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1
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Wu EH, Guo Z, Zhu WM. Postoperative diarrhea in Crohn's disease: Pathogenesis, diagnosis, and therapy. World J Clin Cases 2023; 11:7-16. [PMID: 36687182 PMCID: PMC9846968 DOI: 10.12998/wjcc.v11.i1.7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/08/2022] [Accepted: 12/23/2022] [Indexed: 01/04/2023] Open
Abstract
Diarrhea is a frequent symptom in postoperative patients with Crohn's diseases (CD), and several different mechanisms likely account for postoperative diarrhea in CD. A targeted strategy based on a comprehensive understanding of postoperative diarrhea is helpful for better postoperative recovery.
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Affiliation(s)
- En-Hao Wu
- Department of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Zhen Guo
- Department of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Wei-Ming Zhu
- Department of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
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2
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Larabi AB, Masson HLP, Bäumler AJ. Bile acids as modulators of gut microbiota composition and function. Gut Microbes 2023; 15:2172671. [PMID: 36740850 PMCID: PMC9904317 DOI: 10.1080/19490976.2023.2172671] [Citation(s) in RCA: 127] [Impact Index Per Article: 63.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 01/16/2023] [Indexed: 02/07/2023] Open
Abstract
Changes in the composition of gut-associated microbial communities are associated with many human illnesses, but the factors driving dysbiosis remain incompletely understood. One factor governing the microbiota composition in the gut is bile. Bile acids shape the microbiota composition through their antimicrobial activity and by activating host signaling pathways that maintain gut homeostasis. Although bile acids are host-derived, their functions are integrally linked to bacterial metabolism, which shapes the composition of the intestinal bile acid pool. Conditions that change the size or composition of the bile acid pool can trigger alterations in the microbiota composition that exacerbate inflammation or favor infection with opportunistic pathogens. Therefore, manipulating the composition or size of the bile acid pool might be a promising strategy to remediate dysbiosis.
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Affiliation(s)
- Anaïs B. Larabi
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, Davis, CA, USA
| | - Hugo L. P. Masson
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, Davis, CA, USA
| | - Andreas J. Bäumler
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, Davis, CA, USA
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3
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Choden T, Cohen NA. The gut microbiome and the immune system. EXPLORATION OF MEDICINE 2022. [DOI: 10.37349/emed.2022.00087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
The human body contains trillions of microbes which generally live in symbiosis with the host. The interaction of the gut microbiome with elements of the host immune system has far-reaching effects in the development of normal gut and systemic immune responses. Disturbances to this intricate relationship may be responsible for a multitude of gastrointestinal and systemic immune mediated diseases. This review describes the development of the gut microbiome and its interaction with host immune cells in both health and disease states.
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Affiliation(s)
- Tenzin Choden
- Section of Gastroenterology, Hepatology and Nutrition, University of Chicago Medicine, Chicago, IL 60637, USA
| | - Nathaniel Aviv Cohen
- Section of Gastroenterology, Hepatology and Nutrition, University of Chicago Medicine, Chicago, IL 60637, USA; Inflammatory Bowel Disease Center, Department of Gastroenterology and Liver Diseases, Tel Aviv Medical Center, Tel Aviv 6423906, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
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4
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Specific Secondary Bile Acids Control Chicken Necrotic Enteritis. Pathogens 2021; 10:pathogens10081041. [PMID: 34451506 PMCID: PMC8427939 DOI: 10.3390/pathogens10081041] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/13/2021] [Accepted: 08/13/2021] [Indexed: 12/19/2022] Open
Abstract
Necrotic enteritis (NE), mainly induced by the pathogens of Clostridium perfringens and coccidia, causes huge economic losses with limited intervention options in the poultry industry. This study investigated the role of specific bile acids on NE development. Day-old broiler chicks were assigned to six groups: noninfected, NE, and NE with four bile diets of 0.32% chicken bile, 0.15% commercial ox bile, 0.15% lithocholic acid (LCA), or 0.15% deoxycholic acid (DCA). The birds were infected with Eimeria maxima at day 18 and C. perfringens at day 23 and 24. The infected birds developed clinical NE signs. The NE birds suffered severe ileitis with villus blunting, crypt hyperplasia, epithelial line disintegration, and massive immune cell infiltration, while DCA and LCA prevented the ileitis histopathology. NE induced severe body weight gain (BWG) loss, while only DCA prevented NE-induced BWG loss. Notably, DCA reduced the NE-induced inflammatory response and the colonization and invasion of C. perfringens compared to NE birds. Consistently, NE reduced the total bile acids in the ileal digesta, while dietary DCA and commercial bile restored it. Together, this study showed that DCA and LCA reduced NE histopathology, suggesting that secondary bile acids, but not total bile acid levels, play an essential role in controlling the enteritis.
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5
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Sun R, Xu C, Feng B, Gao X, Liu Z. Critical roles of bile acids in regulating intestinal mucosal immune responses. Therap Adv Gastroenterol 2021; 14:17562848211018098. [PMID: 34104213 PMCID: PMC8165529 DOI: 10.1177/17562848211018098] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 04/27/2021] [Indexed: 02/04/2023] Open
Abstract
Bile acids are a class of cholesterol derivatives that have been known for a long time for their critical roles in facilitating the digestion and absorption of lipid from the daily diet. The transformation of primary bile acids produced by the liver to secondary bile acids appears under the action of microbiota in the intestine, greatly expanding the molecular diversity of the intestinal environment. With the discovery of several new receptors of bile acids and signaling pathways, bile acids are considered as a family of important metabolites that play pleiotropic roles in regulating many aspects of human overall health, especially in the maintenance of the microbiota homeostasis and the balance of the mucosal immune system in the intestine. Accordingly, disruption of the process involved in the metabolism or circulation of bile acids is implicated in many disorders that mainly affect the intestine, such as inflammatory bowel disease and colon cancer. In this review, we discuss the different metabolism profiles in diseases associated with the intestinal mucosa and the diverse roles of bile acids in regulating the intestinal immune system. Furthermore, we also summarize recent advances in the field of new drugs that target bile acid signaling and highlight the importance of bile acids as a new target for disease intervention.
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Affiliation(s)
| | | | | | - Xiang Gao
- Department of Gastroenterology, The Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China
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6
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Hughes LE, Ford C, Brookes MJ, Gama R. Bile acid diarrhoea: Current and potential methods of diagnosis. Ann Clin Biochem 2020; 58:22-28. [PMID: 32998535 DOI: 10.1177/0004563220966139] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Chronic diarrhoea is common and mostly due to diarrhoea predominant irritable bowel syndrome. Diarrhoea predominant irritable bowel syndrome affects about 11% of the population; however, up to a third of these patients actually have bile acid diarrhoea. There are, therefore, more than one million sufferers of bile acid diarrhoea in the UK. Bile acid diarrhoea is caused by small bowel malabsorption of bile acids and the increased bile acids in the large intestine cause diarrhoea. Once diagnosed, the treatment of bile acid diarrhoea is simple and effective. Bile acid diarrhoea , however, is often not diagnosed because of a lack of easily available and reliable diagnostic methods. In the United Kingdom, the radiolabelled 23-seleno-25-homotaurocholic acid test is the gold-standard method of diagnosis. 23-seleno-25-homotaurocholic acid test, however, is expensive, inconvenient to the patient, involves radiation exposure and has limited availability. As such, a laboratory biomarker is desirable. This review briefly discusses the pathophysiology and management of bile acid diarrhoea and critically evaluates methods for its diagnosis, including serum 7α-hydroxy-4-cholesten-3-one, faecal bile acid measurement, serum fibroblast growth factor 19, urine-2-propanol, and the 14C-glycocholate breath and stool test.
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Affiliation(s)
- Lauren E Hughes
- Clinical Chemistry, Royal Wolverhampton NHS Trust, Wolverhampton, UK
| | - Clare Ford
- Clinical Chemistry, Royal Wolverhampton NHS Trust, Wolverhampton, UK
| | - Matthew J Brookes
- Department of Gastroenterology, Royal Wolverhampton NHS Trust, Wolverhampton, UK.,Faculty of Education, Health and Wellbeing, University of Wolverhampton, Wolverhampton, UK
| | - Rousseau Gama
- Clinical Chemistry, Royal Wolverhampton NHS Trust, Wolverhampton, UK.,School of Medicine and Clinical Practice, Wolverhampton University, Wolverhampton, UK
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7
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Abstract
Bile acids (BAs) are the central signals in enterohepatic communication, and they also integrate microbiota-derived signals into enterohepatic signaling. The tissue distribution and signaling pathways activated by BAs through natural receptors, farsenoid X receptor and G protein-coupled BA receptor 1 (GPBAR1, also known as Takeda G-coupled receptor 5), have led to a greater understanding of the mechanisms and potential therapeutic agents. BA diarrhea is most commonly encountered in ileal resection or disease, in idiopathic disorders (with presentation similar to functional diarrhea or irritable bowel syndrome with diarrhea), and in association with malabsorption such as chronic pancreatitis or celiac disease. Diagnosis of BA diarrhea is based on Se-homocholic acid taurine retention, 48-hour fecal BA excretion, or serum 7αC4; the latter being a marker of hepatic BA synthesis. BA diarrhea tends to be associated with higher body mass index, increased stool weight and stool fat, and acceleration of colonic transit. Biochemical markers of increased BA synthesis or excretion are available through reference laboratories. Current treatment of BA diarrhea is based on BA sequestrants, and, in the future, it is anticipated that farsenoid X receptor agonists may also be effective. The optimal conditions for an empiric trial with BA sequestrants as a diagnostic test are still unclear. However, such therapeutic trials are widely used in clinical practice. Some national guidelines recommend definitive diagnosis of BA diarrhea over empirical trial.
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8
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Fitzpatrick LR, Jenabzadeh P. IBD and Bile Acid Absorption: Focus on Pre-clinical and Clinical Observations. Front Physiol 2020; 11:564. [PMID: 32595517 PMCID: PMC7303840 DOI: 10.3389/fphys.2020.00564] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 05/07/2020] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel disease (IBD) causes chronic inflammation affecting the GI tract. It is classified as consisting of Crohn’s Disease (CD) and Ulcerative Colitis (UC). Bile Acid absorption is altered in both pre-clinical models of Inflammatory Bowel Disease (IB) and in human IBD. The bile acid transporter apical sodium dependent bile acid transporter (ASBT) showed decreased expression in rats with TNBS colitis. Decreased ASBT expression has also been described in murine, canine and rabbit models of intestinal inflammation. Human IBD studies have shown that an inflamed ileum can interrupt enterohepatic recirculation of bile acid, which could be due to inflammatory cytokine induced repression of the ASBT promoter. There are different hypotheses as to why ASBT is downregulated during CD. In addition, one study has demonstrated the beneficial effect of a glucocorticoid on ASBT expression, when treating IBD. Our aim in this paper was to systematically review various aspects of bile acid malabsorption in animal models of intestinal inflammation, as well as in IBD.
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Affiliation(s)
- Leo R Fitzpatrick
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, CA, United States
| | - Paniz Jenabzadeh
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, CA, United States
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9
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An Inverse Correlation of Serum Fibroblast Growth Factor 19 with Abdominal Pain and Inflammatory Markers in Patients with Ulcerative Colitis. Gastroenterol Res Pract 2020; 2020:2389312. [PMID: 32565779 PMCID: PMC7275953 DOI: 10.1155/2020/2389312] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 05/06/2020] [Indexed: 02/07/2023] Open
Abstract
Background and Aims Bile acids (BA) play an important role in the modulation of numerous gut functions. Fibroblast growth factor 19 (FGF19) is the ileal hormone regulating BA homeostasis. The aim of the study was to evaluate serum FGF19 level and its correlation with clinical and endoscopic disease activity indices along with inflammatory biomarkers including serum CRP and fecal calprotectin levels in patients with ulcerative colitis (UC). Methods Fasting serum FGF19 level was measured using ELISA test in 16 patients with active UC (7 F, 9 M), 15 patients with nonactive UC (8 F, 7 M), and 19 healthy controls (11 F, 8 M). The disease activity was assessed based on the clinical and endoscopic evaluations as well as serum CRP and fecal calprotectin level measurement. Results The median serum FGF19 level was higher in patients with nonactive UC (175.3 pg/ml (108.7-342.3)) than in patients with active UC (114.3 pg/ml (68.9-155.3), p = 0.093). The median FGF19 level in healthy controls amounted to 151.6 pg/ml (90.6-224.2), and there were no statistically significant differences between the patients with active and nonactive UC compared to the healthy controls. An inverse correlation was observed between FGF19 level and abdominal pain intensity (R = –0.48, p = 0.007) as well as fecal calprotectin (R = –0.38, p = 0.036) and CRP levels (R = –0.36, p = 0.045). The serum FGF19 level was not correlated neither with clinical nor endoscopic disease activity indices. Conclusions The inverse correlations between FGF19 level and abdominal pain as well as inflammatory markers in UC may imply its potential analgesic and anti-inflammatory effects.
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10
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Bansal M, Fu Y, Alrubaye B, Abraha M, Almansour A, Gupta A, Liyanage R, Wang H, Hargis B, Sun X. A secondary bile acid from microbiota metabolism attenuates ileitis and bile acid reduction in subclinical necrotic enteritis in chickens. J Anim Sci Biotechnol 2020; 11:37. [PMID: 32190299 PMCID: PMC7069026 DOI: 10.1186/s40104-020-00441-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Accepted: 02/24/2020] [Indexed: 12/18/2022] Open
Abstract
Background Clostridium perfringens-induced chicken necrotic enteritis (NE) is responsible for substantial economic losses worldwide annually. Recently, as a result of antibiotic growth promoter prohibition, the prevalence of NE in chickens has reemerged. This study was aimed to reduce NE through titrating dietary deoxycholic acid (DCA) as an effective antimicrobial alternative. Materials and methods Day-old broiler chicks were assigned to six groups and fed diets supplemented with 0 (basal diet), 0.8, 1.0 and 1.5 g/kg (on top of basal diet) DCA. The birds were challenged with Eimeria maxima (20,000 oocysts/bird) at d 18 and C. perfringens (109 CFU/bird per day) at d 23, 24, and 25 to induce NE. The birds were sacrificed at d 26 when ileal tissue and digesta were collected for analyzing histopathology, mRNA accumulation and C. perfringens colonization by real-time PCR, targeted metabolomics of bile acids, fluorescence in situ hybridization (FISH), or terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Results At the cellular level, birds infected with E. maxima and C. perfringens developed subclinical NE and showed shortening villi, crypt hyperplasia and immune cell infiltration in ileum. Dietary DCA alleviated the NE-induced ileal inflammation in a dose-dependent manner compared to NE control birds. Consistent with the increased histopathological scores, subclinical NE birds suffered body weight gain reduction compared to the uninfected birds, an effect attenuated with increased doses of dietary DCA. At the molecular level, the highest dose of DCA at 1.5 g/kg reduced C. perfringens luminal colonization compared to NE birds using PCR and FISH. Furthermore, the dietary DCA reduced subclinical NE-induced intestinal inflammatory gene expression and cell apoptosis using PCR and TUNEL assays. Upon further examining ileal bile acid pool through targeted metabolomics, subclinical NE reduced the total bile acid level in ileal digesta compared to uninfected birds. Notably, dietary DCA increased total bile acid and DCA levels in a dose-dependent manner compared to NE birds. Conclusion These results indicate that DCA attenuates NE-induced intestinal inflammation and bile acid reduction and could be an effective antimicrobial alternative against the intestinal disease.
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Affiliation(s)
- Mohit Bansal
- 1Center of Excellence for Poultry Science, University of Arkansas, 1260 W Maple St. O409, Fayetteville, AR 72701 USA
| | - Ying Fu
- 1Center of Excellence for Poultry Science, University of Arkansas, 1260 W Maple St. O409, Fayetteville, AR 72701 USA.,2CEMB, University of Arkansas, Fayetteville, AR 72701 USA
| | - Bilal Alrubaye
- 1Center of Excellence for Poultry Science, University of Arkansas, 1260 W Maple St. O409, Fayetteville, AR 72701 USA.,2CEMB, University of Arkansas, Fayetteville, AR 72701 USA
| | - Mussie Abraha
- 1Center of Excellence for Poultry Science, University of Arkansas, 1260 W Maple St. O409, Fayetteville, AR 72701 USA
| | - Ayidh Almansour
- 1Center of Excellence for Poultry Science, University of Arkansas, 1260 W Maple St. O409, Fayetteville, AR 72701 USA.,2CEMB, University of Arkansas, Fayetteville, AR 72701 USA
| | - Anamika Gupta
- 1Center of Excellence for Poultry Science, University of Arkansas, 1260 W Maple St. O409, Fayetteville, AR 72701 USA
| | - Rohana Liyanage
- 3Department of Chemistry, University of Arkansas, Fayetteville, AR 72701 USA
| | - Hong Wang
- 1Center of Excellence for Poultry Science, University of Arkansas, 1260 W Maple St. O409, Fayetteville, AR 72701 USA
| | - Billy Hargis
- 1Center of Excellence for Poultry Science, University of Arkansas, 1260 W Maple St. O409, Fayetteville, AR 72701 USA
| | - Xiaolun Sun
- 1Center of Excellence for Poultry Science, University of Arkansas, 1260 W Maple St. O409, Fayetteville, AR 72701 USA.,2CEMB, University of Arkansas, Fayetteville, AR 72701 USA.,3Department of Chemistry, University of Arkansas, Fayetteville, AR 72701 USA
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11
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Ticho AL, Malhotra P, Dudeja PK, Gill RK, Alrefai WA. Intestinal Absorption of Bile Acids in Health and Disease. Compr Physiol 2019; 10:21-56. [PMID: 31853951 PMCID: PMC7171925 DOI: 10.1002/cphy.c190007] [Citation(s) in RCA: 140] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The intestinal reclamation of bile acids is crucial for the maintenance of their enterohepatic circulation. The majority of bile acids are actively absorbed via specific transport proteins that are highly expressed in the distal ileum. The uptake of bile acids by intestinal epithelial cells modulates the activation of cytosolic and membrane receptors such as the farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (GPBAR1), which has a profound effect on hepatic synthesis of bile acids as well as glucose and lipid metabolism. Extensive research has focused on delineating the processes of bile acid absorption and determining the contribution of dysregulated ileal signaling in the development of intestinal and hepatic disorders. For example, a decrease in the levels of the bile acid-induced ileal hormone FGF15/19 is implicated in bile acid-induced diarrhea (BAD). Conversely, the increase in bile acid absorption with subsequent overload of bile acids could be involved in the pathophysiology of liver and metabolic disorders such as fatty liver diseases and type 2 diabetes mellitus. This review article will attempt to provide a comprehensive overview of the mechanisms involved in the intestinal handling of bile acids, the pathological implications of disrupted intestinal bile acid homeostasis, and the potential therapeutic targets for the treatment of bile acid-related disorders. Published 2020. Compr Physiol 10:21-56, 2020.
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Affiliation(s)
- Alexander L. Ticho
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Pooja Malhotra
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Pradeep K. Dudeja
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
- jesse Brown VA Medical Center, Chicago, Illinois, USA
| | - Ravinder K. Gill
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Waddah A. Alrefai
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
- jesse Brown VA Medical Center, Chicago, Illinois, USA
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12
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Guan S, Jia B, Chao K, Zhu X, Tang J, Li M, Wu L, Xing L, Liu K, Zhang L, Wang X, Gao X, Huang M. UPLC–QTOF-MS-Based Plasma Lipidomic Profiling Reveals Biomarkers for Inflammatory Bowel Disease Diagnosis. J Proteome Res 2019; 19:600-609. [PMID: 31821004 DOI: 10.1021/acs.jproteome.9b00440] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Su Guan
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, P. R. China
| | - Bingjie Jia
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, P. R. China
| | - Kang Chao
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, P. R. China
| | - Xia Zhu
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
| | - Jian Tang
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, P. R. China
| | - Miao Li
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, P. R. China
| | - Lvying Wu
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, P. R. China
| | - Lei Xing
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, P. R. China
| | - Kun Liu
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, P. R. China
| | - Lei Zhang
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, P. R. China
| | - Xueding Wang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
| | - Xiang Gao
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, P. R. China
| | - Min Huang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
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13
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Battat R, Duijvestein M, Casteele NV, Singh S, Dulai PS, Valasek MA, Mimms L, McFarland J, Hester KD, Renshaw M, Jain A, Sandborn WJ, Boland BS. Serum Concentrations of 7α-hydroxy-4-cholesten-3-one Are Associated With Bile Acid Diarrhea in Patients With Crohn's Disease. Clin Gastroenterol Hepatol 2019; 17:2722-2730.e4. [PMID: 30448597 PMCID: PMC6520204 DOI: 10.1016/j.cgh.2018.11.012] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 10/31/2018] [Accepted: 11/02/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Patients with Crohn's disease (CD) often have bile acid diarrhea (BAD), due to bile acid malabsorption following ileal resection (IR). Bile acid malabsorption increases production of 7α-hydroxy-4-cholesten-3-one (C4), a bile acid precursor. We investigated relationships between serum concentrations of C4 and BAD in patients with CD. METHODS We collected demographic data, serum samples, and information on the presence of diarrhea (>3 liquid bowel movements/day), as well as clinical, endoscopic, and histologic scores from 26 patients with CD and IR, 21 patients with CD without IR, and 37 patients with ulcerative colitis (UC). We compared serum concentrations of C4 and fibroblast growth factor 19 (FGF19) between groups. We performed area under the receiver operating characteristic curve (AUROC) analysis to identify the optimal cutoff C4 concentrations for the diagnosis of diarrhea attributable to bile acid malabsorption (BAD), defined as diarrhea and a serum concentration of FGF19 <60 pg/mL. RESULTS Patients with UC had a median serum C4 concentration of 11.8 ng/mL, whereas patients with CD and IR with ileitis (documented endoscopically) had a median concentration of 100.0 ng/mL (P compared to UC < .0001) and patients with CD and IR without ileitis had a median concentration of 51.6 ng/mL (P compared to UC < .001). Patients with CD without IR did not have a significantly higher median concentration of C4 than patients with UC (P = .71), regardless of ileitis (P = .34). When endoscopic findings were confirmed histologically, similar results were found to analyses using endoscopic findings alone. A higher proportion of patients with active UC had diarrhea (72.0% vs 0 patients with inactive UC; P < .001), but their median concentrations of C4 did not differ significantly from that of patients with inactive UC (12.1 ng/mL vs 9.7 ng/mL; P = .3). A cutoff concentration of C4 of 48.3 ng/mL or greater identified patients with diarrhea attributable to bile acid malabsorption with 90.9% sensitivity, 84.4% specificity, and an AUROC 0.94. A significantly higher proportion of patients with concentrations of C4 above this cutoff had BAD (50.0%) than below this cutoff (1.8%) (P < .001). When we analyzed only patients with diarrhea, a C4 cutoff of 48.3 ng/mL identified those with low FGF19 concentrations (<60 pg/mL) with 91% sensitivity and 95.5% specificity (AUROC, 0.99). Above this cutoff, 83.3% of patients had a serum concentration of FGF19 <60 pg/mL compared to 4.5% below this threshold (P < .0001). C4 concentrations correlated with the number of daily bowel movements (r = 0.41; P = .004) and correlated inversely with FGF19 concentrations (r = -0.72; P<.0001). CONCLUSION We observed significantly increased serum concentrations of C4 in patients with CD with IR, compared to patients with UC. A cutoff concentration of C4 above 48.3 ng/mL identifies patients with diarrhea likely attributable to bile acid malabsorption (BAD) with an AUROC value of 0.94. Increased serum levels of bile acid precursors identify patients with diarrhea and a low serum concentration of FGF19, and concentrations of C4 correlate with daily liquid bowel movements and correlate inversely with FGF19 concentrations. C4 may be a biomarker to identify patients with diarrhea attributable to bile acid malabsorption.
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Affiliation(s)
- Robert Battat
- Division of Gastroenterology, University of California San Diego, La Jolla, California, USA
| | - Marjolijn Duijvestein
- Division of Gastroenterology, University of California San Diego, La Jolla, California, USA.,Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands
| | - Niels Vande Casteele
- Division of Gastroenterology, University of California San Diego, La Jolla, California, USA
| | - Siddharth Singh
- Division of Gastroenterology, University of California San Diego, La Jolla, California, USA
| | - Parambir S. Dulai
- Division of Gastroenterology, University of California San Diego, La Jolla, California, USA
| | - Mark A. Valasek
- Department of Pathology, University of California San Diego, La Jolla, California, USA
| | - Larry Mimms
- Prometheus Laboratories Inc., San Diego, California
| | | | | | - Mark Renshaw
- Prometheus Laboratories Inc., San Diego, California
| | - Anjali Jain
- Prometheus Laboratories Inc., San Diego, California
| | - William J Sandborn
- Division of Gastroenterology, University of California San Diego, La Jolla, California, USA
| | - Brigid S Boland
- Division of Gastroenterology, University of California San Diego, La Jolla, California.
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14
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Abstract
The incidence of paediatric Crohn's disease (CD) and ulcerative colitis (UC) is increasing. Surgical intervention is required during childhood in approximately 25% of children diagnosed with CD, and for 10% of those diagnosed with UC. Although there is evidence that the rate of surgical intervention undertaken in children is decreasing since the introduction of biologic therapy, this may only represent a delay rather than true reversal of the risk of surgery. Surgery for CD is not curative and limited resection is the key principle thus preserving bowel length. For UC, subtotal colectomy is relatively curative; ileo-anal pouch anastomosis can be performed to restore bowel continuity.
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Affiliation(s)
- Arun Kelay
- Department of Paediatric Surgery, University Hospital Southampton, Southampton, UK
| | - Lucinda Tullie
- Department of Paediatric Surgery, University Hospital Southampton, Southampton, UK
| | - Michael Stanton
- Department of Paediatric Surgery, University Hospital Southampton, Southampton, UK
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15
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Offei SD, Arman HD, Yoshimoto FK. Chemical synthesis of 7α-hydroxycholest-4-en-3-one, a biomarker for irritable bowel syndrome and bile acid malabsorption. Steroids 2019; 151:108449. [PMID: 31302111 DOI: 10.1016/j.steroids.2019.108449] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 06/19/2019] [Accepted: 07/06/2019] [Indexed: 10/26/2022]
Abstract
7α-Hydroxy-cholest-4-en-3-one is a biomarker for bile acid loss, irritable bowel syndrome, and other diseases associated with defective bile acid biosynthesis. Furthermore, 7α-hydroxy-cholest-4-en-3-one is the physiological substrate for cytochrome P450 8B1 (P450 8B1 or CYP8B1), the oxysterol 12α-hydroxylase enzyme implicated in obesity and cardiovascular health. We report the chemical synthesis of this physiologically important oxysterol beginning with cholesterol. The key feature of this synthesis involves a regioselective C3-allylic oxidation of a 3-desoxy-Δ4-7α-formate steroid precursor to form 7α-formyloxy-cholest-4-en-3-one, which was saponified to yield 7α-hydroxy-cholest-4-en-3-one.
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Affiliation(s)
- Samuel D Offei
- Department of Chemistry, The University of Texas at San Antonio, San Antonio, TX 78249-0698, United States
| | - Hadi D Arman
- Department of Chemistry, The University of Texas at San Antonio, San Antonio, TX 78249-0698, United States
| | - Francis K Yoshimoto
- Department of Chemistry, The University of Texas at San Antonio, San Antonio, TX 78249-0698, United States.
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16
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Barros LL, Farias AQ, Rezaie A. Gastrointestinal motility and absorptive disorders in patients with inflammatory bowel diseases: Prevalence, diagnosis and treatment. World J Gastroenterol 2019; 25:4414-4426. [PMID: 31496621 PMCID: PMC6710178 DOI: 10.3748/wjg.v25.i31.4414] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 07/04/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD), Crohn`s disease and ulcerative colitis, are chronic conditions associated with high morbidity and healthcare costs. The natural history of IBD is variable and marked by alternating periods of flare and remission. Even though the use of newer therapeutic targets has been associated with higher rates of mucosal healing, a great proportion of IBD patients remain symptomatic despite effective control of inflammation. These symptoms may include but not limited to abdominal pain, dyspepsia, diarrhea, urgency, fecal incontinence, constipation or bloating. In this setting, commonly there is an overlap with gastrointestinal (GI) motility and absorptive disorders. Early recognition of these conditions greatly improves patient care and may decrease the risk of mistreatment. Therefore, in this review we describe the prevalence, diagnosis and treatment of GI motility and absorptive disorders that commonly affect patients with IBD.
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Affiliation(s)
- Luísa Leite Barros
- Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo 05403-000, Brazil
| | - Alberto Queiroz Farias
- Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo 05403-000, Brazil
| | - Ali Rezaie
- Division of Gastroenterology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA 90048, United States
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17
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Das P, Marcišauskas S, Ji B, Nielsen J. Metagenomic analysis of bile salt biotransformation in the human gut microbiome. BMC Genomics 2019; 20:517. [PMID: 31234773 PMCID: PMC6591925 DOI: 10.1186/s12864-019-5899-3] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 06/12/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND In the biochemical milieu of human colon, bile acids act as signaling mediators between the host and its gut microbiota. Biotransformation of primary to secondary bile acids have been known to be involved in the immune regulation of human physiology. Several 16S amplicon-based studies with inflammatory bowel disease (IBD) subjects were found to have an association with the level of fecal bile acids. However, a detailed investigation of all the bile salt biotransformation genes in the gut microbiome of healthy and IBD subjects has not been performed. RESULTS Here, we report a comprehensive analysis of the bile salt biotransformation genes and their distribution at the phyla level. Based on the analysis of shotgun metagenomes, we found that the IBD subjects harbored a significantly lower abundance of these genes compared to the healthy controls. Majority of these genes originated from Firmicutes in comparison to other phyla. From metabolomics data, we found that the IBD subjects were measured with a significantly low level of secondary bile acids and high levels of primary bile acids compared to that of the healthy controls. CONCLUSIONS Our bioinformatics-driven approach of identifying bile salt biotransformation genes predicts the bile salt biotransformation potential in the gut microbiota of IBD subjects. The functional level of dysbiosis likely contributes to the variation in the bile acid pool. This study sets the stage to envisage potential solutions to modulate the gut microbiome with the objective to restore the bile acid pool in the gut.
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Affiliation(s)
- Promi Das
- Department of Biology and Biological Engineering, Chalmers University of Technology, SE-41296 Gothenburg, Sweden
| | - Simonas Marcišauskas
- Department of Biology and Biological Engineering, Chalmers University of Technology, SE-41296 Gothenburg, Sweden
| | - Boyang Ji
- Department of Biology and Biological Engineering, Chalmers University of Technology, SE-41296 Gothenburg, Sweden
| | - Jens Nielsen
- Department of Biology and Biological Engineering, Chalmers University of Technology, SE-41296 Gothenburg, Sweden
- Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, DK-2800 Lyngby, Denmark
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18
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Guard BC, Honneffer JB, Jergens AE, Jonika MM, Toresson L, Lawrence YA, Webb CB, Hill S, Lidbury JA, Steiner JM, Suchodolski JS. Longitudinal assessment of microbial dysbiosis, fecal unconjugated bile acid concentrations, and disease activity in dogs with steroid-responsive chronic inflammatory enteropathy. J Vet Intern Med 2019; 33:1295-1305. [PMID: 30957301 PMCID: PMC6524081 DOI: 10.1111/jvim.15493] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2018] [Accepted: 03/21/2019] [Indexed: 01/08/2023] Open
Abstract
Background Mounting evidence from human studies suggests that bile acid dysmetabolism might play a role in various human chronic gastrointestinal diseases. It is unknown whether fecal bile acid dysmetabolism occurs in dogs with chronic inflammatory enteropathy (CE). Objective To assess microbial dysbiosis, fecal unconjugated bile acids (fUBA), and disease activity in dogs with steroid‐responsive CE. Animals Twenty‐four healthy control dogs and 23 dogs with steroid‐responsive CE. Methods In this retrospective study, fUBA were measured and analyzed. Fecal microbiota were assessed using a dysbiosis index. The canine inflammatory bowel disease activity index was used to evaluate remission of clinical signs. This was a multi‐institutional study where dogs with steroid‐responsive CE were evaluated over time. Results The dysbiosis index was increased in dogs with CE (median, 2.5; range, −6.2 to 6.5) at baseline compared with healthy dogs (median, −4.5; range, −6.5 to −2.6; P = .002) but did not change in dogs with CE over time. Secondary fUBA were decreased in dogs with CE (median, 29%; range, 1%‐99%) compared with healthy dogs (median, 88%; 4%‐96%; P = .049). The percent of secondary fUBA in dogs with CE increased from baseline values (median, 28%; range, 1%‐99%) after 2‐3 months of treatment (median, 94%; range, 1%‐99%; P = 0.0183). Conclusions and Clinical Importance These findings suggest that corticosteroids regulate fecal bile acids in dogs with CE. Additionally, resolution of clinical activity index in dogs with therapeutically managed CE and bile acid dysmetabolism are likely correlated. However, subclinical disease (i.e., microbial dysbiosis) can persist in dogs with steroid‐responsive CE.
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Affiliation(s)
- Blake C Guard
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, Texas A&M University, College Station, Texas
| | - Julia B Honneffer
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, Texas A&M University, College Station, Texas
| | - Albert E Jergens
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, Iowa
| | - Michelle M Jonika
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, Texas A&M University, College Station, Texas
| | - Linda Toresson
- Evidensia Specialist Animal Hospital, Helsingborg, Sweden.,Helsinki University, Helsinki, Finland
| | - Yuri A Lawrence
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, Texas A&M University, College Station, Texas
| | - Craig B Webb
- Clinical Sciences Department, Colorado State University, Fort Collins, Colorado
| | - Steve Hill
- Veterinary Specialty Hospital, San Diego, California
| | - Jonathan A Lidbury
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, Texas A&M University, College Station, Texas
| | - Joerg M Steiner
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, Texas A&M University, College Station, Texas
| | - Jan S Suchodolski
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, Texas A&M University, College Station, Texas
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19
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Volk N, Siegel CA. Defining Failure of Medical Therapy for Inflammatory Bowel Disease. Inflamm Bowel Dis 2019; 25:74-77. [PMID: 30016434 DOI: 10.1093/ibd/izy238] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Indexed: 12/15/2022]
Abstract
Over the past 2 decades, advances in biologic and small molecule therapeutics have resulted in a rapid increase in our armamentarium of therapies for inflammatory bowel disease. Despite these advancements, Crohn's disease and ulcerative colitis remain chronic and progressive diseases. One of the primary reasons for persistent inflammation and bowel damage is failure of medical therapy. With growing therapeutic options, there is an increased temptation to quickly move to the next therapy and label the prior therapy as a failure; however, this can lead to inadequate optimization of medications and poor control of disease. On the other hand, failure to recognize ongoing mucosal inflammation despite optimized treatment and moving to the next agent can lead to progression of disease and long-term complications. As our options for medical therapy continue to increase, it has become more important to recognize failure of therapy in order to promptly move to the next therapeutic agent without abandoning therapies prematurely. In this review, we aim to define failure of medical therapy for inflammatory bowel disease with the goal of offering guidance on when it is appropriate to attempt optimization of current medical treatment as opposed to moving on to the next agent or treatment approach.
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Affiliation(s)
- Neil Volk
- Dartmouth-Hitchcock Inflammatory Bowel Disease Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
| | - Corey A Siegel
- Dartmouth-Hitchcock Inflammatory Bowel Disease Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
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20
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Hegyi P, Maléth J, Walters JR, Hofmann AF, Keely SJ. Guts and Gall: Bile Acids in Regulation of Intestinal Epithelial Function in Health and Disease. Physiol Rev 2018; 98:1983-2023. [PMID: 30067158 DOI: 10.1152/physrev.00054.2017] [Citation(s) in RCA: 192] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Epithelial cells line the entire surface of the gastrointestinal tract and its accessory organs where they primarily function in transporting digestive enzymes, nutrients, electrolytes, and fluid to and from the luminal contents. At the same time, epithelial cells are responsible for forming a physical and biochemical barrier that prevents the entry into the body of harmful agents, such as bacteria and their toxins. Dysregulation of epithelial transport and barrier function is associated with the pathogenesis of a number of conditions throughout the intestine, such as inflammatory bowel disease, chronic diarrhea, pancreatitis, reflux esophagitis, and cancer. Driven by discovery of specific receptors on intestinal epithelial cells, new insights into mechanisms that control their synthesis and enterohepatic circulation, and a growing appreciation of their roles as bioactive bacterial metabolites, bile acids are currently receiving a great deal of interest as critical regulators of epithelial function in health and disease. This review aims to summarize recent advances in this field and to highlight how bile acids are now emerging as exciting new targets for disease intervention.
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Affiliation(s)
- Peter Hegyi
- Momentum Translational Gastroenterology Research Group, Hungarian Academy of Sciences-University of Szeged , Szeged , Hungary ; Institute for Translational Medicine, Medical School, University of Pécs , Pécs , Hungary ; Momentum Epithelial Cell Signalling and Secretion Research Group and First Department of Medicine, University of Szeged , Szeged , Hungary ; Division of Digestive Diseases, Department of Gastroenterology, Hammersmith Hospital, Imperial College London , London , United Kingdom ; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California ; and Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin , Ireland
| | - Joszef Maléth
- Momentum Translational Gastroenterology Research Group, Hungarian Academy of Sciences-University of Szeged , Szeged , Hungary ; Institute for Translational Medicine, Medical School, University of Pécs , Pécs , Hungary ; Momentum Epithelial Cell Signalling and Secretion Research Group and First Department of Medicine, University of Szeged , Szeged , Hungary ; Division of Digestive Diseases, Department of Gastroenterology, Hammersmith Hospital, Imperial College London , London , United Kingdom ; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California ; and Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin , Ireland
| | - Julian R Walters
- Momentum Translational Gastroenterology Research Group, Hungarian Academy of Sciences-University of Szeged , Szeged , Hungary ; Institute for Translational Medicine, Medical School, University of Pécs , Pécs , Hungary ; Momentum Epithelial Cell Signalling and Secretion Research Group and First Department of Medicine, University of Szeged , Szeged , Hungary ; Division of Digestive Diseases, Department of Gastroenterology, Hammersmith Hospital, Imperial College London , London , United Kingdom ; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California ; and Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin , Ireland
| | - Alan F Hofmann
- Momentum Translational Gastroenterology Research Group, Hungarian Academy of Sciences-University of Szeged , Szeged , Hungary ; Institute for Translational Medicine, Medical School, University of Pécs , Pécs , Hungary ; Momentum Epithelial Cell Signalling and Secretion Research Group and First Department of Medicine, University of Szeged , Szeged , Hungary ; Division of Digestive Diseases, Department of Gastroenterology, Hammersmith Hospital, Imperial College London , London , United Kingdom ; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California ; and Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin , Ireland
| | - Stephen J Keely
- Momentum Translational Gastroenterology Research Group, Hungarian Academy of Sciences-University of Szeged , Szeged , Hungary ; Institute for Translational Medicine, Medical School, University of Pécs , Pécs , Hungary ; Momentum Epithelial Cell Signalling and Secretion Research Group and First Department of Medicine, University of Szeged , Szeged , Hungary ; Division of Digestive Diseases, Department of Gastroenterology, Hammersmith Hospital, Imperial College London , London , United Kingdom ; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California ; and Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin , Ireland
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21
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Abstract
PURPOSE OF REVIEW To provide an update on the prevalence, pathophysiology, disease associations, and treatment options for bile acid malabsorption (BAM). RECENT FINDINGS •Molecular mechanisms-BAs prevent water reabsorption and increase water secretion by intracellular mediators, increasing aquaporin channels and intracellular permeability. •Inflammatory bowel disease-new molecular mechanisms of BAM are identified in patients without ileal disease, including changes in expression of ileal BA transporter and nuclear receptors involved in BA homeostasis. •Microscopic colitis-BAM is one of the mechanisms leading to microscopic colitis. •Diagnostic testing-new diagnostic tests have been launched in the USA (serum C4 and fecal 48-h BA excretion); stimulated FGF19 has higher detection of BAM compared to fasting sample alone. •Treatment-investigational FXR agonists may provide a daily, oral option for treatment of BAM instead of BA sequestrants. There is a greater appreciation of the biological role of bile acids across multiple fields of medicine, including gastrointestinal indications.
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Affiliation(s)
- Priya Vijayvargiya
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton Bldg., Rm. 8-110, 200 First Street S.W, Rochester, MN, 55905, USA
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton Bldg., Rm. 8-110, 200 First Street S.W, Rochester, MN, 55905, USA.
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22
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Scoville EA, Allaman MM, Brown CT, Motley AK, Horst SN, Williams CS, Koyama T, Zhao Z, Adams DW, Beaulieu DB, Schwartz DA, Wilson KT, Coburn LA. Alterations in Lipid, Amino Acid, and Energy Metabolism Distinguish Crohn's Disease from Ulcerative Colitis and Control Subjects by Serum Metabolomic Profiling. Metabolomics 2018; 14:17. [PMID: 29681789 PMCID: PMC5907923 DOI: 10.1007/s11306-017-1311-y] [Citation(s) in RCA: 142] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 12/21/2017] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Biomarkers are needed in inflammatory bowel disease (IBD) to help define disease activity and identify underlying pathogenic mechanisms. We hypothesized that serum metabolomics, which produces unique metabolite profiles, can aid in this search. OBJECTIVES The aim of this study was to characterize serum metabolomic profiles in patients with IBD, and to assess for differences between patients with ulcerative colitis (UC), Crohn's disease (CD), and non- IBD subjects. METHODS Serum samples from 20 UC, 20 CD, and 20 non-IBD control subjects were obtained along with patient characteristics, including medication use and clinical disease activity. Non-targeted metabolomic profiling was performed using ultra-high performance liquid chromatography/mass spectrometry (UPLC-MS/MS) optimized for basic or acidic species and hydrophilic interaction liquid chromatography (HILIC/UPLC-MS/MS). RESULTS In total, 671 metabolites were identified. Comparing IBD and control subjects revealed 173 significantly altered metabolites (27 increased and 146 decreased). The majority of the alterations occurred in lipid-, amino acid-, and energy-related metabolites. Comparing only CD and control subjects revealed 286 significantly altered metabolites (54 increased and 232 decreased), whereas comparing UC and control subjects revealed only 5 significantly altered metabolites (all decreased). Hierarchal clustering using significant metabolites separated CD from UC and control subjects. CONCLUSIONS We demonstrate that a number of lipid-, amino acid-, and tricarboxylic acid (TCA) cycle- related metabolites were significantly altered in IBD patients, more specifically in CD. Therefore, alterations in lipid and amino acid metabolism and energy homeostasis may play a key role in the pathogenesis of CD.
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Affiliation(s)
- Elizabeth A Scoville
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave., 1030C MRB IV, Nashville, TN, 37232, USA
| | - Margaret M Allaman
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave., 1030C MRB IV, Nashville, TN, 37232, USA
| | - Caroline T Brown
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave., 1030C MRB IV, Nashville, TN, 37232, USA
| | - Amy K Motley
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave., 1030C MRB IV, Nashville, TN, 37232, USA
| | - Sara N Horst
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave., 1030C MRB IV, Nashville, TN, 37232, USA
| | - Christopher S Williams
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave., 1030C MRB IV, Nashville, TN, 37232, USA
- Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA
| | - Tatsuki Koyama
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Zhiguo Zhao
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Dawn W Adams
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave., 1030C MRB IV, Nashville, TN, 37232, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA
| | - Dawn B Beaulieu
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave., 1030C MRB IV, Nashville, TN, 37232, USA
| | - David A Schwartz
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave., 1030C MRB IV, Nashville, TN, 37232, USA
| | - Keith T Wilson
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave., 1030C MRB IV, Nashville, TN, 37232, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Center for Mucosal Inflammation and Cancer, Nashville, TN, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA
| | - Lori A Coburn
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave., 1030C MRB IV, Nashville, TN, 37232, USA.
- Vanderbilt Center for Mucosal Inflammation and Cancer, Nashville, TN, USA.
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA.
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23
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Kang L, Connolly TM, Weng N, Jian W. LC-MS/MS quantification of 7α-hydroxy-4-cholesten-3-one (C4) in rat and monkey plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2017; 1064:49-55. [PMID: 28915417 DOI: 10.1016/j.jchromb.2017.09.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Revised: 08/31/2017] [Accepted: 09/02/2017] [Indexed: 11/26/2022]
Abstract
7α-hydroxy-4-cholesten-3-one (C4) is an oxidative enzymatic product of cholesterol metabolism via cholesterol 7α-hydroxylase, an enzyme also known as cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1). C4 is a stable intermediate in the rate limiting pathway of bile acid biosynthesis. Previous studies showed that plasma C4 levels correlated with CYP7A1 enzymatic activity and could serve as a biomarker for bile acid synthesis. Here we developed and qualified a simple and robust high-throughput method using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) to quantify C4 in rat and monkey plasma. As C4 being an endogenous compound, this method used calibration standards in 50/50: acetonitrile/water (v/v). In order to mimic the incurred samples, quality control samples were prepared in the authentic plasma. Stable isotope labeled C4 (C4-d7) was used as the internal standard. The sample volume for analysis was 20μL and the sample preparation method was protein precipitation with acetonitrile. The average endogenous C4 concentrations, from 10 different lots of rat and monkey plasma, were 53.0±16.5ng/mL and 6.8±5.6ng/mL, respectively. Based on these observed endogenous C4 levels, the calibration curve ranges were established at 1-200ng/mL and 0.5-100ng/mL for rat assay and monkey assay, respectively. The method was qualified with acceptable accuracy, precision, linearity, and specificity. Matrix effect, recovery, and plasma stability of bench-top, freeze-thaw, and long-term frozen storage were also evaluated. The method has been successfully applied to pre-clinical studies.
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Affiliation(s)
- Lijuan Kang
- Janssen Research & Development, Johnson & Johnson, 1400 McKean Road, Spring House, PA, 19477, USA
| | - Thomas M Connolly
- Janssen Research & Development, Johnson & Johnson, 1400 McKean Road, Spring House, PA, 19477, USA
| | - Naidong Weng
- Janssen Research & Development, Johnson & Johnson, 1400 McKean Road, Spring House, PA, 19477, USA
| | - Wenying Jian
- Janssen Research & Development, Johnson & Johnson, 1400 McKean Road, Spring House, PA, 19477, USA.
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24
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Martin FP, Su MM, Xie GX, Guiraud SP, Kussmann M, Godin JP, Jia W, Nydegger A. Urinary metabolic insights into host-gut microbial interactions in healthy and IBD children. World J Gastroenterol 2017; 23:3643-3654. [PMID: 28611517 PMCID: PMC5449421 DOI: 10.3748/wjg.v23.i20.3643] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 03/29/2017] [Accepted: 05/04/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To identify metabolic signatures in urine samples from healthy and inflammatory bowel disease (IBD) children. METHODS We applied liquid chromatography and gas chromatography coupled to targeted mass spectrometry (MS)-based metabolite profiling to identify and quantify bile acids and host-gut microbial metabolites in urine samples collected from 21 pediatric IBD patients monitored three times over one year (baseline, 6 and 12 mo), and 27 age- and gender-matched healthy children. RESULTS urinary metabolic profiles of IBD children differ significantly from healthy controls. Such metabolic differences encompass central energy metabolism, amino acids, bile acids and gut microbial metabolites. In particular, levels of pyroglutamic acid, glutamic acid, glycine and cysteine, were significantly higher in IBD children in the course of the study. This suggests that glutathione cannot be optimally synthesized and replenished. Whilst alterations of the enterohepatic circulation of bile acids in pediatric IBD patients is known, we show here that non-invasive urinary bile acid profiling can assess those altered hepatic and intestinal barrier dysfunctions. CONCLUSION The present study shows how non-invasive sampling of urine followed by targeted MS-based metabonomic analysis can elucidate and monitor the metabolic status of children with different GI health/disease status.
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25
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Amil-Dias J, Kolacek S, Turner D, Pærregaard A, Rintala R, Afzal NA, Karolewska-Bochenek K, Bronsky J, Chong S, Fell J, Hojsak I, Hugot JP, Koletzko S, Kumar D, Lazowska-Przeorek I, Lillehei C, Lionetti P, Martin-de-Carpi J, Pakarinen M, Ruemmele FM, Shaoul R, Spray C, Staiano A, Sugarman I, Wilson DC, Winter H, Kolho KL. Surgical Management of Crohn Disease in Children: Guidelines From the Paediatric IBD Porto Group of ESPGHAN. J Pediatr Gastroenterol Nutr 2017; 64:818-835. [PMID: 28267075 DOI: 10.1097/mpg.0000000000001562] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The incidence of Crohn disease (CD) has been increasing and surgery needs to be contemplated in a substantial number of cases. The relevant advent of biological treatment has changed but not eliminated the need for surgery in many patients. Despite previous publications on the indications for surgery in CD, there was a need for a comprehensive review of existing evidence on the role of elective surgery and options in pediatric patients affected with CD. We present an expert opinion and critical review of the literature to provide evidence-based guidance to manage these patients. Indications, surgical options, risk factors, and medications in pre- and perioperative period are reviewed in the light of available evidence. Risks and benefits of surgical options are addressed. An algorithm is proposed for the management of postsurgery monitoring, timing for follow-up endoscopy, and treatment options.
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Affiliation(s)
- Jorge Amil-Dias
- *Department of Pediatrics, Centro Hospitalar, S. João, Porto, Portugal †Children's Hospital Zagreb, Faculty of Medicine, Zagreb, Croatia ‡The Juliet Keidan Institute of Pediatric Gastroenterology & Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel §Department of Pediatrics, Hvidovre University Hospital, Hvidovre, Denmark ||Pediatric Surgery, Children's Hospital, University of Helsinki, Helsinki, Finland ¶Department of Pediatric Gastroenterology, University Hospital Southampton, Southampton, UK #Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw, Warsaw, Poland **Department of Pediatrics, University Hospital Motol, Prague, Czech Republic ††Queen Mary's Hospital for Children, Epsom and St Helier NHS Trust, Surrey ‡‡Chelsea and Westminster Hospital, London, UK §§Paris-Diderot Sorbonne-Paris-Cité University and Robert Debré Hospital, Paris, France ||||Pediatric Gastroenterology and Hepatology, Dr. von Hauner Children's Hospital, Ludwig Maximilians-University, Munich, Germany ¶¶St George's, University of London, London, UK ##Boston Children's Hospital and Harvard Medical School, Boston, MA ***Department NEUROFARBA, University of Florence - Meyer Hospital, Florence, Italy †††Unit for the Comprehensive Care of Pediatric Inflammatory Bowel Disease, Hospital Sant Joan de Déu, Barcelona, Spain ‡‡‡Department of Pediatric Gastroenterology, Necker Enfants Malades University Hospital, Sorbonne Paris Cité University, Paris Descartes University, Institut IMAGINE - INSERM U1163, Paris, France §§§Pediatric Gastroenterology Institute, Ruth Children's Hospital, Rambam Medical Center, Haifa, Israel ||||||Department of Pediatric Gastroenterology, Bristol Royal Hospital for Children, Bristol, UK ¶¶¶Department of Translational Medical Science, Section of Pediatrics, University of Naples "Federico II," Naples, Italy ###Department of Pediatric Surgery, Leeds Children's Hospital, Leeds General Infirmary, Leeds, UK ****Child Life and Health, University of Edinburgh, Scotland, UK ††††MassGeneral Hospital for Children, Harvard Medical School, Boston, MA ‡‡‡‡Children's Hospital, University of Helsinki, Helsinki, Finland
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Staley C, Weingarden AR, Khoruts A, Sadowsky MJ. Interaction of gut microbiota with bile acid metabolism and its influence on disease states. Appl Microbiol Biotechnol 2017; 101:47-64. [PMID: 27888332 PMCID: PMC5203956 DOI: 10.1007/s00253-016-8006-6] [Citation(s) in RCA: 390] [Impact Index Per Article: 48.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 11/09/2016] [Accepted: 11/11/2016] [Indexed: 01/18/2023]
Abstract
Primary bile acids serve important roles in cholesterol metabolism, lipid digestion, host-microbe interactions, and regulatory pathways in the human host. While most bile acids are reabsorbed and recycled via enterohepatic cycling, ∼5% serve as substrates for bacterial biotransformation in the colon. Enzymes involved in various transformations have been characterized from cultured gut bacteria and reveal taxa-specific distribution. More recently, bioinformatic approaches have revealed greater diversity in isoforms of these enzymes, and the microbial species in which they are found. Thus, the functional roles played by the bile acid-transforming gut microbiota and the distribution of resulting secondary bile acids, in the bile acid pool, may be profoundly affected by microbial community structure and function. Bile acids and the composition of the bile acid pool have historically been hypothesized to be associated with several disease states, including recurrent Clostridium difficile infection, inflammatory bowel diseases, metabolic syndrome, and several cancers. Recently, however, emphasis has been placed on how microbial communities in the dysbiotic gut may alter the bile acid pool to potentially cause or mitigate disease onset. This review highlights the current understanding of the interactions between the gut microbial community, bile acid biotransformation, and disease states, and addresses future directions to better understand these complex associations.
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Affiliation(s)
- Christopher Staley
- BioTechnology Institute, Center for Immunology University of Minnesota, Minneapolis, MN
| | - Alexa R Weingarden
- BioTechnology Institute, Center for Immunology University of Minnesota, Minneapolis, MN
| | - Alexander Khoruts
- BioTechnology Institute, Center for Immunology University of Minnesota, Minneapolis, MN
- Division of Gastroenterology, Department of Medicine, Center for Immunology University of Minnesota, Minneapolis, MN
| | - Michael J Sadowsky
- BioTechnology Institute, Center for Immunology University of Minnesota, Minneapolis, MN
- Department of Soil, Water and Climate, University of Minnesota, St. Paul, MN
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Bodewes FAJA, Verkade HJ, Wilschanski M. Gastroenterological endpoints in drug trials for cystic fibrosis. Pediatr Pulmonol 2016; 51:S18-S22. [PMID: 27442207 DOI: 10.1002/ppul.23528] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Revised: 06/28/2016] [Accepted: 07/03/2016] [Indexed: 12/28/2022]
Abstract
The phenotype of cystic fibrosis includes a wide variety of clinical and biochemical gastrointestinal presentations. These gastrointestinal characteristics of the disease have come under renewed interest as potential outcome measures and clinical endpoints for therapeutic trials in cystic fibrosis. Established gastrointestinal clinical endpoints, like e.g. fecal elastase-1, are already used in trials. Other potential gastrointestinal outcome measures gather more scientific interest for evaluation in future trials. Gastrointestinal outcome measures look particularly relevant and promising for trials in CF patients with normal lung function or therapeutic studies in young children and infants. We review, the currently reported gastrointestinal effects of CFTR modulation therapies and discuss the potential of gastrointestinal outcome measures for therapeutic trials in cystic fibrosis. Pediatr Pulmonol. 2016;51:S18-S22. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Frank A J A Bodewes
- Department of Pediatric Gastroenterology, University Medical Center Groningen, Groningen, The Netherlands.
| | - Henkjan J Verkade
- Department of Pediatric Gastroenterology, University Medical Center Groningen, Groningen, The Netherlands
| | - Micheal Wilschanski
- Pediatric Gastroenterology Unit, Division of Pediatrics, Hadassah University Hospitals, Jerusalem, Israel
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Deng QJ, Deng DJ, Che J, Zhao HR, Yu JJ, Lu YY. Hypothalamic paraventricular nucleus stimulation reduces intestinal injury in rats with ulcerative colitis. World J Gastroenterol 2016; 22:3769-3776. [PMID: 27076761 PMCID: PMC4814739 DOI: 10.3748/wjg.v22.i14.3769] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2015] [Revised: 01/11/2016] [Accepted: 01/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect and mechanism of stimulation of the hypothalamic paraventricular nucleus with glutamate acid in rats with ulcerative colitis (UC).
METHODS: The rats were anesthetized with 10% chloral hydrate via abdominal injection and treated with an equal volume of TNBS + 50% ethanol enema, injected into the upper section of the anus with the tail facing up. Colonic damage scores were calculated after injecting a certain dose of glutamic acid into the paraventricular nucleus (PVN), and the effect of the nucleus tractus solitarius (NTS) and vagus nerve in alleviating UC injury through chemical stimulation of the PVN was observed in rats. Expression changes of C-myc, Apaf-1, caspase-3, interleukin (IL)-6, and IL-17 during the protection against UC injury through chemical stimulation of the PVN in rats were detected by Western blot. Malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in colon tissues of rats were measured by colorimetric methods.
RESULTS: Chemical stimulation of the PVN significantly reduced UC in rats in a dose-dependent manner. The protective effects of the chemical stimulation of the PVN on rats with UC were eliminated after chemical damage to the PVN. After glutamate receptor antagonist kynurenic acid was injected into the PVN, the protective effects of the chemical stimulation of the PVN were eliminated in rats with UC. After AVP-Vl receptor antagonist ([Deamino-penl, val4, D-Arg8]-vasopressin) was injected into NTS or bilateral chemical damage to NTS, the protective effect of the chemical stimulation of PVN on UC was also eliminated. After chemical stimulation of the PVN, SOD activity increased, MDA content decreased, C-myc protein expression significantly increased, caspase-3 and Apaf-1 protein expression significantly decreased, and IL-6 and IL-17 expression decreased in colon tissues in rats with UC.
CONCLUSION: Chemical stimulation of the hypothalamic PVN provides a protective effect against UC injury in rats. Hypothalamic PVN, NTS and vagus nerve play key roles in this process.
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Nikaki K, Gupte GL. Assessment of intestinal malabsorption. Best Pract Res Clin Gastroenterol 2016; 30:225-35. [PMID: 27086887 DOI: 10.1016/j.bpg.2016.03.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 02/26/2016] [Accepted: 03/01/2016] [Indexed: 01/31/2023]
Abstract
Significant efforts have been made in the last decade to either standardize the available tests for intestinal malabsorption or to develop new, more simple and reliable techniques. The quest is still on and, unfortunately, clinical practice has not dramatically changed. The investigation of intestinal malabsorption is directed by the patient's history and baseline tests. Endoscopy and small bowel biopsies play a major role although non-invasive tests are favored and often performed early on the diagnostic algorithm, especially in paediatric and fragile elderly patients. The current clinically available methods and research tools are summarized in this review article.
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Affiliation(s)
- K Nikaki
- Paediatric Liver Unit (including Small Bowel Transplantation), Birmingham Children's Hospital NHS Foundation Trust, Steelhouse Lane, Birmingham, B4 6NH, UK
| | - G L Gupte
- Paediatric Liver Unit (including Small Bowel Transplantation), Birmingham Children's Hospital NHS Foundation Trust, Steelhouse Lane, Birmingham, B4 6NH, UK.
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Gu X, Song Y, Chai Y, Lu F, Gonzalez FJ, Fan G, Qi Y. GC-MS metabolomics on PPARα-dependent exacerbation of colitis. MOLECULAR BIOSYSTEMS 2016; 11:1329-37. [PMID: 25790429 DOI: 10.1039/c5mb00048c] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, was found to exacerbate inflammation and tissue injury in experimental acute colitis mice. Through lipidomics analysis, bioactive sphingolipids were significantly up-regulated in the colitis group. In this study, to provide further insight into the PPARα-dependent exacerbation of colitis, gas chromatography-mass spectrometry (GC/MS) based metabolomics was employed to investigate the serum and colon of dextran sulfate sodium (DSS)-induced colitis mice treated with fenofibrate, with particular emphasis on changes in low-molecular-weight metabolites. With the aid of multivariate analysis and metabolic pathway analysis, potential metabolite markers in the amino acid metabolism, urea cycle, purine metabolism, and citrate cycle were highlighted, such as glycine, serine, threonine, malic acid, isocitric acid, uric acid, and urea. The level changes of these metabolites in either serum or colons of colitis mice were further potentiated following fenofibrate treatment. Accordingly, the expression of threonine aldolase and phosphoserine aminotransferase 1 was significantly up-regulated in colitis mice and further potentiated in fenofibrate/DSS-treated mice. It was revealed that beyond the control of lipid metabolism, PPARα also shows effects on the above pathways, resulting in enhanced protein catabolism and energy expenditure, increased bioactive sphingolipid metabolism and proinflammatory state, which were possibly related to the exacerbated colitis.
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Affiliation(s)
- Xueqin Gu
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
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Bodewes FAJA, Verkade HJ, Taminiau JAJM, Borowitz D, Wilschanski M. Cystic fibrosis and the role of gastrointestinal outcome measures in the new era of therapeutic CFTR modulation. J Cyst Fibros 2015; 14:169-77. [PMID: 25677689 DOI: 10.1016/j.jcf.2015.01.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Revised: 01/20/2015] [Accepted: 01/20/2015] [Indexed: 01/01/2023]
Abstract
With the development of new drugs that directly affect CFTR protein function, clinical trials are being designed or initiated for a growing number of patients with cystic fibrosis. The currently available and accepted clinical endpoints, FEV1 and BMI, have limitations. The aim of this report is to draw attention to the need and the ample possibilities for the development and validation of relevant gastrointestinal clinical endpoints for scientific evaluation of CFTR modulation treatment, particularly in young children and infants. The gastrointestinal tract offers very good opportunities to measure CFTR protein function and systematically evaluate CF related clinical outcomes based on the principal clinical gastrointestinal manifestations of CF: intestinal pH, intestinal transit time, intestinal bile salt malabsorption, intestinal inflammation, exocrine pancreatic function and intestinal fat malabsorption. We present a descriptive analysis of a variety of gastrointestinal outcome measures for clinical relevance, reliability, validity, responsiveness to interventions, feasibility in particular in young children and the availability of reference values.
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Affiliation(s)
- Frank A J A Bodewes
- Pediatric Gastroenterology and Hepatology, University of Groningen, University Medical Center, Groningen, The Netherlands.
| | - Henkjan J Verkade
- Pediatric Gastroenterology and Hepatology, University of Groningen, University Medical Center, Groningen, The Netherlands
| | | | - Drucy Borowitz
- Department of Pediatrics, State University of New York at Buffalo School of Medicine and Biomedical Sciences, Women and Children's Hospital of Buffalo, Buffalo, NY, United States
| | - Michael Wilschanski
- Pediatric Gastroenterology, Hadassah Hebrew University Medical Center, Jerusalem, Israel
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Nolan JD, Johnston IM, Pattni SS, Dew T, Orchard TR, Walters JRF. Diarrhea in Crohn’s disease: investigating the role of the ileal hormone fibroblast growth factor 19. J Crohns Colitis 2015; 9:125-31. [PMID: 25518063 DOI: 10.1093/ecco-jcc/jju022] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Bile acids [BA] are usually reabsorbed by the terminal ileum, but this process is frequently abnormal in Crohn’s disease [CD]. BA malabsorption occurs, and excess colonic BA cause secretory diarrhea. Furthermore, the hormone fibroblast growth factor 19 [FGF19] is synthesized in the ileum in response to BA absorption and regulates BA synthesis. We hypothesized that reduced serum FGF19 levels will be associated with diarrheal symptoms and disease activity in both ileal resected[IR-CD] and non-resected CD [NR-CD] patients. METHODS Fasting serum FGF19 levels were measured in 58 patients [23 IR-CD patients and 35NR-CD patients]. Disease activity was assessed using the Harvey Bradshaw Index and C-reactive protein [CRP]. Stool frequency, Bristol Stool Form Scale and length of previous ileal resection were recorded. FGF19 levels were also compared with healthy and diarrhea control patients. RESULTS FGF19 levels were inversely correlated with ileal resection length in IR-CD patients[r = -0.54, p = 0.02]. In NR-CD patients, median FGF19 levels were significantly lower in patients with active disease compared with inactive disease [103 vs. 158 pg/ml, p = 0.04] and in those with symptoms of diarrhea compared with those without [86 vs. 145 pg/ml, p = 0.035]. FGF19 levels were inversely correlated with stool frequency, Bristol stool form and CRP in NR-CD patients with ileal disease. CONCLUSIONS Reduced FGF19 levels are associated with ileal resection, diarrhea and disease activity. FGF19 may have utility as a biomarker for functioning ileum in CD. This study supports a potential role of FGF19 in guiding treatments for diarrhea in Crohn’s disease.
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Abstract
Biological therapy revolutionized the treatment of inflammatory bowel disease (IBD) during the last decade. These monoclonal antibodies, which target tumor necrosis factor (TNF), integrins or IL12/23, have been approved-or are in development for-both Crohn's disease (CD) and ulcerative colitis (UC). Early use of these agents taught clinicians that induction and maintenance therapy, coupled with immunomodulator agents, reduced the immunogenicity of these agents, and led to sustained remission in many patients. More recent data has demonstrated that, through dose adjustments, optimizing serum drug levels may also provide more durable maintenance of remission, and improved mucosal healing. This review examines clinical practices that may enhance clinical outcomes from biological therapy in IBD.
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Affiliation(s)
- Alan C Moss
- Division of Gastroenterology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA, USA
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Abstract
Bile acid malabsorption (BAM) is a common but an underestimated and often neglected sign of inflammatory bowel diseases (IBDs), especially those affecting the distal ileum. Clinically relevant BAM is most often present in patients with Crohn's ileitis and particularly in ileal-resected Crohn's disease patients. However, deterioration of bile acid (BA) metabolism occurs also in patients with IBD without ileal disease or in those in clinical remission, and the role of BAM in these patients is not well appreciated by clinicians. In a majority of cases, BAM in IBD is caused by impaired conjugated BA reabsorption, mediated by apical sodium/BA cotransporting polypeptide, localized at the luminal surface of the ileal enterocytes. As a consequence, numerous pathological sequelae may occur, including the malfunction of lipid digestion with clinical steatorrhea, impaired intestinal motility, and/or significant changes in the intestinal microflora environment. In this review, a detailed description of the pathophysiological mechanisms of BAM-related diarrhea is presented. Although BAM is present in a significant number of patients with Crohn's disease, its laboratory assessment is not routinely included in diagnostic workups, partially because of costs, logistical reasons, or the unavailability of the more sophisticated laboratory equipment needed. Simultaneously, novel findings related to the effects of the BA signaling pathways on immune functions (mediated through TGR5, cell membrane G protein-coupled BA receptor 1, nuclear farnesoid X receptor, nuclear pregnane X receptor, or nuclear vitamin D receptor) are discussed along with intestinal metabolism in its relationship to the pathogenesis of IBD.
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