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Tews HC, Schmelter F, Kandulski A, Büchler C, Schmid S, Schlosser S, Elger T, Loibl J, Sommersberger S, Fererberger T, Gunawan S, Kunst C, Gülow K, Bettenworth D, Föh B, Maaß C, Solbach P, Günther UL, Derer S, Marquardt JU, Sina C, Müller M. Unique Metabolomic and Lipidomic Profile in Serum From Patients With Crohn's Disease and Ulcerative Colitis Compared With Healthy Control Individuals. Inflamm Bowel Dis 2024; 30:2405-2417. [PMID: 38156773 PMCID: PMC11630276 DOI: 10.1093/ibd/izad298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND Accurate biomarkers for disease activity and progression in patients with inflammatory bowel disease (IBD) are a prerequisite for individual disease characterization and personalized therapy. We show that metabolic profiling of serum from IBD patients is a promising approach to establish biomarkers. The aim of this work was to characterize metabolomic and lipidomic serum profiles of IBD patients in order to identify metabolic fingerprints unique to the disease. METHODS Serum samples were obtained from 55 patients with Crohn's disease (CD), 34 patients with ulcerative colitis (UC), and 40 healthy control (HC) individuals and analyzed using proton nuclear magnetic resonance spectroscopy. Classification of patients and HC individuals was achieved by orthogonal partial least squares discriminant analysis and univariate analysis approaches. Disease activity was assessed using the Gastrointestinal Symptom Rating Scale. RESULTS Serum metabolome significantly differed between CD patients, UC patients, and HC individuals. The metabolomic differences of UC and CD patients compared with HC individuals were more pronounced than the differences between UC and CD patients. Differences in serum levels of pyruvic acid, histidine, and the branched-chain amino acids leucine and valine were detected. The size of low-density lipoprotein particles shifted from large to small dense particles in patients with CD. Of note, apolipoprotein A1 and A2 serum levels were decreased in CD and UC patients with higher fecal calprotectin levels. The Gastrointestinal Symptom Rating Scale is negatively associated with the concentration of apolipoprotein A2. CONCLUSIONS Metabolomic assessment of serum samples facilitated the differentiation of IBD patients and HC individuals. These differences were constituted by changes in amino acid and lipoprotein levels. Furthermore, disease activity in IBD patients was associated with decreased levels of the atheroprotective apolipoproteins A1 and A2.
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Affiliation(s)
- Hauke Christian Tews
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Franziska Schmelter
- Institute of Nutritional Medicine, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Arne Kandulski
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Christa Büchler
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Stephan Schmid
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Sophie Schlosser
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Tanja Elger
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Johanna Loibl
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Stefanie Sommersberger
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Tanja Fererberger
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Stefan Gunawan
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Claudia Kunst
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Karsten Gülow
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Dominik Bettenworth
- Department of Medicine B—Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany
- Practice for Internal Medicine, Münster, Germany
| | - Bandik Föh
- Department of Medicine I, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Carlos Maaß
- Department of Medicine I, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Philipp Solbach
- Department of Medicine I, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Ulrich L Günther
- Institute of Chemistry and Metabolomics, University of Lübeck, Lübeck, Germany
| | - Stefanie Derer
- Institute of Nutritional Medicine, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Jens U Marquardt
- Department of Medicine I, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Christian Sina
- Institute of Nutritional Medicine, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
- Department of Medicine I, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
- Fraunhofer Research Institution for Individualized and Cell-Based Medical Engineering, Lübeck, Germany
| | - Martina Müller
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
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Wu Y, Shen J. Unraveling the intricacies of neutrophil extracellular traps in inflammatory bowel disease: Pathways, biomarkers, and promising therapies. Cytokine Growth Factor Rev 2024; 80:156-167. [PMID: 39438227 DOI: 10.1016/j.cytogfr.2024.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 10/06/2024] [Indexed: 10/25/2024]
Abstract
The development of inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, involves various factors and is characterized by persistent inflammation of the mucosal lining. However, the role of neutrophils in this process remains controversial. Neutrophil extracellular traps (NETs), which consist of chromatin, antimicrobial proteins, and oxidative enzymes, are released by neutrophils to trap pathogens. They are also involved in various immune-mediated and vascular diseases. NETs act as a vital defense mechanisms at the gut-mucosal interface and are frequently exposed to bacterial, viral, and fungal threats. However, they can also contribute to inflammation and worsen imbalances in the gut bacteria. Recent studies have suggested that NETs have a significant impact on IBD development. Previous studies have shown increased levels of NETs in tissue and blood samples from patients with IBD, as well as in experimental colitis mouse models. Therefore, this review discusses how NETs are formed and their role in the pathophysiology of IBD. It discusses how NETs may lead to tissue damage and contribute to IBD-associated complications. Moreover, non-invasive biomarkers are needed to replace invasive procedures such as endoscopy to better evaluate the disease status. Given the crucial role of NETs in IBD progression, this review focuses on potential NET biomarkers that can help predict the evolution of IBD. Furthermore, this review identifies potential therapeutic targets for regulating NET production, which could expand the range of available treatment options for IBD.
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Affiliation(s)
- Yilin Wu
- Division of Gastroenterology and Hepatology, Baoshan Branch, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai 200127, China; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China; Shanghai Institute of Digestive Disease, No.160 PuJian Road, China
| | - Jun Shen
- Division of Gastroenterology and Hepatology, Baoshan Branch, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai 200127, China; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China; Shanghai Institute of Digestive Disease, No.160 PuJian Road, China.
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Kumar B, Lorusso E, Fosso B, Pesole G. A comprehensive overview of microbiome data in the light of machine learning applications: categorization, accessibility, and future directions. Front Microbiol 2024; 15:1343572. [PMID: 38419630 PMCID: PMC10900530 DOI: 10.3389/fmicb.2024.1343572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 01/29/2024] [Indexed: 03/02/2024] Open
Abstract
Metagenomics, Metabolomics, and Metaproteomics have significantly advanced our knowledge of microbial communities by providing culture-independent insights into their composition and functional potential. However, a critical challenge in this field is the lack of standard and comprehensive metadata associated with raw data, hindering the ability to perform robust data stratifications and consider confounding factors. In this comprehensive review, we categorize publicly available microbiome data into five types: shotgun sequencing, amplicon sequencing, metatranscriptomic, metabolomic, and metaproteomic data. We explore the importance of metadata for data reuse and address the challenges in collecting standardized metadata. We also, assess the limitations in metadata collection of existing public repositories collecting metagenomic data. This review emphasizes the vital role of metadata in interpreting and comparing datasets and highlights the need for standardized metadata protocols to fully leverage metagenomic data's potential. Furthermore, we explore future directions of implementation of Machine Learning (ML) in metadata retrieval, offering promising avenues for a deeper understanding of microbial communities and their ecological roles. Leveraging these tools will enhance our insights into microbial functional capabilities and ecological dynamics in diverse ecosystems. Finally, we emphasize the crucial metadata role in ML models development.
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Affiliation(s)
- Bablu Kumar
- Università degli Studi di Milano, Milan, Italy
- Department of Biosciences, Biotechnology and Environment, University of Bari A. Moro, Bari, Italy
| | - Erika Lorusso
- Department of Biosciences, Biotechnology and Environment, University of Bari A. Moro, Bari, Italy
- National Research Council, Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Bari, Italy
| | - Bruno Fosso
- Department of Biosciences, Biotechnology and Environment, University of Bari A. Moro, Bari, Italy
| | - Graziano Pesole
- Department of Biosciences, Biotechnology and Environment, University of Bari A. Moro, Bari, Italy
- National Research Council, Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Bari, Italy
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Liu C, Zhan S, Li N, Tu T, Lin J, Li M, Chen M, Zeng Z, Zhuang X. Bile acid alterations associated with indolent course of inflammatory bowel disease. Scand J Gastroenterol 2023; 58:988-997. [PMID: 37070769 DOI: 10.1080/00365521.2023.2200518] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 04/01/2023] [Accepted: 04/04/2023] [Indexed: 04/19/2023]
Abstract
BACKGROUND The indolent course of treatment-naive patients with inflammatory bowel disease (IBD) is confirmed predictable based on clinical characteristics. Current evidences supported that bile acids (BAs) alteration might be promising biomarkers in the field of IBD. We aimed to analyze the alterations of BAs as the disease progresses and explore their predictive value for indolent course of IBD. METHODS The indolent course of IBD was defined as a disease course without need for strict interventions throughout the entire follow-up. A targeted metabolomics method was used to detect the concentration of 27 BAs from serum sample in treatment-naive patients with IBD (Crohn's disease [CD], n = 27; ulcerative colitis [UC], n = 50). Patients with CD and UC were individually divided into two groups for further study according to the median time of indolent course. The overall BAs profile and the clinical value of BAs in predicting indolent course of IBD were identified between different groups. RESULTS For CD, the levels of deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, glycolithocholic acid-3-sulfate disodium salt and iso-lithocholic acid were significantly increased in patients with indolent course > 18 M (p < 0.05). These five BAs owned 83.5% accuracy for predicting indolent course over 18 months in CD. For UC, the concentration of deoxycholic acid and glycodeoxycholic acid were significantly higher, while dehydrocholic acid were lower in patients with indolent course > 48 M (p < 0.05). These three BAs predicted indolent course over 48 months of 69.8% accuracy in UC. CONCLUSION The specific BAs alterations might be potential biomarkers in predicting disease course of IBD patients.
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Affiliation(s)
- Caiguang Liu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shukai Zhan
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Na Li
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tong Tu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jianming Lin
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Manying Li
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhirong Zeng
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaojun Zhuang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Sun R, Jin D, Fei F, Xu Z, Cao B, Li J. Mushroom polysaccharides from Grifola frondosa (Dicks.) Gray and Inonotus obliquus (Fr.) Pilat ameliorated dextran sulfate sodium-induced colitis in mice by global modulation of systemic metabolism and the gut microbiota. Front Pharmacol 2023; 14:1172963. [PMID: 37351508 PMCID: PMC10282762 DOI: 10.3389/fphar.2023.1172963] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 05/09/2023] [Indexed: 06/24/2023] Open
Abstract
Introduction: Polysaccharides from Grifola frondosa (Dicks.) Gray (HSH) and Inonotus obliquus (Fr.) Pilat (BHR) showed noticeable effects on dextran sulfate sodium (DSS)-induced colitis, but their systemic modulation effects have not been fully revealed. This study aimed to investigate the regulation of the gut microbiota and systemic metabolism by HSH and BHR in DSS-induced colitis. Methods: C57BL/6J mice were given DSS (2.5%) in water and were treated with HSH and BHR (200 mg/kg/day) by gavage. Body weight and colon length were recorded, and H&E and AB-PAS staining of the colon were conducted to evaluate the model and the protective effect of the polysaccharides. Additionally, an LC-QTOF/MS-based untargeted metabolomic platform was used to identify the metabolites in the serum, colon tissue, gut contents, and faeces and investigate differential metabolites and metabolic pathways. 16S rDNA gene sequencing was used to measure the composition of bacterial communities. Results: The results showed that the mouse colitis model was established successfully, as evidenced by an increased disease activity index score [2.83 ± 0.62 vs. 0.06 ± 0.14 (p < 0.001)] and shortened colon length [5.43 ± 0.64 cm vs. 7.04 ± 0.29 cm (p < 0.001)], and HSH and BHR ameliorated DSS-induced colitis by improving the disease activity index (2.17 ± 0.28 and 1.83 ± 0.29, respectively) and restoring the colon length (6.12 ± 0.30 cm and 6.62 ± 0.35 cm, respectively). HSH and BHR significantly modulated metabolites involved in aromatic amino acid metabolism, the citrate cycle, purine metabolism, pyrimidine metabolism, etc. HSH and BHR increased the Chao1 index by 64.25% and 60.25%, respectively, and they increased the Shannon index by 13.02% and 10.23%, respectively. They both reversed the increase in the abundances of g_Odoribacter, g_Clostridium, g_AF12, g_Parabacteroides and g_Turicibacter and reversed the decrease in the abundance of g_unclassified_Bacteria induced by DSS. Specifically, HSH reversed the reductions in g_unclassified_Lactobacillales and g_Ruminococcus, and BHR reversed the decreases in g_unidentified_Coriobacteriaceae and g_unclassified_Firmicutes. Discussion: These results suggested that HSH and BHR may ameliorate DSS-induced colitis by global modulation of systemic metabolism and the gut microbiota. Targeting the gut microbiota may be a potentially effective strategy to modulate systemic metabolism and treat colitis.
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Affiliation(s)
- Runbin Sun
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Dandan Jin
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Fei Fei
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhi Xu
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Bei Cao
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Juan Li
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
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Walker HK, Boag AM, Ottka C, Lohi H, Handel I, Gow AG, Mellanby RJ. Serum metabolomic profiles in dogs with chronic enteropathy. J Vet Intern Med 2022; 36:1752-1759. [PMID: 35880501 PMCID: PMC9511094 DOI: 10.1111/jvim.16419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 03/20/2022] [Accepted: 03/25/2022] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Metabolic profiles differ between healthy humans and those with inflammatory bowel disease. Few studies have examined metabolic profiles in dogs with chronic enteropathy (CE). HYPOTHESIS Serum metabolic profiles of dogs with CE are significantly different from those of healthy dogs. ANIMALS Fifty-five dogs with CE and 204 healthy controls. METHODS A cross-sectional study. The serum concentrations of 99 metabolites measured using a canine-specific proton nuclear magnetic resonance spectroscopy platform were studied. A 2-sample unpaired t-test was used to compare the 2 study samples. The threshold for significance was set at P < .05 with a Bonferroni correction for each metabolite group. RESULTS Nineteen metabolites and 18 indices of lipoprotein composition were significantly different between the CE and healthy dogs. Four metabolites were significantly higher in dogs with CE, including phenylalanine (mean and SD) (healthy: 0.0417 mmol/L; [SD] 0.0100; CE: 0.0480 mmol/L; SD: 0.0125; P value: <.001) and lactate (healthy: 1.8751 mmol/L; SD: 0.7808; CE: 2.4827 mmol/L; SD CE: 1.4166; P value: .003). Fifteen metabolites were significantly lower in dogs with CE, including total fatty acids, and glycine (healthy: 0.2273 mmol/L; SD: 0.0794; CE: 0.1828 mmol/L; SD CE: 0.0517; P value: <.001). CONCLUSIONS AND CLINICAL IMPORTANCE The metabolic profile of dogs with CE is significantly different from that of healthy dogs, this opens novel research avenues to develop better diagnostic and prognostic approaches as well as therapeutic trials.
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Affiliation(s)
- Hannah K Walker
- The Royal (Dick) School of Veterinary Studies and the Roslin Institute, Easter Bush Campus, The University of Edinburgh, Midlothian, United Kingdom
| | - Alisdair M Boag
- The Royal (Dick) School of Veterinary Studies and the Roslin Institute, Easter Bush Campus, The University of Edinburgh, Midlothian, United Kingdom
| | - Claudia Ottka
- PetBiomics Ltd, Helsinki, Finland.,Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.,Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Folkhälsan Research Center, Helsinki, Finland
| | - Hannes Lohi
- PetBiomics Ltd, Helsinki, Finland.,Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.,Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Folkhälsan Research Center, Helsinki, Finland
| | - Ian Handel
- The Royal (Dick) School of Veterinary Studies and the Roslin Institute, Easter Bush Campus, The University of Edinburgh, Midlothian, United Kingdom
| | - Adam G Gow
- The Royal (Dick) School of Veterinary Studies and the Roslin Institute, Easter Bush Campus, The University of Edinburgh, Midlothian, United Kingdom
| | - Richard J Mellanby
- The Royal (Dick) School of Veterinary Studies and the Roslin Institute, Easter Bush Campus, The University of Edinburgh, Midlothian, United Kingdom
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Xu X, Ocansey DKW, Hang S, Wang B, Amoah S, Yi C, Zhang X, Liu L, Mao F. The gut metagenomics and metabolomics signature in patients with inflammatory bowel disease. Gut Pathog 2022; 14:26. [PMID: 35729658 PMCID: PMC9215062 DOI: 10.1186/s13099-022-00499-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 05/17/2022] [Indexed: 12/26/2022] Open
Abstract
Inflammatory bowel disease (IBD), a chronic gut immune dysregulation and dysbiosis condition is rapidly increasing in global incidence. Regardless, there is a lack of ideal diagnostic markers, while conventional treatment provides scarce desired results, thus, the exploration for better options. Changes in the gut microbial composition and metabolites either lead to or are caused by the immune dysregulation that characterizes IBD. This study examined the fecal metagenomics and metabolomic changes in IBD patients. A total of 30 fecal samples were collected from 15 IBD patients and 15 healthy controls for 16S rDNA gene sequencing and UHPLC/Q-TOF-MS detection of metabolomics. Results showed that there was a severe perturbation of gut bacteria community composition, diversity, metabolites, and associated functions and metabolic pathways in IBD. This included a significantly decreased abundance of Bacteroidetes and Firmicutes, increased disease-associated phyla such as Proteobacteria and Actinobacteria, and increased Escherichiacoli and Klebsiellapneumoniae in IBD. A total of 3146 metabolites were detected out of which 135 were differentially expressed between IBD and controls. Metabolites with high sensitivity and specificity in differentiating IBD from healthy individuals included 6,7,4′-trihydroxyisoflavone and thyroxine 4′-o-.beta.-d-glucuronide (AUC = 0.92), normorphine and salvinorin a (AUC = 0.90), and trichostachine (AUC = 0.91). Moreover, the IBD group had significantly affected pathways including primary bile acid biosynthesis, vitamin digestion and absorption, and carbohydrate metabolism. This study reveals that the combined evaluation of metabolites and fecal microbiome can be useful to discriminate between healthy subjects and IBD patients and consequently serve as therapeutic and diagnostic targets.
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Affiliation(s)
- Xinwei Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, People's Republic of China
| | - Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, People's Republic of China.,Directorate of University Health Services, University of Cape Coast, PMB, Cape Coast, Ghana
| | - Sanhua Hang
- The People's Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Zhenjiang, 212300, Jiangsu, People's Republic of China
| | - Bo Wang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, People's Republic of China
| | - Samuel Amoah
- Directorate of University Health Services, University of Cape Coast, PMB, Cape Coast, Ghana
| | - Chengxue Yi
- School of Medical Technology, Zhenjiang College, Zhenjiang, 212028, Jiangsu, People's Republic of China
| | - Xu Zhang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, People's Republic of China
| | - Lianqin Liu
- Huai'an Maternity and Children Hospital, Huaian, 223002, Jiangsu, People's Republic of China.
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, People's Republic of China.
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Di Narzo AF, Houten SM, Kosoy R, Huang R, Vaz FM, Hou R, Wei G, Wang WH, Comella PH, Dodatko T, Rogatsky E, Stojmirovic A, Brodmerkel C, Perrigoue J, Hart A, Curran M, Friedman JR, Zhu J, Agrawal M, Cho J, Ungaro R, Dubinsky M, Sands BE, Suárez-Fariñas M, Schadt EE, Colombel JF, Kasarskis A, Hao K, Argmann C. Integrative Analysis of the Inflammatory Bowel Disease Serum Metabolome Improves Our Understanding of Genetic Etiology and Points to Novel Putative Therapeutic Targets. Gastroenterology 2022; 162:828-843.e11. [PMID: 34780722 PMCID: PMC9214725 DOI: 10.1053/j.gastro.2021.11.015] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 11/01/2021] [Accepted: 11/07/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Polygenic and environmental factors are underlying causes of inflammatory bowel disease (IBD). We hypothesized that integration of the genetic loci controlling a metabolite's abundance, with known IBD genetic susceptibility loci, may help resolve metabolic drivers of IBD. METHODS We measured the levels of 1300 metabolites in the serum of 484 patients with ulcerative colitis (UC) and 464 patients with Crohn's disease (CD) and 365 controls. Differential metabolite abundance was determined for disease status, subtype, clinical and endoscopic disease activity, as well as IBD phenotype including disease behavior, location, and extent. To inform on the genetic basis underlying metabolic diversity, we integrated metabolite and genomic data. Genetic colocalization and Mendelian randomization analyses were performed using known IBD risk loci to explore whether any metabolite was causally associated with IBD. RESULTS We found 173 genetically controlled metabolites (metabolite quantitative trait loci, 9 novel) within 63 non-overlapping loci (7 novel). Furthermore, several metabolites significantly associated with IBD disease status and activity as defined using clinical and endoscopic indexes. This constitutes a resource for biomarker discovery and IBD biology insights. Using this resource, we show that a novel metabolite quantitative trait locus for serum butyrate levels containing ACADS was not supported as causal for IBD; replicate the association of serum omega-6 containing lipids with the fatty acid desaturase 1/2 locus and identify these metabolites as causal for CD through Mendelian randomization; and validate a novel association of serum plasmalogen and TMEM229B, which was predicted as causal for CD. CONCLUSIONS An exploratory analysis combining genetics and unbiased serum metabolome surveys can reveal novel biomarkers of disease activity and potential mediators of pathology in IBD.
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Affiliation(s)
- Antonio F. Di Narzo
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Sema4, Stamford, CT, 06902, USA
| | - Sander M. Houten
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Icahn Institute for Data Science and Genomic Technology, New York City, NY, USA
| | - Roman Kosoy
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Icahn Institute for Data Science and Genomic Technology, New York City, NY, USA
| | - Ruiqi Huang
- Center for Biostatistics, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Frédéric M. Vaz
- Department of Clinical Chemistry, Amsterdam Gastroenterology & Metabolism, Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Ruixue Hou
- Center for Biostatistics, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Gabrielle Wei
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Icahn Institute for Data Science and Genomic Technology, New York City, NY, USA
| | - Wen-hui Wang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Icahn Institute for Data Science and Genomic Technology, New York City, NY, USA
| | - Phillip H. Comella
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Icahn Institute for Data Science and Genomic Technology, New York City, NY, USA
| | - Tetyana Dodatko
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Icahn Institute for Data Science and Genomic Technology, New York City, NY, USA
| | - Eduard Rogatsky
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Icahn Institute for Data Science and Genomic Technology, New York City, NY, USA
| | | | | | | | - Amy Hart
- Janssen R&D, LLC, 1400 McKean Road, Spring House, PA, USA
| | - Mark Curran
- Janssen R&D, LLC, 1400 McKean Road, Spring House, PA, USA
| | | | - Jun Zhu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Sema4, Stamford, CT, 06902, USA
- Icahn Institute for Data Science and Genomic Technology, New York City, NY, USA
| | - Manasi Agrawal
- The Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Judy Cho
- The Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ryan Ungaro
- The Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Marla Dubinsky
- The Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Bruce E Sands
- The Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mayte Suárez-Fariñas
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Center for Biostatistics, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Eric E. Schadt
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Sema4, Stamford, CT, 06902, USA
- Icahn Institute for Data Science and Genomic Technology, New York City, NY, USA
| | - Jean-Frederic Colombel
- The Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Andrew Kasarskis
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Sema4, Stamford, CT, 06902, USA
- Icahn Institute for Data Science and Genomic Technology, New York City, NY, USA
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ke Hao
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Sema4, Stamford, CT, 06902, USA
- Icahn Institute for Data Science and Genomic Technology, New York City, NY, USA
| | - Carmen Argmann
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Icahn Institute for Data Science and Genomic Technology, New York City, NY, USA
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9
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Chen R, Zheng J, Li L, Li C, Chao K, Zeng Z, Chen M, Zhang S. Metabolomics facilitate the personalized management in inflammatory bowel disease. Therap Adv Gastroenterol 2021; 14:17562848211064489. [PMID: 34987610 PMCID: PMC8721420 DOI: 10.1177/17562848211064489] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 11/15/2021] [Indexed: 02/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a gastrointestinal disorder characterized by chronic relapsing inflammation and mucosal lesions. Reliable biomarkers for monitoring disease activity, predicting therapeutic response, and disease relapse are needed in the personalized management of IBD. Given the alterations in metabolomic profiles observed in patients with IBD, metabolomics, a new and developing technique for the qualitative and quantitative study of small metabolite molecules, offers another possibility for identifying candidate markers and promising predictive models. With increasing research on metabolomics, it is gradually considered that metabolomics will play a significant role in the management of IBD. In this review, we summarize the role of metabolomics in the assessment of disease activity, including endoscopic activity and histological activity, prediction of therapeutic response, prediction of relapse, and other aspects concerning disease management in IBD. Furthermore, we describe the limitations of metabolomics and highlight some solutions.
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Affiliation(s)
- Rirong Chen
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Jieqi Zheng
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Li Li
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Road 2, Guangzhou 510080, P.R. China
| | - Chao Li
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Kang Chao
- Division of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Zhirong Zeng
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Minhu Chen
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Road 2, Guangzhou 510080, P.R. China
| | - Shenghong Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Road 2, Guangzhou 510080, P.R. China
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10
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Lee EG, Yoon YC, Yoon J, Lee SJ, Oh YK, Kwon SW. Systematic Review of Recent Lipidomics Approaches Toward Inflammatory Bowel Disease. Biomol Ther (Seoul) 2021; 29:582-595. [PMID: 34565718 PMCID: PMC8551739 DOI: 10.4062/biomolther.2021.125] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/17/2021] [Accepted: 08/18/2021] [Indexed: 02/06/2023] Open
Abstract
Researchers have endeavored to identify the etiology of inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis. Though the pathogenesis of inflammatory bowel diseases remains unknown, dysregulation of the immune system in the host gastrointestinal tract is believed to be the major causative factor. Omics is a powerful methodological tool that can reveal biochemical information stored in clinical samples. Lipidomics is a subset of omics that explores the lipid classes associated with inflammation. One objective of the present systematic review was to facilitate the identification of biochemical targets for use in future lipidomic studies on inflammatory bowel diseases. The use of high-resolution mass spectrometry to observe alterations in global lipidomics might help elucidate the immunoregulatory mechanisms involved in inflammatory bowel diseases and discover novel biomarkers for them. Assessment of the characteristics of previous clinical trials on inflammatory bowel diseases could help researchers design and establish patient selection and analytical method criteria for future studies on these conditions. In this study, we curated literature exclusively from four databases and extracted lipidomics-related data from literature, considering criteria. This paper suggests that the lipidomics approach toward research in inflammatory bowel diseases can clarify their pathogenesis and identify clinically valuable biomarkers to predict and monitor their progression.
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Affiliation(s)
- Eun Goo Lee
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Young Cheol Yoon
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Jihyun Yoon
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Seul Ji Lee
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Yu-Kyoung Oh
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Sung Won Kwon
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
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11
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Hurtado-Lorenzo A, Honig G, Weaver SA, Larkin PB, Heller C. Chronic Abdominal Pain in IBD Research Initiative: Unraveling Biological Mechanisms and Patient Heterogeneity to Personalize Treatment and Improve Clinical Outcomes. CROHN'S & COLITIS 360 2021; 3:otab034. [PMID: 36776666 PMCID: PMC9802354 DOI: 10.1093/crocol/otab034] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Andrés Hurtado-Lorenzo
- Research Department, Crohn’s & Colitis Foundation, New York, New York, USA,Address correspondence to: Andrés Hurtado-Lorenzo, PhD, Crohn’s & Colitis Foundation, 733 3rd Ave Suite 510, New York, NY 10017, USA ()
| | - Gerard Honig
- Research Department, Crohn’s & Colitis Foundation, New York, New York, USA
| | | | - Paul B Larkin
- Research Department, Crohn’s & Colitis Foundation, New York, New York, USA
| | - Caren Heller
- Research Department, Crohn’s & Colitis Foundation, New York, New York, USA
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12
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Sung J, Wang L, Long D, Yang C, Merlin D. PepT1-knockout mice harbor a protective metabolome beneficial for intestinal wound healing. Am J Physiol Gastrointest Liver Physiol 2021; 320:G888-G896. [PMID: 33759563 PMCID: PMC8202197 DOI: 10.1152/ajpgi.00299.2020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Genetic knockout (KO) of peptide transporter-1 (PepT1) protein is known to provide resistance to acute colitis and colitis-associated cancer (CAC) in mouse models. However, it was unclear which molecule(s) or pathway(s) formed the basis for these protective effects. Recently, we demonstrated that the PepT1-/- microbiota is sufficient to protect against colitis and CAC. Given that PepT1 KO alters the gut microbiome and thereby changes the intestinal metabolites that are ultimately reflected in the feces, we investigated the fecal metabolites of our PepT1 KO mice. Using a liquid chromatography-mass spectrometry (LC-MS)-based untargeted-metabolomics technique, we found that the fecal metabolites were significantly different between the KO and normal wild-type (WT) mice. Among the altered fecal metabolites, tuberonic acid (TA) was sevenfold higher in KO mouse feces than in WT mouse feces. Accordingly, we studied whether the increased TA could direct an anti-inflammatory effect. Using in vitro models, we discovered that TA not only prevented lipopolysaccharide (LPS)-induced inflammation in macrophages but also improved the epithelial cell healing processes. Our results suggest that TA, and possibly other fecal metabolites, play a crucial role in the pathway(s) associated with the anticolitis effects of PepT1 KO.NEW & NOTEWORTHY Fecal metabolites were significantly different between the KO and normal wild-type (WT) mice. One fecal metabolite, tuberonic acid (TA), was sevenfold higher in KO mouse feces than in WT mouse feces. TA prevented lipopolysaccharide (LPS)-induced inflammation in macrophages and improved the epithelial cell healing process.
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Affiliation(s)
- Junsik Sung
- 1Institute for Biomedical Sciences, Digestive Diseases Research Group, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia
| | - Lixin Wang
- 1Institute for Biomedical Sciences, Digestive Diseases Research Group, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia,2Atlanta Veterans Affairs Medical Center, Decatur, Georgia
| | - Dingpei Long
- 1Institute for Biomedical Sciences, Digestive Diseases Research Group, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia
| | - Chunhua Yang
- 1Institute for Biomedical Sciences, Digestive Diseases Research Group, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia
| | - Didier Merlin
- 1Institute for Biomedical Sciences, Digestive Diseases Research Group, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia,2Atlanta Veterans Affairs Medical Center, Decatur, Georgia
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13
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Amerikanou C, Dimitropoulou E, Gioxari A, Papada E, Tanaini A, Fotakis C, Zoumpoulakis P, Kaliora AC. Linking the IL-17A immune response with NMR-based faecal metabolic profile in IBD patients treated with Mastiha. Biomed Pharmacother 2021; 138:111535. [PMID: 34311533 DOI: 10.1016/j.biopha.2021.111535] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/14/2021] [Accepted: 03/21/2021] [Indexed: 12/28/2022] Open
Abstract
Dysregulation of intestinal immune response plays a critical role in the pathogenesis of Inflammatory Bowel Disease (IBD). Mastiha's anti-inflammatory properties are well established. Our aim was to investigate Mastiha's regulatory effect on IL-17A serum levels in IBD patients. Alterations of the faecal metabolome as a functional readout of microbial activity were explored. A randomized, double-blind, placebo-controlled, parallel-group design was applied for a total of 3 months in active and 6 months in inactive IBD patients. Serum IL-17A increased significantly in Mastiha group (p = 0.006), and the mean change differed significantly between Mastiha and placebo (p = 0.003) even after adjusting for age, sex and BMI (p = 0.001) in inactive patients. In inactive UC patients IL-17A decreased significantly only in placebo (p = 0.033). No significant differences were detected in active disease. Faecal metabolomics indicated that intervention with Mastiha influenced considerably the metabolic profile of IBD patients in remission exhibiting, in between others, increased levels of glycine and tryptophan. Glycine has been proposed to have a therapeutic effect against IBD, while tryptophan derivatives are involved in immunoregalutory mechanisms, such as the Th17 cells differentiation. Thus, it is quite possible that the immunoregulatory role of Mastiha in quiescent IBD involves the regulation of Th17 cells function and differentiation.
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Affiliation(s)
- Charalampia Amerikanou
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece
| | - Eirini Dimitropoulou
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece
| | - Aristea Gioxari
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece
| | - Efstathia Papada
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece
| | - Anthi Tanaini
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece
| | - Charalambos Fotakis
- Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece
| | - Panagiotis Zoumpoulakis
- Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece; Department of Food Science and Technology, University of West Attica, Athens, Greece.
| | - Andriana C Kaliora
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
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14
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Garand M, Kumar M, Huang SSY, Al Khodor S. A literature-based approach for curating gene signatures in multifaceted diseases. J Transl Med 2020; 18:279. [PMID: 32650786 PMCID: PMC7350750 DOI: 10.1186/s12967-020-02408-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Accepted: 06/05/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND AND AIMS The task of identifying a representative and yet manageable target gene list for assessing the pathogenesis of complicated and multifaceted diseases is challenging. Using Inflammatory Bowel Disease (IBD) as an example, we conceived a bioinformatic approach to identify novel genes associated with the various disease subtypes, in combination with known clinical control genes. METHODS From the available literature, we used Acumenta Literature LabTM (LitLab), network analyses, and LitLab Gene Retriever to assemble a gene pool that has a high likelihood of representing immunity-related subtype-specific signatures of IBD. RESULTS We generated six relevant gene lists and 21 intersections that contain genes with unique literature associations to Crohn's Disease (n = 60), Ulcerative Colitis (n = 17), and unclassified (n = 45) subtypes of IBD. From this gene pool, we then filtered and constructed, using network analysis, a final list of 142 genes that are the most representative of the disease and its subtypes. CONCLUSIONS In this paper, we present the bioinformatic construction of a gene panel that putatively contains subtype signatures of IBD, a multifactorial disease. These gene signatures will be tested as biomarkers to classify patients with IBD, which has been a clinically challenging task. Such approach to diagnose and monitor complicated disease pathogenesis is a stepping-stone towards personalized care.
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Affiliation(s)
| | - Manoj Kumar
- Research Department, Sidra Medicine, Doha, Qatar
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15
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Filimoniuk A, Daniluk U, Samczuk P, Wasilewska N, Jakimiec P, Kucharska M, Lebensztejn DM, Ciborowski M. Metabolomic profiling in children with inflammatory bowel disease. Adv Med Sci 2020; 65:65-70. [PMID: 31901795 DOI: 10.1016/j.advms.2019.12.009] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 09/25/2019] [Accepted: 12/23/2019] [Indexed: 02/06/2023]
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) represent inflammatory bowel diseases (IBD) with multifactorial pathogenesis, involving genetic, environmental and microbial factors. Interactions between gut microbiota and immune system result in changes in metabolic pathways. Metabolomics is a comprehensive and quantitative (or semi-quantitative) analysis of metabolites synthetized in human's biological system. It has been shown that metabolic profiling might be used to identify disease biomarkers. Recent findings confirmed alterations in the number of metabolites in patients with IBD. However, most of the studies included adult individuals with ongoing treatment which might have affected the metabolite profiling. Therefore, the aim of our study was to collect the knowledge about metabolomics in paediatric patients with CD or UC based on the currently published literature.
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Affiliation(s)
- Aleksandra Filimoniuk
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok, Bialystok, Poland
| | - Urszula Daniluk
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok, Bialystok, Poland.
| | - Paulina Samczuk
- Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
| | - Natalia Wasilewska
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok, Bialystok, Poland
| | - Piotr Jakimiec
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok, Bialystok, Poland
| | - Magdalena Kucharska
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok, Bialystok, Poland
| | - Dariusz M Lebensztejn
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok, Bialystok, Poland
| | - Michał Ciborowski
- Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
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16
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Metabolomic Analysis of the Liver of a Dextran Sodium Sulfate-Induced Acute Colitis Mouse Model: Implications of the Gut-Liver Connection. Cells 2020; 9:cells9020341. [PMID: 32024178 PMCID: PMC7072179 DOI: 10.3390/cells9020341] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 01/21/2020] [Accepted: 01/29/2020] [Indexed: 01/18/2023] Open
Abstract
The incidence of ulcerative colitis (UC) is increasing worldwide, and it has become a growing problem in Asia. Previous research on UC has focused on serum, plasma, urine, gut tissues, and fecal metabolic profiling, but a comprehensive investigation into the correlation between the severity of colitis and changes in liver metabolism is still lacking. Since the liver and gut exchange nutrients and metabolites through a complex network, intestinal diseases can affect both the liver and other organs. In the present study, concentration-dependent dextran sodium sulfate (DSS)-induced ulcerative colitis was employed to examine changes in liver metabolism using a proton nuclear magnetic resonance spectroscopy (1H-NMR)-and ultra-performance liquid chromatography time of flight mass spectroscopy (UPLC-TOF MS)-based metabolomics study. Using the multivariate statistical analysis method orthogonal projections to latent structures discriminant analysis (OPLS-DA), changes in metabolites depending on the DSS dose could be clearly distinguished. Specifically, hepatic metabolites involved in one-carbon metabolism, carnitine-related metabolism, and nucleotide synthesis were found to be affected by intestinal inflammation, implying the existence of a metabolic connection between the gut and liver. We are currently investigating the significance of this metabolic condition in UC.
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17
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Mazumdar C, Driggers EM, Turka LA. The Untapped Opportunity and Challenge of Immunometabolism: A New Paradigm for Drug Discovery. Cell Metab 2020; 31:26-34. [PMID: 31839485 DOI: 10.1016/j.cmet.2019.11.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 10/24/2019] [Accepted: 11/14/2019] [Indexed: 12/14/2022]
Abstract
Here, we explore the manipulation of immune cell metabolism as a strategy in target discovery and drug development for immune-mediated diseases. Comparing exploitation of metabolic pathways to kill tumor cells for cancer treatment with the reprogramming of immune cells to treat autoimmune diseases highlights differences that confer several advantages to the latter (including a more favorable therapeutic index and greater target stability). We discuss technological capabilities and gaps, including the challenge of relating in vitro observations to in vivo biology. Finally, we conclude by identifying future opportunities that will move the field forward and accelerate drug discovery.
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18
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Integrating omics for a better understanding of Inflammatory Bowel Disease: a step towards personalized medicine. J Transl Med 2019; 17:419. [PMID: 31836022 PMCID: PMC6909475 DOI: 10.1186/s12967-019-02174-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 12/08/2019] [Indexed: 02/06/2023] Open
Abstract
Background Inflammatory Bowel Disease (IBD) is a multifactorial chronic disease. Understanding only one aspect of IBD pathogenesis does not reflect the complex nature of IBD nor will it improve its clinical management. Therefore, it is vital to dissect the interactions between the different players in IBD pathogenesis in order to understand the biology of the disease and enhance its clinical outcomes. Aims To provide an overview of the available omics data used to assess the potential mechanisms through which various players are contributing to IBD pathogenesis and propose a precision medicine model to fill the current knowledge gap in IBD. Results Several studies have reported microbial dysbiosis, immune and metabolic dysregulation in IBD patients, however, this data is not sufficient to create signatures that can differentiate between the disease subtypes or between disease relapse and remission. Conclusions We summarized the current knowledge in the application of omics in IBD patients, and we showed that the current knowledge gap in IBD hinders the improvements of clinical decision for treatment as well as the prediction of disease relapse. We propose one way to fill this gap by implementing integrative analysis of various omics datasets generated from one patient at a single time point.
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19
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Seo SH, Unno T, Park SE, Kim EJ, Lee YM, Na CS, Son HS. Korean Traditional Medicine ( Jakyakgamcho-tang) Ameliorates Colitis by Regulating Gut Microbiota. Metabolites 2019; 9:metabo9100226. [PMID: 31615012 PMCID: PMC6835967 DOI: 10.3390/metabo9100226] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 10/10/2019] [Accepted: 10/12/2019] [Indexed: 02/07/2023] Open
Abstract
The objective of this study was to examine the anti-colitis activity of Jakyakgamcho-tang (JGT) in dextran sulfate sodium (DSS)-induced colitis and explore changes of the gut microbial community using 16S rRNA amplicon sequencing and metabolomics approaches. It was found that treatment with JGT or 5-aminosalicylic acid (5-ASA) alleviated the severity of colitis symptoms by suppressing inflammatory cytokine levels of IL-6, IL-12, and IFN-γ. The non-metric multidimensional scaling analysis of gut microbiome revealed that JGT groups were clearly separated from the DSS group, suggesting that JGT administration altered gut microbiota. The operational taxonomic units (OTUs) that were decreased by DSS but increased by JGT include Akkermansia and Allobaculum. On the other hand, OTUs that were increased by DSS but decreased by 5-ASA or JGT treatments include Bacteroidales S24-7, Ruminococcaceae, and Rikenellaceae, and the genera Bacteroides, Parabacteroides, Oscillospira, and Coprobacillus. After JGT administration, the metabolites, including most amino acids and lactic acid that were altered by colitis induction, became similar to those of the control group. This study demonstrates that JGT might have potential to effectively treat colitis by restoring dysbiosis of gut microbiota and host metabolites.
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Affiliation(s)
- Seung-Ho Seo
- School of Korean Medicine, Dongshin University, Naju 58245, Korea.
| | - Tatsuya Unno
- School of Life Sciences, Faculty of Biotechnology, SARI Jeju National University, Jeju 63243, Korea.
- Subtropical/tropical Organism Gene Bank Jeju National University, Jeju 63243, Korea.
| | - Seong-Eun Park
- School of Korean Medicine, Dongshin University, Naju 58245, Korea.
| | - Eun-Ju Kim
- School of Korean Medicine, Dongshin University, Naju 58245, Korea.
| | - Yu-Mi Lee
- School of Korean Medicine, Dongshin University, Naju 58245, Korea.
| | - Chang-Su Na
- School of Korean Medicine, Dongshin University, Naju 58245, Korea.
| | - Hong-Seok Son
- School of Korean Medicine, Dongshin University, Naju 58245, Korea.
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20
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Mallick H, Franzosa EA, Mclver LJ, Banerjee S, Sirota-Madi A, Kostic AD, Clish CB, Vlamakis H, Xavier RJ, Huttenhower C. Predictive metabolomic profiling of microbial communities using amplicon or metagenomic sequences. Nat Commun 2019; 10:3136. [PMID: 31316056 PMCID: PMC6637180 DOI: 10.1038/s41467-019-10927-1] [Citation(s) in RCA: 150] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Accepted: 06/06/2019] [Indexed: 02/07/2023] Open
Abstract
Microbial community metabolomics, particularly in the human gut, are beginning to provide a new route to identify functions and ecology disrupted in disease. However, these data can be costly and difficult to obtain at scale, while amplicon or shotgun metagenomic sequencing data are readily available for populations of many thousands. Here, we describe a computational approach to predict potentially unobserved metabolites in new microbial communities, given a model trained on paired metabolomes and metagenomes from the environment of interest. Focusing on two independent human gut microbiome datasets, we demonstrate that our framework successfully recovers community metabolic trends for more than 50% of associated metabolites. Similar accuracy is maintained using amplicon profiles of coral-associated, murine gut, and human vaginal microbiomes. We also provide an expected performance score to guide application of the model in new samples. Our results thus demonstrate that this 'predictive metabolomic' approach can aid in experimental design and provide useful insights into the thousands of community profiles for which only metagenomes are currently available.
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Affiliation(s)
- Himel Mallick
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA
| | - Eric A Franzosa
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA
| | - Lauren J Mclver
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA
| | - Soumya Banerjee
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA
| | - Alexandra Sirota-Madi
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA
| | - Aleksandar D Kostic
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA
| | - Clary B Clish
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Hera Vlamakis
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Ramnik J Xavier
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
- Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
- Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
| | - Curtis Huttenhower
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.
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Dong LN, Wang M, Guo J, Wang JP. Role of intestinal microbiota and metabolites in inflammatory bowel disease. Chin Med J (Engl) 2019; 132:1610-1614. [PMID: 31090547 PMCID: PMC6616233 DOI: 10.1097/cm9.0000000000000290] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE The metabolites produced by the gut microbiota are of interest to scientists. The objective of this review was to provide an updated summary of progress regarding the microbiota and their metabolites and influences on the pathogenesis of inflammatory bowel disease (IBD). DATA SOURCES The author retrieved information from the PubMed database up to January 2018, using various combinations of search terms, including IBD, microbiota, and metabolite. STUDY SELECTION Both clinical studies and animal studies of intestinal microbiota and metabolites in IBD were selected. The information explaining the possible pathogenesis of microbiota in IBD was organized. RESULTS In IBD patients, the biodiversity of feces/mucosa-associated microbiota is decreased, and the probiotic microbiota is also decreased, whereas the pathogenic microbiota are increased. The gut microbiota may be a target for diagnosis and treatment of IBD. Substantial amounts of data support the view that the microbiota and their metabolites play pivotal roles in IBD by affecting intestinal permeability and the immune response. CONCLUSIONS This review highlights the advances in recent gut microbiota research and clarifies the importance of the gut microbiota in IBD pathogenesis. Future research is needed to study the function of altered bacterial community compositions and the roles of metabolites.
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Affiliation(s)
- Li-Na Dong
- Central Laboratory, Shanxi Provincial People's Hospital, Affiliate of Shanxi Medical University, Taiyuan, Shanxi 030012, China
| | - Mu Wang
- Department of Neurology, Shanxi Provincial People's Hospital, Affiliate of Shanxi Medical University, Taiyuan, Shanxi 030012, China
| | - Jian Guo
- Department of General Surgery, Shanxi Provincial People's Hospital, Affiliate of Shanxi Medical University, Taiyuan, Shanxi 030012, China
| | - Jun-Ping Wang
- Department of Gastroenterology, Shanxi Provincial People's Hospital, Affiliate of Shanxi Medical University, Taiyuan, Shanxi 030012, China
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22
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Thomaidou A, Chatziioannou AC, Deda O, Benaki D, Gika H, Mikros E, Agakidis C, Raikos N, Theodoridis G, Sarafidis K. A pilot case-control study of urine metabolomics in preterm neonates with necrotizing enterocolitis. J Chromatogr B Analyt Technol Biomed Life Sci 2019; 1117:10-21. [PMID: 30991202 DOI: 10.1016/j.jchromb.2019.04.019] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 04/01/2019] [Accepted: 04/07/2019] [Indexed: 12/27/2022]
Abstract
Necrotizing enterocolitis (NEC) is a leading cause of gastrointestinal morbidity and mortality in preterm neonates. The aim of this pilot study was to explore using metabolomics alternations in the urine metabolites related to NEC that could possibly serve as diagnostic biomarkers of the disease. Urine samples were prospectively collected at the day of initial evaluation for NEC from 15 diseased preterm neonates (five Bell's stage I and ten stage II/III) and an equal number of matched controls. Urine metabolic profiles were assessed using non-targeted nuclear magnetic resonance spectroscopy and targeted liquid chromatography-tandem mass spectrometry monitoring 108 metabolites. Multivariate statistical models with data from either analytical approach showed clear separation between the metabolic profiles of neonates with NEC and controls. Twenty-five discriminant metabolites were identified belonging to amino and organic acids, sugars and vitamins. A number of metabolite combinations were found to have an excellent diagnostic performance in detecting neonates developing NEC. Our results show that the metabolic profile of neonates with NEC differs significantly from that of controls, making possible their separation using urine metabolomic analysis. Nevertheless, whether the small set of significant metabolites detected in this investigation could be used as early diagnostic biomarkers of NEC should be validated in larger studies.
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Affiliation(s)
- Agathi Thomaidou
- 1(st) Department of Neonatology, School of Medicine, Aristotle University of Thessaloniki, Greece
| | | | - Olga Deda
- Laboratory of Forensic Medicine and Toxicology, School of Medicine, Aristotle University of Thessaloniki, Greece; Biomic_AUTh, Center for Interdisciplinary Research and Innovation (CIRI-AUTH), Balkan Center, B1.4, Thessaloniki, 10th km Thessaloniki-Thermi Rd, P.O. Box 8318, 57001, Greece
| | - Dimitra Benaki
- School of Pharmacy, National and Kapodistrian University of Athens, Greece
| | - Helen Gika
- Laboratory of Forensic Medicine and Toxicology, School of Medicine, Aristotle University of Thessaloniki, Greece; Biomic_AUTh, Center for Interdisciplinary Research and Innovation (CIRI-AUTH), Balkan Center, B1.4, Thessaloniki, 10th km Thessaloniki-Thermi Rd, P.O. Box 8318, 57001, Greece
| | - Emmanouel Mikros
- School of Pharmacy, National and Kapodistrian University of Athens, Greece
| | - Charalampos Agakidis
- 1(st) Department of Neonatology, School of Medicine, Aristotle University of Thessaloniki, Greece
| | - Nikolaos Raikos
- Laboratory of Forensic Medicine and Toxicology, School of Medicine, Aristotle University of Thessaloniki, Greece; Biomic_AUTh, Center for Interdisciplinary Research and Innovation (CIRI-AUTH), Balkan Center, B1.4, Thessaloniki, 10th km Thessaloniki-Thermi Rd, P.O. Box 8318, 57001, Greece
| | - Georgios Theodoridis
- School of Chemistry, Aristotle University of Thessaloniki, Greece; Biomic_AUTh, Center for Interdisciplinary Research and Innovation (CIRI-AUTH), Balkan Center, B1.4, Thessaloniki, 10th km Thessaloniki-Thermi Rd, P.O. Box 8318, 57001, Greece
| | - Kosmas Sarafidis
- 1(st) Department of Neonatology, School of Medicine, Aristotle University of Thessaloniki, Greece; Biomic_AUTh, Center for Interdisciplinary Research and Innovation (CIRI-AUTH), Balkan Center, B1.4, Thessaloniki, 10th km Thessaloniki-Thermi Rd, P.O. Box 8318, 57001, Greece.
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Papada E, Amerikanou C, Torović L, Kalogeropoulos N, Tzavara C, Forbes A, Kaliora AC. Plasma free amino acid profile in quiescent Inflammatory Bowel Disease patients orally administered with Mastiha (Pistacia lentiscus); a randomised clinical trial. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 56:40-47. [PMID: 30668352 DOI: 10.1016/j.phymed.2018.08.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 06/04/2018] [Accepted: 08/06/2018] [Indexed: 06/09/2023]
Abstract
BACKGROUND Natural products have been studied regarding their effectiveness on Inflammatory Bowel Disease (IBD). HYPOTHESIS/PURPOSE To examine the effects of Mastiha (Pistacia lentiscus var. Chia) on clinical course and amino acid (AA) profile of patients in remission. STUDY DESIGN This is a randomised, double-blind, placebo-controlled clinical trial. METHODS Patients (n = 68) were randomly allocated to Mastiha (2.8 g/day) or placebo adjunct to stable medication. Free AAs were identified applying Gas Chromatography-Mass Spectrometry in plasma. Medical-dietary history, Inflammatory Bowel Disease Questionnaire, Harvey-Bradshaw Index, Partial Mayo Score, biochemical, faecal and blood inflammatory markers were assessed. Primary endpoint was the clinical relapse rate at 6 months. Secondary endpoints included variations in free AAs, inflammatory biomarkers and quality of life. Statistical significance was set at 0.05. RESULTS Concerning AAs and biochemical data, alanine (p = 0.006), valine (p = 0.047), proline (p = 0.022), glutamine (p < 0.001) and tyrosine (p = 0.043) along with total cholesterol (p = 0.032) and LDL cholesterol (p = 0.045) increased only in placebo group compared with baseline and the change between the study groups was significantly different. Inflammatory markers had not a significantly different change between the two groups, even serum IL-6, faecal calprotectin and faecal lactoferrin increased only in the placebo group. Although Mastiha was not proven superior to placebo in remission rate (17.6% vs. 23.5%, p = 0.549), attenuation in increase of free AAs levels in verum group is reported. CONCLUSION Mastiha inhibited an increase in plasma free AAs seen in patients with quiescent IBD. Since change of AAs is considered an early prognostic marker of disease activity, this indicates a potential role of Mastiha in remission maintenance.
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Affiliation(s)
- Efstathia Papada
- Department of Dietetics and Nutritional Science, School of Health Science and Education, Harokopio University, Athens, Greece
| | - Charalampia Amerikanou
- Department of Dietetics and Nutritional Science, School of Health Science and Education, Harokopio University, Athens, Greece
| | - Ljilja Torović
- Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Nick Kalogeropoulos
- Department of Dietetics and Nutritional Science, School of Health Science and Education, Harokopio University, Athens, Greece
| | - Chara Tzavara
- Department of Dietetics and Nutritional Science, School of Health Science and Education, Harokopio University, Athens, Greece
| | - Alastair Forbes
- Norwich Medical School, University of East Anglia, Bob Champion Building, James Watson Road, Norwich NR4 7UQ, United Kingdom
| | - Andriana C Kaliora
- Department of Dietetics and Nutritional Science, School of Health Science and Education, Harokopio University, Athens, Greece.
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Karu N, Deng L, Slae M, Guo AC, Sajed T, Huynh H, Wine E, Wishart DS. A review on human fecal metabolomics: Methods, applications and the human fecal metabolome database. Anal Chim Acta 2018; 1030:1-24. [DOI: 10.1016/j.aca.2018.05.031] [Citation(s) in RCA: 136] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 05/05/2018] [Accepted: 05/09/2018] [Indexed: 12/19/2022]
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Timing for the second fecal microbiota transplantation to maintain the long-term benefit from the first treatment for Crohn's disease. Appl Microbiol Biotechnol 2018; 103:349-360. [PMID: 30357440 PMCID: PMC6311185 DOI: 10.1007/s00253-018-9447-x] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 10/01/2018] [Accepted: 10/03/2018] [Indexed: 12/14/2022]
Abstract
Increasing evidence has shown that fecal microbiota transplantation (FMT) could be a promising treatment option for Crohn's disease (CD). However, the frequency of FMT for CD treatment remains unclear. This study aimed to evaluate the optimal timing for administering the second course of FMT to maintain the long-term clinical effects from the first FMT for patients with CD. Sixty-nine patients with active CD who underwent FMT twice and benefited from the first FMT were enrolled in this study. Clinical response, stool microbiota, and urine metabolome of patients were assessed during the follow-up. The median time of maintaining clinical response to the first FMT in total 69 patients was 125 days (IQR, 82.5-225.5). The time of maintaining clinical response to the second FMT in 56 of 69 patients was 176.5 days (IQR, 98.5-280). The fecal microbiota composition of each patient post the first FMT was closer to that of his/her donor. Compared to that of the baseline, patients prior to the second course of FMT showed significant differences in urinary metabolic profiles characterized by increased indoxyl sulfate, 4-hydroxyphenylacetate, creatinine, dimethylamine, glycylproline, hippurate, and trimethylamine oxide (TMAO). This study demonstrated that patients with CD could be administered the second course of FMT less than 4 months after the first FMT for maintaining the clinical benefits from the first FMT. This was supported by the host-microbial metabolism changes in patients with active CD. Trial registration: ClinicalTrials.gov , NCT01793831. Registered 18 February 2013. https://clinicaltrials.gov/ct2/show/NCT01793831?term=NCT01793831&rank=1.
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Murgia A, Hinz C, Liggi S, Denes J, Hall Z, West J, Santoru ML, Piras C, Manis C, Usai P, Atzori L, Griffin JL, Caboni P. Italian cohort of patients affected by inflammatory bowel disease is characterised by variation in glycerophospholipid, free fatty acids and amino acid levels. Metabolomics 2018; 14:140. [PMID: 30830399 DOI: 10.1007/s11306-018-1439-4] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 10/05/2018] [Indexed: 01/08/2023]
Abstract
BACKGROUND Inflammatory bowel disease is a group of pathologies characterised by chronic inflammation of the intestine and an unclear aetiology. Its main manifestations are Crohn's disease and ulcerative colitis. Currently, biopsies are the most used diagnostic tests for these diseases and metabolomics could represent a less invasive approach to identify biomarkers of disease presence and progression. OBJECTIVES The lipid and the polar metabolite profile of plasma samples of patients affected by inflammatory bowel disease have been compared with healthy individuals with the aim to find their metabolomic differences. Also, a selected sub-set of samples was analysed following solid phase extraction to further characterise differences between pathological samples. METHODS A total of 200 plasma samples were analysed using drift tube ion mobility coupled with time of flight mass spectrometry and liquid chromatography for the lipid metabolite profile analysis, while liquid chromatography coupled with triple quadrupole mass spectrometry was used for the polar metabolite profile analysis. RESULTS Variations in the lipid profile between inflammatory bowel disease and healthy individuals were highlighted. Phosphatidylcholines, lyso-phosphatidylcholines and fatty acids were significantly changed among pathological samples suggesting changes in phospholipase A2 and arachidonic acid metabolic pathways. Variations in the levels of cholesteryl esters and glycerophospholipids were also found. Furthermore, a decrease in amino acids levels suggests mucosal damage in inflammatory bowel disease. CONCLUSIONS Given good statistical results and predictive power of the model produced in our study, metabolomics can be considered as a valid tool to investigate inflammatory bowel disease.
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Affiliation(s)
- Antonio Murgia
- Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy
- Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK
| | - Christine Hinz
- Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK
| | - Sonia Liggi
- Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK
| | - Jùlìa Denes
- Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK
| | - Zoe Hall
- Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK
| | - James West
- Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK
| | | | - Cristina Piras
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Cristina Manis
- Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy
| | - Paolo Usai
- Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy
| | - Luigi Atzori
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Julian L Griffin
- Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK
| | - Pierluigi Caboni
- Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.
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Guerville M, Hamilton MK, Ronveaux CC, Ellero-Simatos S, Raybould HE, Boudry G. Chronic refined low-fat diet consumption reduces cholecystokinin satiation in rats. Eur J Nutr 2018; 58:2497-2510. [PMID: 30069617 DOI: 10.1007/s00394-018-1802-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 07/30/2018] [Indexed: 01/03/2023]
Abstract
PURPOSE Reduced ability of cholecystokinin (CCK) to induce satiation contributes to hyperphagia and weight gain in high-fat/high-sucrose (HF/HS) diet-induced obesity, and has been linked to altered gut microbiota. Rodent models of obesity use chow or low-fat (LF) diets as control diets; the latter has been shown to alter gut microbiota and metabolome. We aimed to determine whether LF-diet consumption impacts CCK satiation in rats and if so, whether this is prevented by addition of inulin to LF diet. METHODS Rats (n = 40) were fed, for 8 weeks, a chow diet (chow) or low-fat (10%) or high-fat/high-sucrose (45 and 17%, respectively) refined diets with either 10% cellulose (LF and HF/HS) or 10% inulin (LF-I and HF/HS-I). Caecal metabolome was assessed by 1H-NMR-based metabolomics. CCK satiation was evaluated by measuring the suppression of food intake after intraperitoneal CCK injection (1 or 3 µg/kg). RESULTS LF-diet consumption altered the caecal metabolome, reduced caecal weight, and increased IAP activity, compared to chow. CCK-induced inhibition of food intake was abolished in LF diet-fed rats compared to chow-fed rats, while HF/HS diet-fed rats responded only to the highest CCK dose. Inulin substitution ameliorated caecal atrophy, reduced IAP activity, and modulated caecal metabolome, but did not improve CCK-induced satiety in either LF- or HF/HS-fed rats. CONCLUSIONS CCK signaling is impaired by LF-diet consumption, highlighting that caution must be taken when using LF diet until a more suitable refined control diet is identified.
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Affiliation(s)
- Mathilde Guerville
- Institut Numecan, INRA INSERM Univ Rennes 1, Domaine de la Prise, 35590, Saint-Gilles, France
| | - M Kristina Hamilton
- Department of Anatomy, Physiology and Cell Biology, UC Davis School of Veterinary Medicine, Davis, CA, USA
| | - Charlotte C Ronveaux
- Department of Anatomy, Physiology and Cell Biology, UC Davis School of Veterinary Medicine, Davis, CA, USA
| | - Sandrine Ellero-Simatos
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Helen E Raybould
- Department of Anatomy, Physiology and Cell Biology, UC Davis School of Veterinary Medicine, Davis, CA, USA
| | - Gaëlle Boudry
- Institut Numecan, INRA INSERM Univ Rennes 1, Domaine de la Prise, 35590, Saint-Gilles, France.
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Abstract
Inflammatory bowel disease (IBD), including Crohn disease and ulcerative colitis, is characterized by chronic intestinal inflammation due to a complex interaction of genetic determinants, disruption of mucosal barriers, aberrant inflammatory signals, loss of tolerance, and environmental triggers. Importantly, the incidence of pediatric IBD is rising, particularly in children younger than 10 years. In this review, we discuss the clinical presentation of these patients and highlight environmental exposures that may affect disease risk, particularly among people with a background genetic risk. With regard to both children and adults, we review advancements in understanding the intestinal epithelium, the mucosal immune system, and the resident microbiota, describing how dysfunction at any level can lead to diseases like IBD. We conclude with future directions for applying advances in IBD genetics to better understand pathogenesis and develop therapeutics targeting key pathogenic nodes.
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Affiliation(s)
- Joanna M Peloquin
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease and.,Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02114.,Harvard Medical School, Boston, Massachusetts 02115; , , ,
| | - Gautam Goel
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02114.,Harvard Medical School, Boston, Massachusetts 02115; , , ,
| | - Eduardo J Villablanca
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease and.,Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02114.,Harvard Medical School, Boston, Massachusetts 02115; , , ,
| | - Ramnik J Xavier
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease and.,Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02114.,Harvard Medical School, Boston, Massachusetts 02115; , , , .,Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142.,Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
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McNerney MP, Styczynski MP. Small molecule signaling, regulation, and potential applications in cellular therapeutics. WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE 2017; 10. [PMID: 28960879 DOI: 10.1002/wsbm.1405] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 07/20/2017] [Accepted: 08/14/2017] [Indexed: 12/19/2022]
Abstract
Small molecules have many important roles across the tree of life: they regulate processes from metabolism to transcription, they enable signaling within and between species, and they serve as the biochemical building blocks for cells. They also represent valuable phenotypic endpoints that are promising for use as biomarkers of disease states. In the context of engineering cell-based therapeutics, they hold particularly great promise for enabling finer control over the therapeutic cells and allowing them to be responsive to extracellular cues. The natural signaling and regulatory functions of small molecules can be harnessed and rewired to control cell activity and delivery of therapeutic payloads, potentially increasing efficacy while decreasing toxicity. To that end, this review considers small molecule-mediated regulation and signaling in bacteria. We first discuss some of the most prominent applications and aspirations for responsive cell-based therapeutics. We then describe the transport, signaling, and regulation associated with three classes of molecules that may be exploited in the engineering of therapeutic bacteria: amino acids, fatty acids, and quorum-sensing signaling molecules. We also present examples of existing engineering efforts to generate cells that sense and respond to levels of different small molecules. Finally, we discuss future directions for how small molecule-mediated regulation could be harnessed for therapeutic applications, as well as some critical considerations for the ultimate success of such endeavors. WIREs Syst Biol Med 2018, 10:e1405. doi: 10.1002/wsbm.1405 This article is categorized under: Biological Mechanisms > Cell Signaling Biological Mechanisms > Metabolism Translational, Genomic, and Systems Medicine > Therapeutic Methods.
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Affiliation(s)
- Monica P McNerney
- School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Mark P Styczynski
- School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA
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Magnolol, a Natural Polyphenol, Attenuates Dextran Sulfate Sodium-Induced Colitis in Mice. Molecules 2017; 22:molecules22071218. [PMID: 28726741 PMCID: PMC6152296 DOI: 10.3390/molecules22071218] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 07/18/2017] [Accepted: 07/18/2017] [Indexed: 02/07/2023] Open
Abstract
Magnolol is a lignan with anti-inflammatory activity identified in Magnolia officinalis. Ulcerative colitis (UC), one of the types of inflammatory bowel disease (IBD), is a disease that causes inflammation and ulcers in the colon. To investigate the effect of magnolol in dextran sulfate sodium (DSS)-induced experimental UC model, male C57 mice were treated with 2% DSS drinking water for 5 consecutive days followed by intragastric administration with magnolol (5, 10 and 15 mg/kg) daily for 7 days. The results showed that magnolol significantly attenuated disease activity index, inhibited colonic shortening, reduced colonic lesions and suppressed myeloperoxidase (MPO) activity. Moreover, colonic pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) induced by colitis were dramatically decreased by magnolol. To further unveil the metabolic signatures upon magnolol treatment, mass spectrometry-based metabolomic analysis of the small molecular metabolites in mice serum were performed. Compared with controls, abnormality of serum metabolic phenotypes in DSS-treated mice were effectively reversed by different doses of magnolol. In particular, magnolol treatment effectively elevated the serum levels of tryptophan metabolites including kynurenic acid (KA), 5-hydroxyindoleacetic acid, indoleacetic acid (IAA), indolelactic acid and indoxylsulfuric acid, which are potential aryl hydrocarbon receptor (AHR) ligands to impact colitis. These findings suggest that magnolol exerts anti-inflammatory effect on DSS-induced colitis and its underlying mechanisms are associated with the restoring of tryptophan metabolites that inhibit the colonic inflammation.
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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: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2017] [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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Kolho KL, Pessia A, Jaakkola T, de Vos WM, Velagapudi V. Faecal and Serum Metabolomics in Paediatric Inflammatory Bowel Disease. J Crohns Colitis 2017; 11:321-334. [PMID: 27609529 DOI: 10.1093/ecco-jcc/jjw158] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 09/07/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Inflammatory bowel disease [IBD] is considered to result from the interplay between host and intestinal microbiota but its pathogenesis is incompletely understood. While IBD in adults has shown to be associated with marked changes in body fluid metabolomics, there are only few studies in children. Hence, this prospective study addressed the faecal and serum metabolomics in newly diagnosed paediatric IBD. METHODS Paediatric patients with IBD undergoing diagnostic endoscopies and controls also with endoscopy but no signs of inflammation provided blood and stool samples in a tertiary care hospital. Blood inflammatory markers and faecal calprotectin levels were determined. The serum and faecal metabolomics were determined using ultra-high pressure liquid chromatography coupled to a mass spectrometer. RESULTS Serum and faecal metabolite profiles in newly diagnosed paediatric IBD patients were different from healthy controls and categorized Crohn's disease and ulcerative colitis [UC] patients into separate groups. In serum, amino acid metabolism, folate biosynthesis and signalling pathways were perturbed in Crohn's disease; in UC also sphingolipid metabolic pathways were perturbed when compared to controls. In faecal samples, there was an increased level of several metabolites in UC in contrast to low or intermediate levels in Crohn's disease. There was a clear correlation with the level of inflammation, i.e. faecal calprotectin levels and the profile of various biologically important metabolites [carnosine, ribose and, most significantly, choline]. CONCLUSION Characterization of inflammatory pattern using metabolomics analysis is a promising tool for better understanding disease pathogenesis of paediatric IBD.
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Affiliation(s)
- Kaija-Leena Kolho
- Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, FIN-00029, Finland
| | - Alberto Pessia
- Metabolomics Unit, Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, FIN-00029, Finland
| | - Tytti Jaakkola
- Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, FIN-00029, Finland
| | - Willem M de Vos
- Immunobiology Program, Department of Bacteriology & Immunology, University of Helsinki, Helsinki, FIN-00029, Finland.,Laboratory of Microbiology, Wageningen University, 6703 HB Wageningen, The Netherlands.,Department of Veterinary Biosciences, University of Helsinki, Helsinki, FIN-00029, Finland
| | - Vidya Velagapudi
- Metabolomics Unit, Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, FIN-00029, Finland
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Abstract
Despite advances in our understanding of the pathophysiology underlying inflammatory bowel disease, there remains a significant need for biomarkers that can differentiate between Crohn's disease and ulcerative colitis with high sensitivity and specificity, in a cost-efficient manner. As the focus on personalized approaches to the delivery of medical treatment increases, new biomarkers are being developed to predict an individual's response to therapy and their overall disease course. In this review, we will outline many of the existing and recently developed biomarkers, detailing their role in the assessment of patients with inflammatory bowel disease. We will identify opportunities for improvement in our biomarkers, including better differentiation between the subtypes of inflammatory bowel disease. We will also discuss new targets and strategies in biomarker development, including combining modalities to create biomarker signatures to improve the ability to predict disease courses and response to therapy among individual patients.
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Masselli G, Mastroiacovo I, De Marco E, Francione G, Casciani E, Polettini E, Gualdi G. Current tecniques and new perpectives research of magnetic resonance enterography in pediatric Crohn's disease. World J Radiol 2016; 8:668-82. [PMID: 27551337 PMCID: PMC4965351 DOI: 10.4329/wjr.v8.i7.668] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2015] [Revised: 03/24/2016] [Accepted: 04/07/2016] [Indexed: 02/06/2023] Open
Abstract
Crohn's disease affects more than 500000 individuals in the United States, and about 25% of cases are diagnosed during the pediatric period. Imaging of the bowel has undergone dramatic changes in the past two decades. The endoscopy with biopsy is generally considered the diagnostic reference standard, this combination can evaluates only the mucosa, not inflammation or fibrosis in the mucosa. Actually, the only modalities that can visualize submucosal tissues throughout the small bowel are the computed tomography (CT) enterography (CTE) with the magnetic resonance enterography (MRE). CT generally is highly utilized, but there is growing concern over ionizing radiation and cancer risk; it is a very important aspect to keep in consideration in pediatric patients. In contrast to CTE, MRE does not subject patients to ionizing radiation and can be used to detect detailed morphologic information and functional data of bowel disease, to monitor the effects of medical therapy more accurately, to detect residual active disease even in patients showing apparent clinical resolution and to guide treatment more accurately.
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Sarosiek I, Schicho R, Blandon P, Bashashati M. Urinary metabolites as noninvasive biomarkers of gastrointestinal diseases: A clinical review. World J Gastrointest Oncol 2016; 8:459-465. [PMID: 27190585 PMCID: PMC4865713 DOI: 10.4251/wjgo.v8.i5.459] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 01/12/2016] [Accepted: 03/09/2016] [Indexed: 02/05/2023] Open
Abstract
The diagnosis of gastrointestinal (GI) disorders is usually based on invasive techniques such as endoscopy. A key important factor in GI cancer is early diagnosis which warrants development of non- or less-invasive diagnostic techniques. In addition, monitoring and surveillance are other important parts in the management of GI diseases. Metabolomics studies with nuclear magnetic resonance and mass spectrometry can measure the concentration of more than 3000 chemical compounds in the urine providing possible chemical signature in different diseases and during health. In this review, we discuss the urinary metabolomics signature of different GI diseases including GI cancer and elaborate on how these biomarkers could be used for the classification, early diagnosis and the monitoring of the patients. Moreover, we discuss future directions of this still evolving field of research.
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Smirnov KS, Maier TV, Walker A, Heinzmann SS, Forcisi S, Martinez I, Walter J, Schmitt-Kopplin P. Challenges of metabolomics in human gut microbiota research. Int J Med Microbiol 2016; 306:266-279. [PMID: 27012595 DOI: 10.1016/j.ijmm.2016.03.006] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Revised: 03/08/2016] [Accepted: 03/09/2016] [Indexed: 01/17/2023] Open
Abstract
The review highlights the role of metabolomics in studying human gut microbial metabolism. Microbial communities in our gut exert a multitude of functions with huge impact on human health and disease. Within the meta-omics discipline, gut microbiome is studied by (meta)genomics, (meta)transcriptomics, (meta)proteomics and metabolomics. The goal of metabolomics research applied to fecal samples is to perform their metabolic profiling, to quantify compounds and classes of interest, to characterize small molecules produced by gut microbes. Nuclear magnetic resonance spectroscopy and mass spectrometry are main technologies that are applied in fecal metabolomics. Metabolomics studies have been increasingly used in gut microbiota related research regarding health and disease with main focus on understanding inflammatory bowel diseases. The elucidated metabolites in this field are summarized in this review. We also addressed the main challenges of metabolomics in current and future gut microbiota research. The first challenge reflects the need of adequate analytical tools and pipelines, including sample handling, selection of appropriate equipment, and statistical evaluation to enable meaningful biological interpretation. The second challenge is related to the choice of the right animal model for studies on gut microbiota. We exemplified this using NMR spectroscopy for the investigation of cross-species comparison of fecal metabolite profiles. Finally, we present the problem of variability of human gut microbiota and metabolome that has important consequences on the concepts of personalized nutrition and medicine.
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Affiliation(s)
- Kirill S Smirnov
- Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum München, Ingolstädter Landstraße 1, Neuherberg, 85764, Germany
| | - Tanja V Maier
- Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum München, Ingolstädter Landstraße 1, Neuherberg, 85764, Germany
| | - Alesia Walker
- Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum München, Ingolstädter Landstraße 1, Neuherberg, 85764, Germany
| | - Silke S Heinzmann
- Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum München, Ingolstädter Landstraße 1, Neuherberg, 85764, Germany
| | - Sara Forcisi
- Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum München, Ingolstädter Landstraße 1, Neuherberg, 85764, Germany
| | - Inés Martinez
- Department of Agriculture, Food and Nutritional Science, University of Alberta, T6G 2E1 Edmonton, AB, Canada
| | - Jens Walter
- Department of Agriculture, Food and Nutritional Science, University of Alberta, T6G 2E1 Edmonton, AB, Canada
| | - Philippe Schmitt-Kopplin
- Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum München, Ingolstädter Landstraße 1, Neuherberg, 85764, Germany; Chair of Analytical Food Chemistry, Technische Universität München, Alte Akademie 10, 85354 Freising, Germany; ZIEL, Institute for Food & Health, Weihenstephaner Berg 1, 85354 Freising, Germany.
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Hisamatsu T, Ono N, Imaizumi A, Mori M, Suzuki H, Uo M, Hashimoto M, Naganuma M, Matsuoka K, Mizuno S, Kitazume MT, Yajima T, Ogata H, Iwao Y, Hibi T, Kanai T. Decreased Plasma Histidine Level Predicts Risk of Relapse in Patients with Ulcerative Colitis in Remission. PLoS One 2015; 10:e0140716. [PMID: 26474176 PMCID: PMC4608807 DOI: 10.1371/journal.pone.0140716] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 09/28/2015] [Indexed: 12/19/2022] Open
Abstract
Ulcerative colitis (UC) is characterized by chronic intestinal inflammation. Patients with UC have repeated remission and relapse. Clinical biomarkers that can predict relapse in UC patients in remission have not been identified. To facilitate the prediction of relapse of UC, we investigated the potential of novel multivariate indexes using statistical modeling of plasma free amino acid (PFAA) concentrations. We measured fasting PFAA concentrations in 369 UC patients in clinical remission, and 355 were observed prospectively for up to 1 year. Relapse rate within 1 year was 23% (82 of 355 patients). The age- and gender-adjusted hazard ratio for the lowest quartile compared with the highest quartile of plasma histidine concentration was 2.55 (95% confidence interval: 1.41–4.62; p = 0.0020 (log-rank), p for trend = 0.0005). We demonstrated that plasma amino acid profiles in UC patients in clinical remission can predict the risk of relapse within 1 year. Decreased histidine level in PFAAs was associated with increased risk of relapse. Metabolomics could be promising for the establishment of a non-invasive predictive marker in inflammatory bowel disease.
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Affiliation(s)
- Tadakazu Hisamatsu
- Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
- Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan
- * E-mail:
| | - Nobukazu Ono
- Institute for Innovation, Ajinomoto Co. Inc., Kawasaki, Japan
| | - Akira Imaizumi
- Institute for Innovation, Ajinomoto Co. Inc., Kawasaki, Japan
| | - Maiko Mori
- Institute for Innovation, Ajinomoto Co. Inc., Kawasaki, Japan
| | - Hiroaki Suzuki
- Research Institute, Ajinomoto Pharmaceuticals Co. Ltd., Kawasaki, Japan
| | - Michihide Uo
- Research Institute, Ajinomoto Pharmaceuticals Co. Ltd., Kawasaki, Japan
| | - Masaki Hashimoto
- Research Institute, Ajinomoto Pharmaceuticals Co. Ltd., Kawasaki, Japan
| | - Makoto Naganuma
- Center for Diagnostic and Therapeutic Endoscopy, Keio University, Tokyo, Japan
| | - Katsuyoshi Matsuoka
- Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Shinta Mizuno
- Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Mina T. Kitazume
- Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Tomoharu Yajima
- Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Haruhiko Ogata
- Center for Diagnostic and Therapeutic Endoscopy, Keio University, Tokyo, Japan
| | - Yasushi Iwao
- Center for Preventive Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Toshifumi Hibi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - Takanori Kanai
- Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
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Dubinsky M, Braun J. Diagnostic and Prognostic Microbial Biomarkers in Inflammatory Bowel Diseases. Gastroenterology 2015; 149:1265-1274.e3. [PMID: 26284597 PMCID: PMC5302020 DOI: 10.1053/j.gastro.2015.08.006] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2015] [Revised: 08/08/2015] [Accepted: 08/12/2015] [Indexed: 12/14/2022]
Abstract
The microbiome plays multifaceted roles in the pathogenesis of inflammatory bowel diseases (IBD). Accordingly, the clinical challenge of patient heterogeneity in disease phenotype and response to treatment should in part be addressed by biomarkers that detect the host response to microbiota, and the levels of microbial taxa and products eliciting the host response in susceptible individuals. Molecular analysis has revealed much evidence for microbial taxonomic membership and microbial products in association with IBD, but their utility as clinical biomarkers is still in its infancy. A rich area of progress has been the development and validation of host serologic microbial biomarkers, which have achieved a distinctive position in the diagnosis and prognosis in IBD, and as a template for defining other categories of microbial biomarkers in disease state and phenotype.
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Affiliation(s)
- Marla Dubinsky
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York.
| | - Jonathan Braun
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
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Sands BE. Biomarkers of Inflammation in Inflammatory Bowel Disease. Gastroenterology 2015; 149:1275-1285.e2. [PMID: 26166315 DOI: 10.1053/j.gastro.2015.07.003] [Citation(s) in RCA: 270] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 07/02/2015] [Accepted: 07/06/2015] [Indexed: 02/07/2023]
Abstract
Recent observations suggest that subjective measures of disease activity in inflammatory bowel disease (IBD) are often misleading. Objective measures of inflammation are more closely associated with important long-term outcomes, but often depend upon invasive and costly procedures such as ileocolonoscopy and cross-sectional imaging by computed tomography or magnetic resonance imaging. Noninvasive, accurate, and inexpensive measures of intestinal inflammation would allow clinicians to adopt widely the paradigm of adjusting therapies with a goal of controlling inflammation. Blood, stool, and urine markers have all been explored as indicators of intestinal inflammation in IBD, and although none has been universally adopted, some have been well-characterized, and others hold great promise. Serum C-reactive protein and fecal calprotectin are among the best-studied noninvasive biomarkers of inflammation in IBD, and their test characteristics have been described in the setting of differentiating IBD from irritable bowel syndrome, for grading inflammation, to describe the response to therapy, and in demonstrating recurrent inflammation after medical or surgically induced remission. High-throughput research platforms, including gene expression arrays, metabolomics and proteomics, are also being applied to the discovery of novel biomarkers of inflammation. It is certain that biomarkers of inflammation will attain growing importance in the clinic as we strive for more effective and cost-effective strategies to treat patients with IBD.
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Affiliation(s)
- Bruce E Sands
- Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.
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MRI for Crohn's Disease: Present and Future. BIOMED RESEARCH INTERNATIONAL 2015; 2015:786802. [PMID: 26413543 PMCID: PMC4564596 DOI: 10.1155/2015/786802] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Revised: 10/09/2014] [Accepted: 12/11/2014] [Indexed: 12/18/2022]
Abstract
Crohn's disease (CD) is a chronic inflammatory condition with relapsing-remitting behavior, often causing strictures or penetrating bowel damage. Its lifelong clinical course necessitates frequent assessment of disease activity and complications. Computed tomography (CT) enterography has been used as primary imaging modality; however, the concern for radiation hazard limits its use especially in younger population. Magnetic resonance (MR) imaging has advantages of avoiding radiation exposure, lower incidence of adverse events, ability to obtain dynamic information, and good soft-tissue resolution. MR enterography (MRE) with oral contrast agent has been used as primary MR imaging modality of CD with high sensitivity, specificity, and interobserver agreement. The extent of inflammation as well as transmural ulcers and fibrostenotic diseases can be detected with MRE. Novel MR techniques such as diffusion-weighted MRI (DWI), motility study, PET-MRI, and molecular imaging are currently investigated for further improvement of diagnosis and management of CD. MR spectroscopy is a remarkable molecular imaging tool to analyze metabolic profile of CD with human samples such as plasma, urine, or feces, as well as colonic mucosa itself.
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Tontini GE, Vecchi M, Pastorelli L, Neurath MF, Neumann H. Differential diagnosis in inflammatory bowel disease colitis: State of the art and future perspectives. World J Gastroenterol 2015; 21:21-46. [PMID: 25574078 PMCID: PMC4284336 DOI: 10.3748/wjg.v21.i1.21] [Citation(s) in RCA: 137] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 07/31/2014] [Accepted: 09/16/2014] [Indexed: 02/06/2023] Open
Abstract
Distinction between Crohn’s disease of the colon-rectum and ulcerative colitis or inflammatory bowel disease (IBD) type unclassified can be of pivotal importance for a tailored clinical management, as each entity often involves specific therapeutic strategies and prognosis. Nonetheless, no gold standard is available and the uncertainty of diagnosis may frequently lead to misclassification or repeated examinations. Hence, we have performed a literature search to address the problem of differential diagnosis in IBD colitis, revised current and emerging diagnostic tools and refined disease classification strategies. Nowadays, the differential diagnosis is an untangled issue, and the proper diagnosis cannot be reached in up to 10% of patients presenting with IBD colitis. This topic is receiving emerging attention, as medical therapies, surgical approaches and leading prognostic outcomes require more and more disease-specific strategies in IBD patients. The optimization of standard diagnostic approaches based on clinical features, biomarkers, radiology, endoscopy and histopathology appears to provide only marginal benefits. Conversely, emerging diagnostic techniques in the field of gastrointestinal endoscopy, molecular pathology, genetics, epigenetics, metabolomics and proteomics have already shown promising results. Novel advanced endoscopic imaging techniques and biomarkers can shed new light for the differential diagnosis of IBD, better reflecting diverse disease behaviors based on specific pathogenic pathways.
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42
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Multi-omics analysis of inflammatory bowel disease. Immunol Lett 2014; 162:62-8. [PMID: 25131220 DOI: 10.1016/j.imlet.2014.07.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Revised: 06/21/2014] [Accepted: 07/29/2014] [Indexed: 12/16/2022]
Abstract
Crohn's disease and ulcerative colitis, known together as inflammatory bowel disease (IBD), are severe autoimmune disorders now causing gut inflammation and ulceration, among other symptoms, in up to 1 in 250 people worldwide. Incidence and prevalence of IBD have been increasing dramatically over the past several decades, although the causes for this increase are still unknown. IBD has both a complex genotype and a complex phenotype, and although it has received substantial attention from the medical research community over recent years, much of the etiology remains unexplained. Genome-wide association studies have identified a rich genetic signature of disease risk in patients with IBD, consisting of at least 163 genetic loci. Many of these loci contain genes directly involved in microbial handling, indicating that the genetic architecture of the disease has been driven by host-microbe interactions. In addition, systematic shifts in gut microbiome structure (enterotype) and function have been observed in patients with IBD. Furthermore, both the host genotype and enterotype are associated with aspects of the disease phenotype, including location of the disease. This provides strong evidence of interactions between host genotype and enterotype; however, there is a lack of published multi-omics data from IBD patients, and a lack of bioinformatics tools for modeling such systems. In this article we discuss, from a computational biologist's point of view, the potential benefits of and the challenges involved in designing and analyzing such multi-omics studies of IBD.
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Bjerrum JT, Nyberg C, Olsen J, Nielsen OH. Assessment of the validity of a multigene analysis in the diagnostics of inflammatory bowel disease. J Intern Med 2014; 275:484-93. [PMID: 24206446 DOI: 10.1111/joim.12160] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVES The findings of a previous multigene study indicated that the expression of a panel of seven specific genes had strong differential power regarding inflammatory bowel disease (IBD) versus non-IBD, as well as ulcerative colitis (UC) versus Crohn's disease (CD). This prospective confirmatory study based on an independent patient cohort from a national Danish IBD centre was conducted in an attempt to verify these earlier observations. DESIGN, SETTING AND PARTICIPANTS A total of 119 patients were included in the study (CD, UC and controls). Three mucosal biopsies were retrieved from the left side of the colon of each patient. RNA was extracted, and RT-PCR was performed to retain expression profiles from the seven selected genes. Expression data from the training set (18 CD, 20 UC and 20 controls) were used to build a classification model, using quadratic discriminant analysis, and data from the test set (20 CD, 21 UC and 20 controls) were used to test the validity of the model. RESULTS The present investigation did not confirm the previous observation that a panel of seven specific genes is able to distinguish between patients with CD and UC, whereas the discriminative power for IBD versus control subjects was substantiated. CONCLUSION Our results fail to demonstrate that the previously identified seven-gene classification model is able to discriminate between CD and UC but suggest that the gene panel merely discriminates between inflamed and noninflamed colonic tissue. Thus, a reliable and simple diagnostic tool is still warranted for optimal diagnosis and treatment of patients with IBD, especially the subgroup with unclassified disease.
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Affiliation(s)
- J T Bjerrum
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Cellular & Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
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High-performance isotope-labeling liquid chromatography mass spectrometry for investigating the effect of drinking Goji tea on urine metabolome profiling. Sci China Chem 2014. [DOI: 10.1007/s11426-014-5113-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Di Lena M, Travaglio E, Altomare DF. Metabolomics: a potential powerful ally in the fight against cancer. Colorectal Dis 2014; 16:235-8. [PMID: 24354548 DOI: 10.1111/codi.12523] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- M Di Lena
- Department of Emergency and Organ Transplantation, University Aldo Moro of Bari, Bari, Italy
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