of patients with a genetic predisposition to proximal bowel cancer, however this pattern may also occur in low risk groups, such as Indian vegetarians, suggesting that they may predispose to right-sided bowel cancer only in the presence of other, as yet unknown factors. If bile acids are involved in the causation of large bowel cancer, they may be part of a complex set of interacting factors.
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Affiliation(s)
- A Haines
- Department of Primary Care and Population Sciences, Royal Free and University College Medical School, London, UK.
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Shetty K, Rybicki L, Brzezinski A, Carey WD, Lashner BA. The risk for cancer or dysplasia in ulcerative colitis patients with primary sclerosing cholangitis. Am J Gastroenterol 1999; 94:1643-9. [PMID: 10364038 DOI: 10.1111/j.1572-0241.1999.01156.x] [Citation(s) in RCA: 194] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Recent studies have implicated primary sclerosing cholangitis (PSC) as a risk factor for colorectal cancer (CRC) in ulcerative colitis (UC). Our study was designed to define both the risk and the risk factors for CRC or dysplasia in a large UC cohort with PSC. METHODS Patients with UC and PSC were compared with a random sample of UC controls without PSC. Patients were analyzed from the inception of disease until an outcome or censor. RESULTS Thirty-three (25%) of 132 UC patients with PSC developed CRC or dysplasia compared with 11 (5.6%) of 196 controls (adjusted relative risk 3.15, 95% confidence interval 1.37-7.27). Possible risk factors were chronic disease activity and lack of folate supplementation. Of 17 CRCs in the PSC group, 76% occurred proximal to the splenic flexure and 35% presented at an advanced stage, compared with one of five (20%) CRCs in controls being proximal and none being advanced. Six (4.5%) PSC patients, and no controls, died of CRC (p < 0.01). CONCLUSIONS UC patients with PSC are at increased risk of developing CRC or dysplasia. Chronically active disease may be a risk factor, whereas folate could have a protective effect. CRCs associated with PSC are more likely to be proximal, to be diagnosed at a more advanced stage, and to be fatal.
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Affiliation(s)
- K Shetty
- Center for Inflammatory Bowel Disease, Department of Gastroenterology, Cleveland Clinic Foundation, Ohio 44195, USA
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Jenkins DJ, Kendall CW, Mehling CC, Parker T, Rao AV, Agarwal S, Novokmet R, Jones PJ, Raeini M, Story JA, Furumoto E, Vidgen E, Griffin LC, Cunnane SC, Ryan MA, Connelly PW. Combined effect of vegetable protein (soy) and soluble fiber added to a standard cholesterol-lowering diet. Metabolism 1999; 48:809-16. [PMID: 10381159 DOI: 10.1016/s0026-0495(99)90184-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Dietary treatment of hyperlipidemia focuses on reducing saturated fat and dietary cholesterol. Other aspects of diet are not emphasized at present, despite growing evidence that a number of plant components decrease serum cholesterol. We therefore determined whether a combination of two plant components, vegetable protein and soluble fiber, further reduce serum lipids when incorporated into the currently advocated low-saturated-fat diet. Thirty-one hyperlipidemic men and women ate two 1-month low-fat (<7% of total energy from saturated fat), low-cholesterol (<80 mg cholesterol/d) metabolic diets in a randomized crossover study. The major differences between test and control diets were an increased amount of vegetable protein (93% v 23% of total protein), of which 33 g/d was soy, and a doubling of soluble fiber. Fasting blood samples were obtained at the start and end of each phase. On the last 3 days of each phase, fecal collections were obtained. Compared with the low-fat control diet, the test diet decreased total cholesterol (6.2% +/- 1.2%, P < .001), low-density lipoprotein (LDL) cholesterol (6.7% +/- 1.7%, P < .001), apolipoprotein B (8.2% +/- 1.2%, P < .001), and the ratios of LDL to high-density lipoprotein (HDL) cholesterol (6.3% +/- 2.0%, P = .004) and apolipoprotein B to A-I (5.4% +/- 1.5%, P = .001). A combination of vegetable protein and soluble fiber significantly improved the lipid-lowering effect of a low-saturated-fat diet. The results support expanding the current dietary advice to include increased vegetable protein and soluble fiber intake so that the gap in effectiveness between a good diet and drug therapy is reduced.
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Affiliation(s)
- D J Jenkins
- Clinical Nutrition and Risk Factor Modification Center and the Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada
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van Klinken BJ, Dekker J, van Gool SA, van Marle J, Büller HA, Einerhand AW. MUC5B is the prominent mucin in human gallbladder and is also expressed in a subset of colonic goblet cells. THE AMERICAN JOURNAL OF PHYSIOLOGY 1998; 274:G871-8. [PMID: 9612268 DOI: 10.1152/ajpgi.1998.274.5.g871] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
To elucidate the roles of human gallbladder mucin (HGBM), such as in gallstone formation and cytoprotection, it is essential to identify HGBM and study its expression. This was performed by metabolic labeling, Western blotting, immunohistochemistry, and RT-PCR. In a large number of individuals, antibodies against purified HGBM and against MUC5B detected a mucin precursor (approximately 470 kDa) in the gallbladder and colon, but not in the small intestine. In the gallbladder, Western blotting using specific anti-MUC5B antibodies showed that this mucin precursor represented an identical mucin, MUC5B. RT-PCR experiments demonstrated a similar tissue distribution pattern of MUC5B mRNA. Immunohistochemistry with anti-HGBM and anti-MUC5B showed staining in gallbladder epithelial cells and colonic goblet cells in the crypt base, but not in the small intestine; double labeling showed that HGBM was located in small granules within goblet cells, colocalizing to MUC2-containing goblet cells. Metabolic labeling demonstrated the secretion of mature MUC5B in the colon. Conclusively, MUC5B is identified as the prominent HGBM and is also expressed and secreted in the colon.
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Affiliation(s)
- B J van Klinken
- Department of Electron Microscopy, Emma Children's Hospital AMC, University of Amsterdam, The Netherlands
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Velázquez OC, Seto RW, Choi J, Zhou D, Breen F, Fisher JD, Rombeau JL. Butyrate inhibits deoxycholate-induced increase in colonic mucosal DNA and protein synthesis in vivo. Dis Colon Rectum 1997; 40:1368-75. [PMID: 9369115 DOI: 10.1007/bf02050825] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
PURPOSE Crypt surface hyperproliferation is an intermediate biomarker of colon cancer risk. In vitro studies indicate that the short-chain fatty acid and antineoplastic agent butyrate may reverse the crypt surface hyperproliferation induced by the secondary bile acid and tumor promoter, deoxycholate. We hypothesized that butyrate may reverse deoxycholate-induced crypt surface proliferation in vivo. METHODS Thirty-one Sprague-Dawley rats (250-300 g) underwent surgical isolation of the colon and 24-hour luminal instillation of either sodium chloride, butyrate, deoxycholate, or butyrate plus deoxycholate (all solutions, 2 ml; pH 7; total sodium = 20 mM). Study variables included colon weight, mucosal DNA, mucosal protein, and proliferating cell nuclear antigen immunohistochemistry, labeling of which was determined in five crypt compartments from base to surface (12 crypts per rat). Labeling indexes were calculated as proliferating cell nuclear antigen immunohistochemistry-labeled cells divided by total counted cells in the whole colonic crypt and each of five crypt compartments. The phi(h) value (an index of premalignant risk) was calculated as the ratio of labeled cells in the two surface compartments divided by the total labeled cells. RESULTS Deoxycholate significantly increased colon wet weight, mucosal protein, total crypt labeling indexes, crypt surface labeling indexes, and the phi(h) value and raised the mucosal DNA content. Butyrate alone slightly reduced total mucosal DNA and protein content. The combination of butyrate plus deoxycholate significantly decreased mucosal DNA and tended to reduce mucosal protein compared with deoxycholate alone. In contrast to prior in vitro findings, butyrate plus deoxycholate did not reverse the deoxycholate-induced surface hyperproliferative changes as measured by proliferating cell nuclear antigen labeling. CONCLUSIONS Because co-treatment with butyrate plus deoxycholate inhibits deoxycholate-induced increases in total mucosal DNA and protein content, we conclude that butyrate may play a role in maintaining the proliferative balance of the colonic mucosa, in vivo. However, co-treatment with butyrate plus deoxycholate does not reverse the deoxycholate-induced increases in colon weight and proliferating cell nuclear antigen labeling indexes under the studied experimental conditions.
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Affiliation(s)
- O C Velázquez
- Harrison Department of Surgical Research, University of Pennsylvania Medical Center, Philadelphia 19104, USA
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Leidenius MH, Färkkilä MA, Kärkkäinen P, Taskinen EI, Kellokumpu IH, Höckerstedt KA. Colorectal dysplasia and carcinoma in patients with ulcerative colitis and primary sclerosing cholangitis. Scand J Gastroenterol 1997; 32:706-11. [PMID: 9246712 DOI: 10.3109/00365529708996522] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND The aim of this study was to evaluate the role of primary sclerosing cholangitis (PSC) as a cofactor in the dysplasia-carcinoma sequence in ulcerative colitis (UC). METHODS Forty-five patients with UC and concomitant PSC and 45 pair-matched control patients with UC only were examined for colorectal dysplasia and carcinoma. RESULTS The median duration of UC was 11 years in the group with UC and PSC and 15 years in the control group. Thirteen of the 45 patients (29%) with UC and PSC had colorectal neoplasia: 4, carcinoma; 2, high-grade dysplasia; and 7, low-grade dysplasia. Four of the 45 control patients (9%) had neoplastic findings: 1, carcinoma; 1, high-grade dysplasia, and 2, low-grade dysplasia (P < 0.05). CONCLUSION The results suggest that the risk of colorectal dysplasia and carcinoma in patients with UC is increased by concomitant PSC.
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Affiliation(s)
- M H Leidenius
- Fourth Dept. of Surgery, Helsinki University Central Hospital, Finland
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Velázquez OC, Zhou D, Seto RW, Jabbar A, Choi J, Lederer HM, Rombeau JL. In vivo crypt surface hyperproliferation is decreased by butyrate and increased by deoxycholate in normal rat colon: associated in vivo effects on c-Fos and c-Jun expression. JPEN J Parenter Enteral Nutr 1996; 20:243-50. [PMID: 8865104 DOI: 10.1177/0148607196020004243] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Studies on colon carcinogenesis suggest that the short-chain fatty acid butyrate may be protective, whereas the secondary bile acid deoxycholate may promote tumor development. Crypt surface hyperproliferation is regarded as a biomarker of colon cancer risk and can be modulated in vitro by the differentiation inducer butyrate and the tumor promoter deoxycholate. We hypothesized that butyrate decreases and deoxycholate increases crypt surface proliferation in vivo and that these effects are mediated by changes in the expression of the protooncogenes c-Fos and c-Jun, which are known to regulate proliferation and differentiation. METHODS Twenty-five adult Sprague-Dawley rats underwent colonic isolation and 24-hour intraluminal instillation of 10 mmol/L sodium chloride, 10 mmol/ L sodium butyrate, or 10 mmol/L sodium deoxycholate. Proliferation of the whole crypt and five crypt compartments from base to surface was assessed by proliferating cell nuclear antigen immunohistochemistry. The øh value, an index of "premalignant" hyperproliferation, was calculated as the ratio of labeled cells in the two surface compartments divided by the labeled cells in the entire crypt. Expression of c-Fos and c-Jun was evaluated by Western blot. RESULTS Crypt surface proliferation and the øh value were significantly decreased by butyrate and increased by deoxycholate. Butyrate increased colonic expression of c-Jun, whereas deoxycholate significantly induced c-Fos. CONCLUSIONS The in vivo effects on surface proliferation are consistent with a potential protective [corrected] role for butyrate and a promotive role for deoxycholate in colon carcinogenesis. The concurrently observed effects on colonic c-Jun and c-Fos expression represent a novel finding and suggest that direct or indirect modulation of protooncogene expression may be the mechanism by which these dietary byproducts regulate proliferation in vivo.
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Affiliation(s)
- O C Velázquez
- Harrison Department of Surgical Research, University of Pennsylvania Medical Center, Philadelphia, USA
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Korpela JT, Korpela R, Adlercreutz H. Fecal bile acid metabolic pattern after administration of different types of bread. Gastroenterology 1992; 103:1246-53. [PMID: 1327933 DOI: 10.1016/0016-5085(92)91511-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Increased concentrations of fecal bile acids have been suggested to be associated with increased risk of colorectal cancer. Fecal bile acid profiles were determined in 12 healthy Finnish women who included in their normal diets for 2-week periods in turn three different types of bread, 200-300 g/day. The breads contained either low-fiber wheat, whole-meal wheat, or whole-grain rye. During consumption of rye bread, the total mean concentration of fecal free bile acids was 4.77 +/- 0.90 mumol/g of dry feces (mean +/- SEM), which was much lower than with the normal omnivorous diet (8.05 +/- 1.56 mumol/g) or during administration of the low-fiber wheat bread (8.83 +/- 1.56 mumol/g) or the whole-meal wheat bread (7.88 +/- 1.34 mumol/g) (P less than 0.05). This decrease was mainly caused by increased proportions of saponifiable bile acids (P less than 0.01). During intake of the whole-grain rye bread, 46% +/- 3% of the fecal bile acids were in their saponifiable forms; this percentage was 30% +/- 3% during the control period, 30% +/- 4% during the low-fiber wheat bread period, and 27% +/- 4% during the whole-meal wheat bread period. It is concluded that the type of bread significantly effects concentrations of cocarcinogenic and comutagenic free lithocholic and deoxycholic acids by changing modes of conjugation in the gut.
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Affiliation(s)
- J T Korpela
- Department of Clinical Chemistry, University of Helsinki, Meilahti Hospital, Finland
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Broomé U, Lindberg G, Löfberg R. Primary sclerosing cholangitis in ulcerative colitis--a risk factor for the development of dysplasia and DNA aneuploidy? Gastroenterology 1992; 102:1877-80. [PMID: 1587406 DOI: 10.1016/0016-5085(92)90308-l] [Citation(s) in RCA: 139] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
In a 15-year surveillance program for long-standing, total ulcerative colitis (UC), 72 patients were followed up with colonoscopic biopsies. Seventeen patients developed definite dysplasia, carcinoma, and/or DNA aneuploidy. Alkaline phosphatase and transaminases were examined in all patients. In the group with dysplasia, carcinoma, and/or DNA aneuploidy, 5 patients (28%) were found to have primary sclerosing cholangitis (PSC) based on histological and/or cholangiographic criteria. In the group without definite dysplasia or DNA aneuploidy, no patient with PSC appeared, although two patients with other forms of chronic liver disorders were found. The difference in distribution of PSC between the two groups was statistically significant (P = 0.0004). Using logistic regression, the presence of PSC and the duration of UC were identified as independent risk factors associated with dysplasia and/or DNA aneuploidy. Thus, UC patients with PSC seem to run an increased risk of developing colonic dysplasia and/or DNA aneuploidy. Although the reason for the increased risk is still unclear, these results warrant increased surveillance among patients with both PSC and longstanding, total UC.
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Affiliation(s)
- U Broomé
- Department of Medicine, Karolinska Institute, Huddinge University Hospital, Sweden
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Roediger WE, Lawson MJ, Radcliffe BC. Nitrite from inflammatory cells--a cancer risk factor in ulcerative colitis? Dis Colon Rectum 1990; 33:1034-6. [PMID: 2242698 DOI: 10.1007/bf02139219] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Elevated levels of luminal nitrite and a lowered luminal pH were found in 77 percent of patients with acute ulcerative colitis. No luminal nitrite was found in healthy control subjects. Nitrites are a secretory product of activated macrophages and neutrophils of the lamina propria, whereas the lowered luminal pH is due to diminished bicarbonate formation by impaired colonocytes. A hypothesis is put forward that nitrites, lowered pH, and bacterial amines are conducive to formation of carcinogenic n-nitroso compounds, which reflect a cancer risk in patients with ulcerative colitis dependent on the type and extent of inflammatory cell activation as well as metabolic impairment of colonic epithelial cells.
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Affiliation(s)
- W E Roediger
- Department of Surgery, University of Adelaide, Australia
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Fears R, Brown R, Ferres H, Grenier F, Tyrrell AW. Effects of novel bile salts on cholesterol metabolism in rats and guinea-pigs. Biochem Pharmacol 1990; 40:2029-37. [PMID: 2242032 DOI: 10.1016/0006-2952(90)90233-b] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Novel bile salts (quaternary ammonium conjugates) inhibited cholic acid binding and transport in everted ileal sacs in vitro. The cationic piperazine conjugate of lithocholic acid (di-iodide salt, compound 8, BRL 39924A) appeared most active, inhibiting binding by 29% and transport by 59% in guinea-pig ileum (200 microM). BRL 39924A also inhibited taurocholate uptake into guinea-pig ileal sacs and cholate uptake into rat ileal sacs and was selected for further study in vivo. In hyperlipidaemic rats, BRL 39924A significantly raised cholesterol 7 alpha-hydroxylase activity and decreased hepatic accumulation of exogenous cholic acid. HDL cholesterol concentration in the serum increased and the level of VLDL plus LDL cholesterol decreased. In hyperlipidaemic guinea-pigs. BRL 39924A lowered serum total cholesterol and triglyceride levels. Although metabolic changes were less than those achieved with the bile acid sequestrant, cholestyramine, the doses of BRL 39924A used were much lower (100-500 mg/kg body wt). Selective inhibition of receptor mediated bile acid uptake may be associated with local side-effects but these novel bile salts are useful pharmacological tools to examine the effects of receptor blockade on lipoprotein metabolism.
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Affiliation(s)
- R Fears
- Beecham Pharmaceuticals Research Division, Epsom, Surrey, U.K
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Affiliation(s)
- M J Hill
- PHLS-CAMR, Salisbury, Wilts., Great Britain
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Abstract
The development and continued refinement of techniques for the efficient insertion and expression of heterologous DNA sequences from within the genomic context of infectious vaccinia virus recombinants are among the most promising current approaches towards effective immunoprophylaxis against a variety of protozoan, viral, and bacterial human pathogens. Because of its medical relevance, this area is the subject of intense research interest and has evolved rapidly during the past several years. This review (i) provides an updated overview of the technology that exists for assembling recombinant vaccinia virus strains, (ii) discusses the advantages and disadvantages of these approaches, (iii) outlines the areas of outgoing research directed towards overcoming the limitations of current techniques, and (iv) provides some insight (i.e., speculation) about probable future refinements in the use of vaccinia virus as a vector.
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Affiliation(s)
- D E Hruby
- Department of Microbiology, Oregon State University, Corvallis 97331-3804
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