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Deng J, Zhang J, Su M, Li J, Su Y, Zhong Q, Hu J, Chen Y, Liao S, Lin D, Guo X. Fusobacterium mortiferum and its metabolite 5-aminovaleric acid promote the development of colorectal cancer in obese individuals through Wnt/β-catenin pathway by DKK2. Gut Microbes 2025; 17:2502138. [PMID: 40340623 PMCID: PMC12064068 DOI: 10.1080/19490976.2025.2502138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 04/18/2025] [Accepted: 04/29/2025] [Indexed: 05/10/2025] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, with high incidence and mortality rates. An increasing body of research suggests that obesity is a significant risk factor for the development of CRC. Moreover, recent findings have highlighted the close association between the gut microbiota and both obesity and CRC. Despite this, the specific mechanisms by which the gut microbiota influences obesity and CRC remain unclear. This study aims to explore the role of the gut bacterium Fusobacterium mortiferum and its metabolite 5-aminovaleric acid (5-AVA) in the development of obesity and CRC. Our study found that the metabolite 5-aminovaleric acid produced by Fusobacterium mortiferum significantly inhibits the expression of the tumor suppressor DKK2. This inhibition leads to enhanced proliferation of CRC cells. Furthermore, we discovered that Fusobacterium mortiferum and 5-AVA can activate the Wnt/β-catenin signaling pathway by inhibiting DKK2, thereby promoting tumor growth. This finding was validated in CRC mouse models and in vitro experiments. Additional mechanistic studies revealed that 5-AVA interacts with the demethylase KDM6B, affecting the demethylation process of DKK2 and subsequently activating the Wnt/β-catenin signaling pathway. Our study retrospectively collected fecal samples from patients who underwent gastrointestinal endoscopy at the Sixth Affiliated Hospital of Sun Yat-sen University over the past five years. Participants were stratified into a healthy control group and an adenoma group based on the outcomes of their colonoscopies. Following this, we conducted metagenomic analysis to identify differential bacteria, and based on the results, we performed bacterial cultivation and metabolomic profiling. The roles of the targeted bacteria and their metabolites were further validated through animal models and cellular assays, employing techniques such as Western Blot, qPCR, immunohistochemistry, molecular docking simulations, and gene overexpression studies. This study uncovers the potential carcinogenic effects of Fusobacterium mortiferum and 5-AVA in the development of obesity and CRC. Our research emphasizes the complex interplay between the gut microbiota and host metabolism and suggests new directions for future research to explore how modulation of the gut microbiota could prevent and treat CRC.
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Affiliation(s)
- Jiaxin Deng
- Department of Endoscopic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiawei Zhang
- Department of Endoscopic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Mingli Su
- Department of Endoscopic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Juan Li
- Department of Endoscopic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yuping Su
- Department of Endoscopic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qinghua Zhong
- Department of Endoscopic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiancong Hu
- Department of Endoscopic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yongcheng Chen
- Department of Endoscopic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Sen Liao
- Department of Endoscopic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dezheng Lin
- Department of Endoscopic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xuefeng Guo
- Department of Endoscopic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Wang H, Chen Y, Wang Z, Yuan Y, Yue T. Novel selenium-enriched Pichia kudriavzevii as a dietary supplement to alleviate dextran sulfate sodium-induced colitis in mice by modulating the gut microbiota and host metabolism. Food Funct 2024; 15:10698-10716. [PMID: 39378068 DOI: 10.1039/d4fo02598a] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/29/2024]
Abstract
Inflammatory bowel disease (IBD) poses persistent challenges due to its chronic and recurrent nature, exacerbated by the unsatisfactory outcomes of the traditional treatment approaches. In this study, we developed a dietary supplement, selenium-enriched Pichia kudriavzevii (SeY), to alleviate dextran sulfate sodium-induced colitis in mice. The newly developed functional food shows dual-functional activity, acting both as a probiotic and a reliable source of organic selenium. This study aimed to investigate the preventive effects of SeY against dextran sulfate sodium-induced colitis in mice and elucidate the underlying mechanisms. Results showed that SeY, especially at high doses (HSeY), significantly ameliorated colitis symptoms, reduced colonic damage, attenuated inflammatory responses, and mitigated oxidative stress. Furthermore, HSeY strengthened intestinal barrier function by increasing goblet cell numbers, upregulating MUC2 expression, and enhancing tight junction proteins (ZO-1, claudin-1, and occludin). Additionally, HSeY alleviated gut microbiota dysbiosis by promoting the colonization of beneficial bacteria such as norank-f-Muribaculaceae and Bacteroides, while suppressing harmful microorganisms such as norank-f-norank-o-Clostridia-UCG-014. The altered gut microbiota also affected gut metabolism, with differential metabolites primarily associated with amino acids, such as tryptophan metabolism, contributing to the mitigation of oxidative stress and inflammatory responses. Further studies involving antibiotic-mediated depletion of gut flora and fecal microbiota transfer trials corroborated that the preventive effect of HSeY against IBD relied on the gut microbiota. This study provides vital insights into colitis prevention and advances selenium-enriched fortified food-targeted nutritional interventions.
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Affiliation(s)
- Huijuan Wang
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China.
| | - Yue Chen
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China.
| | - Zhouli Wang
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China.
| | - Yahong Yuan
- College of Food Science and Technology, Northwest University, Xi'an, 710069, China
| | - Tianli Yue
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China.
- College of Food Science and Technology, Northwest University, Xi'an, 710069, China
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Casaro S, Prim JG, Gonzalez TD, Cunha F, Bisinotto RS, Chebel RC, Santos JEP, Nelson CD, Jeon SJ, Bicalho RC, Driver JP, Galvão KN. Integrating uterine microbiome and metabolome to advance the understanding of the uterine environment in dairy cows with metritis. Anim Microbiome 2024; 6:30. [PMID: 38802977 PMCID: PMC11131188 DOI: 10.1186/s42523-024-00314-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 05/02/2024] [Indexed: 05/29/2024] Open
Abstract
BACKGROUND Metritis is a prevalent uterine disease that affects the welfare, fertility, and survival of dairy cows. The uterine microbiome from cows that develop metritis and those that remain healthy do not differ from calving until 2 days postpartum, after which there is a dysbiosis of the uterine microbiome characterized by a shift towards opportunistic pathogens such as Fusobacteriota and Bacteroidota. Whether these opportunistic pathogens proliferate and overtake the uterine commensals could be determined by the type of substrates present in the uterus. The objective of this study was to integrate uterine microbiome and metabolome data to advance the understanding of the uterine environment in dairy cows that develop metritis. Holstein cows (n = 104) had uterine fluid collected at calving and at the day of metritis diagnosis. Cows with metritis (n = 52) were paired with cows without metritis (n = 52) based on days after calving. First, the uterine microbiome and metabolome were evaluated individually, and then integrated using network analyses. RESULTS The uterine microbiome did not differ at calving but differed on the day of metritis diagnosis between cows with and without metritis. The uterine metabolome differed both at calving and on the day of metritis diagnosis between cows that did and did not develop metritis. Omics integration was performed between 6 significant bacteria genera and 153 significant metabolites on the day of metritis diagnosis. Integration was not performed at calving because there were no significant differences in the uterine microbiome. A total of 3 bacteria genera (i.e. Fusobacterium, Porphyromonas, and Bacteroides) were strongly correlated with 49 metabolites on the day of metritis diagnosis. Seven of the significant metabolites at calving were among the 49 metabolites strongly correlated with opportunistic pathogenic bacteria on the day of metritis diagnosis. The main metabolites have been associated with attenuation of biofilm formation by commensal bacteria, opportunistic pathogenic bacteria overgrowth, tissue damage and inflammation, immune evasion, and immune dysregulation. CONCLUSIONS The data integration presented herein helps advance the understanding of the uterine environment in dairy cows with metritis. The identified metabolites may provide a competitive advantage to the main uterine pathogens Fusobacterium, Porphyromonas and Bacteroides, and may be promising targets for future interventions aiming to reduce opportunistic pathogenic bacteria growth in the uterus.
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Affiliation(s)
- S Casaro
- Department of Large Animal Clinical Sciences, University of Florida, Gainesville, FL, USA
| | - J G Prim
- Department of Clinical Sciences, Auburn University, Auburn, AL, USA
| | - T D Gonzalez
- Department of Large Animal Clinical Sciences, University of Florida, Gainesville, FL, USA
| | - F Cunha
- Department of Large Animal Clinical Sciences, University of Florida, Gainesville, FL, USA
| | - R S Bisinotto
- Department of Large Animal Clinical Sciences, University of Florida, Gainesville, FL, USA
| | - R C Chebel
- Department of Large Animal Clinical Sciences, University of Florida, Gainesville, FL, USA
| | - J E P Santos
- Department of Animal Sciences, University of Florida, Gainesville, FL, USA
- D. H. Barron Reproductive and Perinatal Biology Research Program, University of Florida, Gainesville, FL, USA
| | - C D Nelson
- Department of Animal Sciences, University of Florida, Gainesville, FL, USA
| | - S J Jeon
- Department of Veterinary Biomedical Sciences, Long Island University, Brookville, NY, USA
| | - R C Bicalho
- FERA Diagnostics and Biologicals, College Station, TX, USA
| | - J P Driver
- Division of Animals Sciences, University of Missouri, Columbia, MO, USA
| | - Klibs N Galvão
- Department of Large Animal Clinical Sciences, University of Florida, Gainesville, FL, USA.
- D. H. Barron Reproductive and Perinatal Biology Research Program, University of Florida, Gainesville, FL, USA.
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Aldars-García L, Gil-Redondo R, Embade N, Riestra S, Rivero M, Gutiérrez A, Rodríguez-Lago I, Fernández-Salazar L, Ceballos D, Manuel Benítez J, Aguas M, Baston-Rey I, Bermejo F, José Casanova M, Lorente R, Ber Y, Ginard D, Esteve M, de Francisco R, García MJ, Francés R, Rodríguez Pescador A, Velayos B, Del Río EG, Marín Pedrosa S, Minguez Sabater A, Barreiro-de Acosta M, Algaba A, Verdejo Gil C, Rivas O, Royo V, Aceituno M, Garre A, Baldán-Martín M, Ramírez C, Sanz-García A, Lozano JJ, Sidorova J, Millet O, Bernardo D, Gisbert JP, Chaparro M. Serum and Urine Metabolomic Profiling of Newly Diagnosed Treatment-Naïve Inflammatory Bowel Disease Patients. Inflamm Bowel Dis 2024; 30:167-182. [PMID: 37536268 DOI: 10.1093/ibd/izad154] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Indexed: 08/05/2023]
Abstract
BACKGROUND AND AIMS Inflammatory bowel disease (IBD) is a prevalent chronic noncurable disease associated with profound metabolic changes. The discovery of novel molecular indicators for unraveling IBD etiopathogenesis and the diagnosis and prognosis of IBD is therefore pivotal. We sought to determine the distinctive metabolic signatures from the different IBD subgroups before treatment initiation. METHODS Serum and urine samples from newly diagnosed treatment-naïve IBD patients and age and sex-matched healthy control (HC) individuals were investigated using proton nuclear magnetic resonance spectroscopy. Metabolic differences were identified based on univariate and multivariate statistical analyses. RESULTS A total of 137 Crohn's disease patients, 202 ulcerative colitis patients, and 338 HC individuals were included. In the IBD cohort, several distinguishable metabolites were detected within each subgroup comparison. Most of the differences revealed alterations in energy and amino acid metabolism in IBD patients, with an increased demand of the body for energy mainly through the ketone bodies. As compared with HC individuals, differences in metabolites were more marked and numerous in Crohn's disease than in ulcerative colitis patients, and in serum than in urine. In addition, clustering analysis revealed 3 distinct patient profiles with notable differences among them based on the analysis of their clinical, anthropometric, and metabolomic variables. However, relevant phenotypical differences were not found among these 3 clusters. CONCLUSIONS This study highlights the molecular alterations present within the different subgroups of newly diagnosed treatment-naïve IBD patients. The metabolomic profile of these patients may provide further understanding of pathogenic mechanisms of IBD subgroups. Serum metabotype seemed to be especially sensitive to the onset of IBD.
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Affiliation(s)
- Laila Aldars-García
- Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria del Hospital de La Princesa, Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | | | - Nieves Embade
- Precision Medicine and Metabolism Lab, CIC bioGUNE, Derio, Spain
| | - Sabino Riestra
- Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain
| | - Montserrat Rivero
- Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Sanitaria Marqués de Valdecilla, Santander, Spain
| | - Ana Gutiérrez
- Hospital General Universitario de Alicante, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto Investigación Sanitaria y Biomédica de Alicante, Alicante, Spain
| | - Iago Rodríguez-Lago
- Hospital Universitario de Galdakao, Biocruces Bizkaia Health Research Institute, Vizcaya, Spain
| | | | - Daniel Ceballos
- Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain
| | - José Manuel Benítez
- Hospital Universitario Reina Sofía, Instituto Maimónides de Investigación Biomédica de Córdoba, Córdoba, Spain
| | - Mariam Aguas
- Hospital Universitari i Politecnic La Fe, La Fe Health Research Institute, Valencia, Spain
| | - Iria Baston-Rey
- Complexo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain
| | - Fernando Bermejo
- Hospital Universitario de Fuenlabrada, Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain
| | - María José Casanova
- Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria del Hospital de La Princesa, Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Rufo Lorente
- Hospital General Universitario de Ciudad Real, Ciudad Real, Spain
| | | | - Daniel Ginard
- Hospital Universitari Son Espases, Palma de Mallorca, Spain
| | - María Esteve
- Hospital Universitari Mutua Terrassa, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Terrassa, Spain
| | - Ruth de Francisco
- Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain
| | - María José García
- Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Sanitaria Marqués de Valdecilla, Santander, Spain
| | - Rubén Francés
- Hospital Clínico Universitario de Valladolid, Valladolid, Spain
| | | | - Benito Velayos
- Hospital Clínico Universitario de Valladolid, Valladolid, Spain
| | - Elena Guerra Del Río
- Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain
| | - Sandra Marín Pedrosa
- Hospital Universitario Reina Sofía, Instituto Maimónides de Investigación Biomédica de Córdoba, Córdoba, Spain
| | | | - Manuel Barreiro-de Acosta
- Departamento Medicina Clínica, Universidad Miguel Hernández de Elche, Instituto Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche, Universidad Miguel Herñandez, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto Investigación Sanitaria y Biomédica de Alicante, Elche, Spain
| | - Alicia Algaba
- Hospital Universitario de Galdakao, Biocruces Bizkaia Health Research Institute, Vizcaya, Spain
| | | | | | - Vanesa Royo
- Hospital Universitari Son Espases, Palma de Mallorca, Spain
| | - Montserrat Aceituno
- Hospital Universitari Mutua Terrassa, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Terrassa, Spain
| | - Ana Garre
- Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria del Hospital de La Princesa, Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Montserrat Baldán-Martín
- Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria del Hospital de La Princesa, Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Cristina Ramírez
- Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria del Hospital de La Princesa, Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Ancor Sanz-García
- Data Analysis Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Madrid, Spain
| | - Juan J Lozano
- Bioinformatics Platform, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
| | - Julia Sidorova
- Bioinformatics Platform, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
| | - Oscar Millet
- Precision Medicine and Metabolism Lab, CIC bioGUNE, Derio, Spain
| | - David Bernardo
- Mucosal Immunology Lab, Unidad de Excelencia Instituto de Biología y Genética Molecular, Universidad de Valladolid, Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Madrid, Spain
| | - Javier P Gisbert
- Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria del Hospital de La Princesa, Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - María Chaparro
- Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria del Hospital de La Princesa, Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
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Li S, Ding H, Qi Z, Yang J, Huang J, Huang L, Zhang M, Tang Y, Shen N, Qian K, Guo Q, Wan J. Serum Metabolic Fingerprints Characterize Systemic Lupus Erythematosus. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2304610. [PMID: 37953381 PMCID: PMC10787061 DOI: 10.1002/advs.202304610] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 10/01/2023] [Indexed: 11/14/2023]
Abstract
Metabolic fingerprints in serum characterize diverse diseases for diagnostics and biomarker discovery. The identification of systemic lupus erythematosus (SLE) by serum metabolic fingerprints (SMFs) will facilitate precision medicine in SLE in an early and designed manner. Here, a discovery cohort of 731 individuals including 357 SLE patients and 374 healthy controls (HCs), and a validation cohort of 184 individuals (SLE/HC, 91/93) are constructed. Each SMF is directly recorded by nano-assisted laser desorption/ionization mass spectrometry (LDI MS) within 1 minute using 1 µL of native serum, which contains 908 mass to charge features. Sparse learning of SMFs achieves the SLE identification with sensitivity/specificity and area-under-the-curve (AUC) up to 86.0%/92.0% and 0.950 for the discovery cohort. For the independent validation cohort, it exhibits no performance loss by affording the sensitivity/specificity and AUC of 89.0%/100.0% and 0.992. Notably, a metabolic biomarker panel is screened out from the SMFs, demonstrating the unique metabolic pattern of SLE patients different from both HCs and rheumatoid arthritis patients. In conclusion, SMFs characterize SLE by revealing its unique metabolic pattern. Different regulation of small molecule metabolites contributes to the precise diagnosis of autoimmune disease and further exploration of the pathogenic mechanisms.
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Affiliation(s)
- Shunxiang Li
- School of Biomedical Engineeringand Med‐X Research InstituteShanghai Jiao Tong UniversityShanghai200030P. R. China
- State Key Laboratory for Oncogenes and Related GenesShanghai Key Laboratory of Gynecologic Oncologyand Department of Obstetrics and GynecologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200127P. R. China
| | - Huihua Ding
- Department of Rheumatologyand Shanghai Institute of RheumatologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200001P. R. China
| | - Ziheng Qi
- School of Chemistry and Molecular EngineeringEast China Normal UniversityShanghai200241P. R. China
| | - Jing Yang
- School of Biomedical Engineeringand Med‐X Research InstituteShanghai Jiao Tong UniversityShanghai200030P. R. China
- State Key Laboratory for Oncogenes and Related GenesShanghai Key Laboratory of Gynecologic Oncologyand Department of Obstetrics and GynecologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200127P. R. China
| | - Jingyi Huang
- School of Biomedical Engineeringand Med‐X Research InstituteShanghai Jiao Tong UniversityShanghai200030P. R. China
| | - Lin Huang
- Shanghai Institute of Thoracic TumorsShanghai Chest HospitalShanghai Jiao Tong UniversityShanghai200030P. R. China
| | - Mengji Zhang
- School of Biomedical Engineeringand Med‐X Research InstituteShanghai Jiao Tong UniversityShanghai200030P. R. China
- State Key Laboratory for Oncogenes and Related GenesShanghai Key Laboratory of Gynecologic Oncologyand Department of Obstetrics and GynecologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200127P. R. China
| | - Yuanjia Tang
- Department of Rheumatologyand Shanghai Institute of RheumatologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200001P. R. China
| | - Nan Shen
- Department of Rheumatologyand Shanghai Institute of RheumatologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200001P. R. China
| | - Kun Qian
- School of Biomedical Engineeringand Med‐X Research InstituteShanghai Jiao Tong UniversityShanghai200030P. R. China
- State Key Laboratory for Oncogenes and Related GenesShanghai Key Laboratory of Gynecologic Oncologyand Department of Obstetrics and GynecologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200127P. R. China
| | - Qiang Guo
- Department of Rheumatologyand Shanghai Institute of RheumatologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200001P. R. China
| | - Jingjing Wan
- School of Chemistry and Molecular EngineeringEast China Normal UniversityShanghai200241P. R. China
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Baldan-Martin M, Chaparro M, Gisbert JP. Systematic Review: Urine Biomarker Discovery for Inflammatory Bowel Disease Diagnosis. Int J Mol Sci 2023; 24:10159. [PMID: 37373307 DOI: 10.3390/ijms241210159] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/12/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) are chronic, heterogeneous, and inflammatory conditions mainly affecting the gastrointestinal tract. Currently, endoscopy is the gold standard test for assessing mucosal activity and healing in clinical practice; however, it is a costly, time-consuming, invasive, and uncomfortable procedure for the patients. Therefore, there is an urgent need for sensitive, specific, fast and non-invasive biomarkers for the diagnosis of IBD in medical research. Urine is an excellent biofluid for discovering biomarkers because it is non-invasive to sample. In this review, we aimed to summarize proteomics and metabolomics studies performed in both animal models of IBD and humans that identify urinary biomarkers for IBD diagnosis. Future large-scale multi-omics studies should be conducted in collaboration with clinicians, researchers, and industry to make progress toward the development of sensitive and specific diagnostic biomarkers, thereby making personalized medicine possible.
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Affiliation(s)
- Montse Baldan-Martin
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28006 Madrid, Spain
| | - María Chaparro
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28006 Madrid, Spain
| | - Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28006 Madrid, Spain
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7
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Ma L, Luo Z, Huang Y, Li Y, Guan J, Zhou T, Du Z, Yong K, Yao X, Shen L, Yu S, Zhong Z, Hu Y, Peng G, Shi X, Cao S. Modulating gut microbiota and metabolites with dietary fiber oat β-glucan interventions to improve growth performance and intestinal function in weaned rabbits. Front Microbiol 2022; 13:1074036. [PMID: 36590438 PMCID: PMC9798315 DOI: 10.3389/fmicb.2022.1074036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022] Open
Abstract
The effect of oat β-glucan on intestinal function and growth performance of weaned rabbits were explored by multi-omics integrative analyses in the present study. New Zealand White rabbits fed oat β-glucan [200 mg/kg body weight (BW)] for 4 weeks, and serum markers, colon histological alterations, colonic microbiome, colonic metabolome, and serum metabolome were measured. The results revealed that oat β-glucan increased BW, average daily gain (ADG), average daily food intake (ADFI), and decreased serum tumor necrosis factor-α (TNF-α) interleukin-1β (IL-1β), and lipopolysaccharide (LPS) contents, but did not affect colonic microstructure. Microbiota community analysis showed oat β-glucan modulated gut microbial composition and structure, increased the abundances of beneficial bacteria Lactobacillus, Prevotellaceae_UCG-001, Pediococcus, Bacillus, etc. Oat β-glucan also increased intestinal propionic acid, valeric acid, and butyric acid concentrations, decreased lysine and aromatic amino acid (AAA) derivative contents. Serum metabolite analysis revealed that oat β-glucan altered host carbohydrate, lipid, and amino acid metabolism. These results suggested that oat β-glucan could inhibit systemic inflammation and protect intestinal function by regulating gut microbiota and related metabolites, which further helps to improve growth performance in weaned rabbits.
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Affiliation(s)
- Li Ma
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China,Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Chengdu University, Chengdu, China
| | - Zhengzhong Luo
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Yixin Huang
- School of Biodiversity, One Health and Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Yan Li
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Jing Guan
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Tao Zhou
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Zhenlong Du
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Kang Yong
- Department of Animal Husbandry and Veterinary Medicine, College of Animal Science and Technology, Chongqing Three Gorges Vocational College, Chongqing, China
| | - Xueping Yao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Liuhong Shen
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Shumin Yu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Zhijun Zhong
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Yanchun Hu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Guangneng Peng
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xiaodong Shi
- Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Chengdu University, Chengdu, China,*Correspondence: Xiaodong Shi,
| | - Suizhong Cao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China,Suizhong Cao,
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8
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Affiliation(s)
- Luciana Scotti
- Federal University of Paraíba, Postgraduate Program in Natural and Synthetic Bioactive Products, 50670-910, João Pessoa, PB, Brazil.,Federal University of Paraiba, Universitary Hospital, Paraiba, Brazil
| | - Marcus T Scotti
- Federal University of Paraíba, Postgraduate Program in Natural and Synthetic Bioactive Products, 50670-910, João Pessoa, PB, Brazil
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9
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Cheng X, Pi Z, Zheng Z, Liu S, Song F, Liu Z. Combined 16S rRNA gene sequencing and metabolomics to investigate the protective effects of Wu-tou Decoction on rheumatoid arthritis in rats. J Chromatogr B Analyt Technol Biomed Life Sci 2022; 1199:123249. [DOI: 10.1016/j.jchromb.2022.123249] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/06/2022] [Accepted: 04/07/2022] [Indexed: 12/12/2022]
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10
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Ren J, Li P, Yan D, Li M, Qi J, Wang M, Zhong G, Wu M. Interplay between the Gut Microbiome and Metabolism in Ulcerative Colitis Mice Treated with the Dietary Ingredient Phloretin. J Microbiol Biotechnol 2021; 31:1409-1419. [PMID: 34373435 PMCID: PMC9705873 DOI: 10.4014/jmb.2104.04038] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/25/2021] [Accepted: 08/06/2021] [Indexed: 12/15/2022]
Abstract
A growing number of healthy dietary ingredients in fruits and vegetables have been shown to exhibit diverse biological activities. Phloretin, a dihydrochalcone flavonoid that is abundant in apples and pears, has anti-inflammatory effects on ulcerative colitis (UC) mice. The gut microbiota and metabolism are closely related to each other due to the existence of the food-gut axis in the human colon. To investigate the interplay of faecal metabolites and the microbiota in UC mice after phloretin treatment, phloretin (60 mg/kg) was administered by gavage to ameliorate dextran sulfate sodium (DSS)-induced UC in mice. Gut microbes and faecal metabolite profiles were detected by high-throughput sequencing and liquid chromatography mass spectrometry (LC-MS) analysis, respectively. The correlations between gut microbes and their metabolites were evaluated by Spearman correlation coefficients. The results indicated that phloretin reshaped the disturbed faecal metabolite profile in UC mice and improved the metabolic pathways by balancing the composition of faecal metabolites such as norepinephrine, mesalazine, tyrosine, 5-acetyl-2,4-dimethyloxazole, and 6-acetyl-2,3-dihydro-2-(hydroxymethyl)-4(1H)-pyridinone. Correlation analysis identified the relations between the gut microbes and their metabolites. Proteus was negatively related to many faecal metabolites, such as norepinephrine, L-tyrosine, laccarin, dopamine glucuronide, and 5-acetyl-2,4-dimethyloxazole. The abundance of unidentified Bacteriodales_S24-7_group was positively related to ecgonine, 15-KETE and 6-acetyl-2,3-dihydro-2-(hydroxymethyl)-4(1H)-pyridinone. The abundance of Christensenellaceae_R-7_group was negatively related to the levels of 15-KETE and netilmicin. Stenotrophomonas and 15-KETE were negatively related, while Intestinimonas and alanyl-serine were positively related. In conclusion, phloretin treatment had positive impacts on faecal metabolites in UC mice, and the changes in faecal metabolites were closely related to the gut microbiota.
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Affiliation(s)
- Jie Ren
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, Henan, P.R. China
| | - Puze Li
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, Henan, P.R. China
| | - Dong Yan
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, Henan, P.R. China
| | - Min Li
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, Henan, P.R. China
| | - Jinsong Qi
- Department of Interventation, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, Henan, P.R. China
| | - Mingyong Wang
- Henan Key Laboratory of Immunology and Targeted Therapy, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang 453003, Henan, P.R. China
| | - Genshen Zhong
- Henan Key Laboratory of Immunology and Targeted Therapy, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang 453003, Henan, P.R. China
| | - Minna Wu
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, Henan, P.R. China,Corresponding author Phone: +86-373-3029130 E-mail:
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11
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Feng W, Liu J, Tan Y, Ao H, Wang J, Peng C. Polysaccharides from Atractylodes macrocephala Koidz. Ameliorate ulcerative colitis via extensive modification of gut microbiota and host metabolism. Food Res Int 2020; 138:109777. [DOI: 10.1016/j.foodres.2020.109777] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 09/20/2020] [Accepted: 10/02/2020] [Indexed: 02/08/2023]
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12
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Ma N, He T, Johnston LJ, Ma X. Host-microbiome interactions: the aryl hydrocarbon receptor as a critical node in tryptophan metabolites to brain signaling. Gut Microbes 2020; 11:1203-1219. [PMID: 32401136 PMCID: PMC7524279 DOI: 10.1080/19490976.2020.1758008] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Tryptophan (Trp) is not only a nutrient enhancer but also has systemic effects. Trp metabolites signaling through the well-known aryl hydrocarbon receptor (AhR) constitute the interface of microbiome-gut-brain axis. However, the pathway through which Trp metabolites affect central nervous system (CNS) function have not been fully elucidated. AhR participates in a broad variety of physiological and pathological processes that also highly relevant to intestinal homeostasis and CNS diseases. Via the AhR-dependent mechanism, Trp metabolites connect bidirectional signaling between the gut microbiome and the brain, mediated via immune, metabolic, and neural (vagal) signaling mechanisms, with downstream effects on behavior and CNS function. These findings shed light on the complex Trp regulation of microbiome-gut-brain axis and add another facet to our understanding that dietary Trp is expected to be a promising noninvasive approach for alleviating systemic diseases.
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Affiliation(s)
- Ning Ma
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Ting He
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Lee J. Johnston
- West Central Research & Outreach Center, University of Minnesota, Morris, MN, USA
| | - Xi Ma
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China,CONTACT Xi Ma State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, No. 2, Yuanmingyuan West Road, Haidian District, Beijing100193, China
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13
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Translational Potential of Metabolomics on Animal Models of Inflammatory Bowel Disease-A Systematic Critical Review. Int J Mol Sci 2020; 21:ijms21113856. [PMID: 32485793 PMCID: PMC7312423 DOI: 10.3390/ijms21113856] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 05/24/2020] [Accepted: 05/26/2020] [Indexed: 12/16/2022] Open
Abstract
In the development of inflammatory bowel disease (IBD), the gut microbiota has been established as a key factor. Recently, metabolomics has become important for understanding the functional relevance of gut microbial changes in disease. Animal models for IBD enable the study of factors involved in disease development. However, results from animal studies may not represent the human situation. The aim of this study was to investigate whether results from metabolomics studies on animal models for IBD were similar to those from studies on IBD patients. Medline and Embase were searched for relevant studies up to May 2017. The Covidence systematic review software was used for study screening, and quality assessment was conducted for all included studies. Data showed a convergence of ~17% for metabolites differentiated between IBD and controls in human and animal studies with amino acids being the most differentiated metabolite subclass. The acute dextran sodium sulfate model appeared as a good model for analysis of systemic metabolites in IBD, but analytical platform, age, and biological sample type did not show clear correlations with any significant metabolites. In conclusion, this systematic review highlights the variation in metabolomics results, and emphasizes the importance of expanding the applied detection methods to ensure greater coverage and convergence between the various different patient phenotypes and animal models of inflammatory bowel disease.
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14
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Ferguson LR. Inflammatory bowel disease: why this provides a useful example of the evolving science of nutrigenomics. J R Soc N Z 2020. [DOI: 10.1080/03036758.2020.1728345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Affiliation(s)
- Lynnette R. Ferguson
- Auckland Cancer Society Research Centre and Discipline of Nutrition and Dietetics, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
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15
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Peron G, Hidalgo-Liberona N, González-Domínguez R, Garcia-Aloy M, Guglielmetti S, Bernardi S, Kirkup B, Kroon PA, Cherubini A, Riso P, Andrés-Lacueva C. Exploring the Molecular Pathways Behind the Effects of Nutrients and Dietary Polyphenols on Gut Microbiota and Intestinal Permeability: A Perspective on the Potential of Metabolomics and Future Clinical Applications. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:1780-1789. [PMID: 31083905 DOI: 10.1021/acs.jafc.9b01687] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
The gut microbiota is involved in the regulation of the intestinal permeability (IP), whose disruption is a frequent condition in older people and is associated with the development of several diseases. The diet can affect the gut microbiota and IP, although the molecular mechanisms involved are unclear. Metabolomics is one of the suitable approaches to study the effects of diet on gut microbiota and IP, although, up to now, the research has focused only on a few dietary components. The aim here was to review the most recent literature concerning the application of metabolomics to the study of the diet-induced alterations of gut microbiota and the effects on IP, with a particular focus on the molecular pathways involved. An additional aim was to give a perspective on the future research involving dietary polyphenols, because despite their potential use in the management of increased IP, few studies have been reported to date.
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Affiliation(s)
- Gregorio Peron
- Biomarkers and Nutrimetabolomics Laboratory, Department of Nutrition, Food Sciences and Gastronomy, Food Technology Reference Net (XaRTA), Nutrition and Food Safety Research Institute (INSA), Faculty of Pharmacy and Food Sciences , University of Barcelona , 08028 Barcelona , Spain
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes) , Instituto de Salud Carlos III , 08028 Barcelona , Spain
| | - Nicole Hidalgo-Liberona
- Biomarkers and Nutrimetabolomics Laboratory, Department of Nutrition, Food Sciences and Gastronomy, Food Technology Reference Net (XaRTA), Nutrition and Food Safety Research Institute (INSA), Faculty of Pharmacy and Food Sciences , University of Barcelona , 08028 Barcelona , Spain
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes) , Instituto de Salud Carlos III , 08028 Barcelona , Spain
| | - Raúl González-Domínguez
- Biomarkers and Nutrimetabolomics Laboratory, Department of Nutrition, Food Sciences and Gastronomy, Food Technology Reference Net (XaRTA), Nutrition and Food Safety Research Institute (INSA), Faculty of Pharmacy and Food Sciences , University of Barcelona , 08028 Barcelona , Spain
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes) , Instituto de Salud Carlos III , 08028 Barcelona , Spain
| | - Mar Garcia-Aloy
- Biomarkers and Nutrimetabolomics Laboratory, Department of Nutrition, Food Sciences and Gastronomy, Food Technology Reference Net (XaRTA), Nutrition and Food Safety Research Institute (INSA), Faculty of Pharmacy and Food Sciences , University of Barcelona , 08028 Barcelona , Spain
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes) , Instituto de Salud Carlos III , 08028 Barcelona , Spain
| | - Simone Guglielmetti
- Department of Food, Environmental and Nutritional Sciences (DeFENS) , Università degli Studi di Milano , 20122 Milan , Italy
| | - Stefano Bernardi
- Department of Food, Environmental and Nutritional Sciences (DeFENS) , Università degli Studi di Milano , 20122 Milan , Italy
| | - Benjamin Kirkup
- Quadram Institute Bioscience , Norwich Research Park, Norwich NR4 7UQ , United Kingdom
| | - Paul Antony Kroon
- Quadram Institute Bioscience , Norwich Research Park, Norwich NR4 7UQ , United Kingdom
| | - Antonio Cherubini
- Geriatria, Accettazione Geriatrica e Centro di Ricerca per l'Invecchiamento , Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)-l'Istituto Nazionale Ricovero e Cura Anziani (INRCA) , 60127 Ancona , Italy
| | - Patrizia Riso
- Department of Food, Environmental and Nutritional Sciences (DeFENS) , Università degli Studi di Milano , 20122 Milan , Italy
| | - Cristina Andrés-Lacueva
- Biomarkers and Nutrimetabolomics Laboratory, Department of Nutrition, Food Sciences and Gastronomy, Food Technology Reference Net (XaRTA), Nutrition and Food Safety Research Institute (INSA), Faculty of Pharmacy and Food Sciences , University of Barcelona , 08028 Barcelona , Spain
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes) , Instituto de Salud Carlos III , 08028 Barcelona , Spain
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16
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Neuroprotective and Neuromodulatory Effects Induced by Cannabidiol and Cannabigerol in Rat Hypo-E22 cells and Isolated Hypothalamus. Antioxidants (Basel) 2020; 9:antiox9010071. [PMID: 31941059 PMCID: PMC7022242 DOI: 10.3390/antiox9010071] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 12/23/2019] [Accepted: 01/10/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Cannabidiol (CBD) and cannabigerol (CBG) are non-psychotropic terpenophenols isolated from Cannabis sativa, which, besides their anti-inflammatory/antioxidant effects, are able to inhibit, the first, and to stimulate, the second, the appetite although there are no studies elucidating their role in the hypothalamic appetite-regulating network. Consequently, the aim of the present research is to investigate the role of CBD and CBG in regulating hypothalamic neuromodulators. Comparative evaluations between oxidative stress and food intake-modulating mediators were also performed. METHODS Rat hypothalamic Hypo-E22 cells and isolated tissues were exposed to either CBD or CBG, and the gene expressions of neuropeptide (NP)Y, pro-opiomelanocortin (POMC) and fatty acid amide hydrolase were assessed. In parallel, the influence of CBD on the synthesis and release of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) was evaluated. The 3-hydroxykinurenine/kinurenic acid (3-HK/KA) ratio was also determined. RESULTS Both CBD and CBG inhibited NPY and POMC gene expression and decreased the 3-HK/KA ratio in the hypothalamus. The same compounds also reduced hypothalamic NE synthesis and DA release, whereas the sole CBD inhibited 5-HT synthesis. CONCLUSION The CBD modulates hypothalamic neuromodulators consistently with its anorexigenic role, whereas the CBG effect on the same mediators suggests alternative mechanisms, possibly involving peripheral pathways.
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Dudzińska E, Szymona K, Kloc R, Gil-Kulik P, Kocki T, Świstowska M, Bogucki J, Kocki J, Urbanska EM. Increased expression of kynurenine aminotransferases mRNA in lymphocytes of patients with inflammatory bowel disease. Therap Adv Gastroenterol 2019; 12:1756284819881304. [PMID: 31666808 PMCID: PMC6801885 DOI: 10.1177/1756284819881304] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 09/18/2019] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Complex interaction of genetic defects with environmental factors seems to play a substantial role in the pathogenesis of inflammatory bowel disease (IBD). Accumulating data implicate a potential role of disturbed tryptophan metabolism in IBD. Kynurenic acid (KYNA), a derivative of tryptophan (TRP) along the kynurenine (KYN) pathway, displays cytoprotective and immunomodulating properties, whereas 3-OH-KYN is a cytotoxic compound, generating free radicals. METHODS The expression of lymphocytic mRNA encoding enzymes synthesizing KYNA (KAT I-III) and serum levels of TRP and its metabolites were evaluated in 55 patients with IBD, during remission or relapse [27 patients with ulcerative colitis (UC) and 28 patients with Crohn's disease (CD)] and in 50 control individuals. RESULTS The increased expression of KAT1 and KAT3 mRNA characterized the entire cohorts of patients with UC and CD, as well as relapse-remission subsets. Expression of KAT2 mRNA was enhanced in patients with UC and in patients with CD in remission. In the entire cohorts of UC or CD, TRP levels were lower, whereas KYN, KYNA and 3-OH-KYN were not altered. When analysed in subsets of patients with UC and CD (active phase-remission), KYNA level was significantly lower during remission than relapse, yet not versus control. Functionally, in the whole groups of patients with UC or CD, the TRP/KYN ratio has been lower than control, whereas KYN/KYNA and KYNA/3-OH-KYN ratios were not altered. The ratio KYN/3-OH-KYN increased approximately two-fold among all patients with CD; furthermore, patients with CD with relapse, manifested a significantly higher KYNA/3-OH-KYN ratio than patients in remission. CONCLUSION The presented data indicate that IBD is associated with an enhanced expression of genes encoding KYNA biosynthetic enzymes in lymphocytes; however, additional mechanisms appear to influence KYNA levels. Higher metabolic conversion of serum TRP in IBD seems to be followed by the functional shift of KYN pathway towards the arm producing KYNA during exacerbation. We propose that KYNA, possibly via interaction with aryl hydrocarbon receptor or G-protein-coupled orphan receptor 35, may serve as a counter-regulatory mechanism, decreasing cytotoxicity and inflammation in IBD. Further longitudinal studies evaluating the individual dynamics of TRP and KYN pathway in patients with IBD, as well as the nature of precise mechanisms regulating KYNA synthesis, should be helpful in better understanding the processes underlying the observed changes.
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Affiliation(s)
- Ewa Dudzińska
- Medical University of Lublin, Chodźki 1 Street,
Lublin, 20-093, Lubelskie, Poland
| | - Kinga Szymona
- Medical University of Lublin, Lublin, Lubelskie,
Poland
| | - Renata Kloc
- Department of Experimental and Clinical
Pharmacology, Medical University of Lublin, Lublin, Lubelskie, Poland
| | - Paulina Gil-Kulik
- Department of Clinical Genetics, Medical
University of Lublin, Lublin, Lubelskie, Poland
| | - Tomasz Kocki
- Department of Experimental and Clinical
Pharmacology, Medical University of Lublin, Lublin, Lubelskie, Poland
| | - Małgorzata Świstowska
- Department of Clinical Genetics, Medical
University of Lublin, Lublin, Lubelskie, Poland
| | - Jacek Bogucki
- Department of Clinical Genetics, Medical
University of Lublin, Lublin, Lubelskie, Poland
| | - Janusz Kocki
- Department of Clinical Genetics, Medical
University of Lublin, Lublin, Lubelskie, Poland
| | - Ewa M. Urbanska
- Department of Experimental and Clinical
Pharmacology, Medical University of Lublin, Lublin, Lubelskie, Poland
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18
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Lécuyer L, Dalle C, Lyan B, Demidem A, Rossary A, Vasson MP, Petera M, Lagree M, Ferreira T, Centeno D, Galan P, Hercberg S, Deschasaux M, Partula V, Srour B, Latino-Martel P, Kesse-Guyot E, Druesne-Pecollo N, Durand S, Pujos-Guillot E, Touvier M. Plasma Metabolomic Signatures Associated with Long-term Breast Cancer Risk in the SU.VI.MAX Prospective Cohort. Cancer Epidemiol Biomarkers Prev 2019; 28:1300-1307. [PMID: 31164347 DOI: 10.1158/1055-9965.epi-19-0154] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 04/12/2019] [Accepted: 05/28/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Breast cancer is a major cause of death in occidental women. The role of metabolism in breast cancer etiology remains unclear. Metabolomics may help to elucidate novel biological pathways and identify new biomarkers to predict breast cancer long before symptoms appear. The aim of this study was to investigate whether untargeted metabolomic signatures from blood draws of healthy women could contribute to better understand and predict the long-term risk of developing breast cancer. METHODS A nested case-control study was conducted within the SU.VI.MAX prospective cohort (13 years of follow-up) to analyze baseline plasma samples of 211 incident breast cancer cases and 211 matched controls by LC/MS. Multivariable conditional logistic regression models were computed. RESULTS A total of 3,565 ions were detected and 1,221 were retained for statistical analysis. A total of 73 ions were associated with breast cancer risk (P < 0.01; FDR ≤ 0.2). Notably, we observed that a lower plasma level of O-succinyl-homoserine (OR = 0.70, 95%CI = [0.55-0.89]) and higher plasma levels of valine/norvaline [1.45 (1.15-1.83)], glutamine/isoglutamine [1.33 (1.07-1.66)], 5-aminovaleric acid [1.46 (1.14-1.87)], phenylalanine [1.43 (1.14-1.78)], tryptophan [1.40 (1.10-1.79)], γ-glutamyl-threonine [1.39 (1.09-1.77)], ATBC [1.41 (1.10-1.79)], and pregnene-triol sulfate [1.38 (1.08-1.77)] were associated with an increased risk of developing breast cancer during follow-up.Conclusion: Several prediagnostic plasmatic metabolites were associated with long-term breast cancer risk and suggested a role of microbiota metabolism and environmental exposure. IMPACT After confirmation in other independent cohort studies, these results could help to identify healthy women at higher risk of developing breast cancer in the subsequent decade and to propose a better understanding of the complex mechanisms involved in its etiology.
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Affiliation(s)
- Lucie Lécuyer
- Sorbonne Paris Cité Epidemiology and Statistics Research Center (CRESS), French National Institute of Health and Medical Research (Inserm) U1153, French National Institute for Agricultural Research (Inra) U1125, French National Conservatory of Arts and Crafts (Cnam), Paris 13 University, Nutritional Epidemiology Research Team (EREN), Bobigny, France.
| | - Céline Dalle
- Clermont Auvergne University, INRA, UNH, Plateforme d'Exploration du Métabolisme, MetaboHUB Clermont, Clermont-Ferrand, France
| | - Bernard Lyan
- Clermont Auvergne University, INRA, UNH, Plateforme d'Exploration du Métabolisme, MetaboHUB Clermont, Clermont-Ferrand, France
| | - Aicha Demidem
- Clermont Auvergne University, INRA, UMR 1019, Human Nutrition Unit (UNH), CRNH Auvergne, Cellular Micro-Environment, Immunomodulation and Nutrition (ECREIN), Clermont-Ferrand, France
| | - Adrien Rossary
- Clermont Auvergne University, INRA, UMR 1019, Human Nutrition Unit (UNH), CRNH Auvergne, Cellular Micro-Environment, Immunomodulation and Nutrition (ECREIN), Clermont-Ferrand, France
| | - Marie-Paule Vasson
- Clermont Auvergne University, INRA, UMR 1019, Human Nutrition Unit (UNH), CRNH Auvergne, Cellular Micro-Environment, Immunomodulation and Nutrition (ECREIN), Clermont-Ferrand, France.,Anticancer Center Jean-Perrin, CHU Clermont-Ferrand, France
| | - Mélanie Petera
- Clermont Auvergne University, INRA, UNH, Plateforme d'Exploration du Métabolisme, MetaboHUB Clermont, Clermont-Ferrand, France
| | - Marie Lagree
- Clermont Auvergne University, Institut de Chimie de Clermont-Ferrand, Plateforme d'Exploration du Métabolisme, MetaboHUB-Clermont, BP 80026, Aubière, France
| | - Thomas Ferreira
- Clermont Auvergne University, INRA, UMR 1019, Human Nutrition Unit (UNH), CRNH Auvergne, Cellular Micro-Environment, Immunomodulation and Nutrition (ECREIN), Clermont-Ferrand, France
| | - Delphine Centeno
- Clermont Auvergne University, INRA, UNH, Plateforme d'Exploration du Métabolisme, MetaboHUB Clermont, Clermont-Ferrand, France
| | - Pilar Galan
- Sorbonne Paris Cité Epidemiology and Statistics Research Center (CRESS), French National Institute of Health and Medical Research (Inserm) U1153, French National Institute for Agricultural Research (Inra) U1125, French National Conservatory of Arts and Crafts (Cnam), Paris 13 University, Nutritional Epidemiology Research Team (EREN), Bobigny, France
| | - Serge Hercberg
- Sorbonne Paris Cité Epidemiology and Statistics Research Center (CRESS), French National Institute of Health and Medical Research (Inserm) U1153, French National Institute for Agricultural Research (Inra) U1125, French National Conservatory of Arts and Crafts (Cnam), Paris 13 University, Nutritional Epidemiology Research Team (EREN), Bobigny, France.,Public Health Department, Avicenne Hospital, Bobigny, France
| | - Mélanie Deschasaux
- Sorbonne Paris Cité Epidemiology and Statistics Research Center (CRESS), French National Institute of Health and Medical Research (Inserm) U1153, French National Institute for Agricultural Research (Inra) U1125, French National Conservatory of Arts and Crafts (Cnam), Paris 13 University, Nutritional Epidemiology Research Team (EREN), Bobigny, France
| | - Valentin Partula
- Sorbonne Paris Cité Epidemiology and Statistics Research Center (CRESS), French National Institute of Health and Medical Research (Inserm) U1153, French National Institute for Agricultural Research (Inra) U1125, French National Conservatory of Arts and Crafts (Cnam), Paris 13 University, Nutritional Epidemiology Research Team (EREN), Bobigny, France
| | - Bernard Srour
- Sorbonne Paris Cité Epidemiology and Statistics Research Center (CRESS), French National Institute of Health and Medical Research (Inserm) U1153, French National Institute for Agricultural Research (Inra) U1125, French National Conservatory of Arts and Crafts (Cnam), Paris 13 University, Nutritional Epidemiology Research Team (EREN), Bobigny, France
| | - Paule Latino-Martel
- Sorbonne Paris Cité Epidemiology and Statistics Research Center (CRESS), French National Institute of Health and Medical Research (Inserm) U1153, French National Institute for Agricultural Research (Inra) U1125, French National Conservatory of Arts and Crafts (Cnam), Paris 13 University, Nutritional Epidemiology Research Team (EREN), Bobigny, France
| | - Emmanuelle Kesse-Guyot
- Sorbonne Paris Cité Epidemiology and Statistics Research Center (CRESS), French National Institute of Health and Medical Research (Inserm) U1153, French National Institute for Agricultural Research (Inra) U1125, French National Conservatory of Arts and Crafts (Cnam), Paris 13 University, Nutritional Epidemiology Research Team (EREN), Bobigny, France
| | - Nathalie Druesne-Pecollo
- Sorbonne Paris Cité Epidemiology and Statistics Research Center (CRESS), French National Institute of Health and Medical Research (Inserm) U1153, French National Institute for Agricultural Research (Inra) U1125, French National Conservatory of Arts and Crafts (Cnam), Paris 13 University, Nutritional Epidemiology Research Team (EREN), Bobigny, France
| | - Stéphanie Durand
- Clermont Auvergne University, INRA, UNH, Plateforme d'Exploration du Métabolisme, MetaboHUB Clermont, Clermont-Ferrand, France
| | - Estelle Pujos-Guillot
- Clermont Auvergne University, INRA, UNH, Plateforme d'Exploration du Métabolisme, MetaboHUB Clermont, Clermont-Ferrand, France
| | - Mathilde Touvier
- Sorbonne Paris Cité Epidemiology and Statistics Research Center (CRESS), French National Institute of Health and Medical Research (Inserm) U1153, French National Institute for Agricultural Research (Inra) U1125, French National Conservatory of Arts and Crafts (Cnam), Paris 13 University, Nutritional Epidemiology Research Team (EREN), Bobigny, France
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19
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Ni J, Xu L, Li W, Zheng C, Wu L. Targeted metabolomics for serum amino acids and acylcarnitines in patients with lung cancer. Exp Ther Med 2019; 18:188-198. [PMID: 31258653 PMCID: PMC6566041 DOI: 10.3892/etm.2019.7533] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Accepted: 12/06/2018] [Indexed: 12/13/2022] Open
Abstract
Lung cancer is one of the most prevalent types of cancer, but accurate diagnosis remains a challenge. The aim of the present study was to create a model using amino acids and acylcarnitines for lung cancer screening. Serum samples were obtained from two groups of patients with lung cancer recruited in 2015 (including 40 patients and 100 matched controls) and 2017 (including 17 patients and 30 matched controls). Using a metabolomics method, 21 metabolites (13 types of amino acids and 8 types of acylcarnitines) were measured using liquid chromatography-tandem mass spectrometry. Data (from the 2015 and 2017 data sets) were analysed using a Mann-Whitney U test, Student's t-test, Welch's F test, receiver-operator characteristic curve or logistic regression in order to investigate the potential biomarkers. Six metabolites (glycine, valine, methionine, citrulline, arginine and C16-carnitine) were indicated to be involved in distinguishing patients with lung cancer from healthy controls. The six discriminating metabolites from the 2017 data set were further analysed using Partial least squares-discriminant analysis (PLS-DA). The PLS-DA model was verified using Spearman's correlation analysis and receiver operating characteristic curve analysis. These results demonstrated that the PLS-DA model using the six metabolites (glycine, valine, methionine, citrulline, arginine and C16-carnitine) had a strong ability to identify lung cancer. Therefore, the PLS-DA model using glycine, valine, methionine, citrulline, arginine and C16-carnitine may become a novel screening tool in patients with lung cancer.
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Affiliation(s)
- Junjun Ni
- Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.,Beijing Harmony Health Medical Diagnostics Co., Ltd., Beijing 101111, P.R. China
| | - Li Xu
- Beijing Harmony Health Medical Diagnostics Co., Ltd., Beijing 101111, P.R. China
| | - Wei Li
- Beijing Harmony Health Medical Diagnostics Co., Ltd., Beijing 101111, P.R. China
| | - Chunmei Zheng
- Beijing Harmony Health Medical Diagnostics Co., Ltd., Beijing 101111, P.R. China
| | - Lijun Wu
- Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
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20
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Tao W, Tian J, Xu T, Xu L, Xie HQ, Zhou Z, Guo Z, Fu H, Yin X, Chen Y, Xu H, Zhang S, Zhang W, Ma C, Ji F, Yang J, Zhao B. Metabolic profiling study on potential toxicity in male mice treated with Dechlorane 602 using UHPLC-ESI-IT-TOF-MS. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2019; 246:141-147. [PMID: 30537652 DOI: 10.1016/j.envpol.2018.11.086] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 11/21/2018] [Accepted: 11/26/2018] [Indexed: 06/09/2023]
Abstract
Dechlorane 602 (Dec 602), a chlorinated flame retardant, has been widely detected in different environmental matrices and biota. However, toxicity data for Dec 602 seldom have been reported. A metabolomics study based on ultra-high performance liquid chromatography coupled with ion trap time-of-flight mass spectrometry was employed to study the urine and sera metabolic profiles of mice administered with Dec 602 (0, 0.001, 0.1, and 10 mg/kg body weight per day) for 7 days. A significant difference in metabolic profiling was observed between the Dec 602 treated group and the control group by multivariate analysis, which directly reflected the metabolic perturbations caused by Dec 602. The metabolomics analyses of urine from Dec 602-exposed animals exhibited an increase in the levels of thymidine and tryptophan as well as a decrease in the levels of tyrosine, 12,13-dihydroxy-9Z-octadecenoic acid, 2-hydroxyhexadecanoic acid and cuminaldehyde. The metabolomics analyses of sera showed a decrease in the levels of kynurenic acid, daidzein, adenosine, xanthurenic acid and hypoxanthine from Dec 602-exposed animals. These findings indicated Dec 602 induced disturbance in phenylalanine, tyrosine and tryptophan biosynthesis, tryptophan metabolism, tyrosine metabolism, pyrimidine metabolism, purine metabolism, ubiquinone and other terpenoid-quinone biosynthesis; phenylalanine metabolism and aminoacyl-tRNA biosynthesis. Significant alterations of immune and neurotransmitter-related metabolites (tyrosine, tryptophan, kynurenic acid, and xanthurenic acid) suggest that the toxic effects of Dec 602 may contribute to its interactions with the immune and neuronal systems. This study demonstrated that the UHPLC-ESI-IT-TOF-MS-based metabolomic approach can obtain more specific insights into the potential toxic effects of Dec 602 at molecular level.
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Affiliation(s)
- Wuqun Tao
- Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Jijing Tian
- Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Tuan Xu
- Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Li Xu
- Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Heidi Qunhui Xie
- Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Zhiguang Zhou
- State Environmental Protection Key Laboratory of Dioxin Pollution Control, National Research Center for Environmental Analysis and Measurement, Beijing, 100029, China
| | - Zhiling Guo
- Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Hualing Fu
- Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Xuejiao Yin
- Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Yangsheng Chen
- Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Haiming Xu
- Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Songyan Zhang
- Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Wanglong Zhang
- Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Chao Ma
- Shimadzu (China) Co.,Ltd, China
| | - Feng Ji
- Shimadzu (China) Co.,Ltd, China
| | - Jun Yang
- Department of Entomology and Nematology, University of California Davis, Davis, CA, USA
| | - Bin Zhao
- Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China.
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21
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Xu X, Yang J, Ning Z, Zhang X. 1H NMR-Based Metabolic Profiling of Urine from Mice Fed Lentinula edodes-Derived Polysaccharides. POL J FOOD NUTR SCI 2018. [DOI: 10.1515/pjfns-2017-0029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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22
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Nusbaum DJ, Sun F, Ren J, Zhu Z, Ramsy N, Pervolarakis N, Kunde S, England W, Gao B, Fiehn O, Michail S, Whiteson K. Gut microbial and metabolomic profiles after fecal microbiota transplantation in pediatric ulcerative colitis patients. FEMS Microbiol Ecol 2018; 94:5053801. [PMID: 30010747 PMCID: PMC6454419 DOI: 10.1093/femsec/fiy133] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 07/10/2018] [Indexed: 12/11/2022] Open
Abstract
Ulcerative colitis is a chronic inflammatory disease of the colon that carries a significant disease burden in children. Therefore, new therapeutic approaches are being explored to help children living with this disease. Fecal microbiota transplantation (FMT) has been successful in some children with ulcerative colitis. However, the mechanism of its therapeutic effect in this patient population is not well understood. To characterize changes in gut microbial and metabolomic profiles after FMT, we performed 16S rRNA gene sequencing, shotgun metagenomic sequencing, virome analysis and untargeted metabolomics by gas chromatography-time of flight-mass spectrometry on stool samples collected before and after FMT from four children with ulcerative colitis who responded to this treatment. Alpha diversity of the gut microbiota increased after intervention, with species richness rising from 251 (S.D. 125) to 358 (S.D. 27). In responders, the mean relative abundance of bacteria in the class Clostridia shifted toward donor levels, increasing from 33% (S.D. 11%) to 54% (S.D. 16%). Patient metabolomic and viromic profiles exhibited a similar but less pronounced shift toward donor profiles after FMT. The fecal concentrations of several metabolites were altered after FMT, correlating with clinical improvement. Larger studies using a similar multi-omics approach may suggest novel strategies for the treatment of pediatric ulcerative colitis.
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Affiliation(s)
- David J Nusbaum
- Keck School of Medicine of the University of Southern California, Department of Pediatrics, Los Angeles, CA, USA 1975 Zonal Ave, Los Angeles, CA, USA 90033
| | - Fengzhu Sun
- Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA 1050 Childs Way, RRI201, Los Angeles, CA, USA 90089
| | - Jie Ren
- Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA 1050 Childs Way, RRI201, Los Angeles, CA, USA 90089
| | - Zifan Zhu
- Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA 1050 Childs Way, RRI201, Los Angeles, CA, USA 90089
| | - Natalie Ramsy
- Keck School of Medicine of the University of Southern California, Department of Pediatrics, Los Angeles, CA, USA 1975 Zonal Ave, Los Angeles, CA, USA 90033
| | - Nicholas Pervolarakis
- Center for Complex Biological Systems, University of California, Irvine, CA, USA 2620 Biological Sciences III, Irvine, CA, USA 92697
| | - Sachin Kunde
- Helen DeVos Children's Hospital, Grand Rapids, MI, USA 35 Michigan St NE, Ste 4150, Grand Rapids, MI, USA 49503
| | - Whitney England
- Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA 3315 McGaugh Hall, Irvine, CA, USA 92697
| | - Bei Gao
- West Coast Metabolomics Center, University of California, Davis, CA, USA 451 Health Sciences Drive, Davis, CA, USA 95616
| | - Oliver Fiehn
- West Coast Metabolomics Center, University of California, Davis, CA, USA 451 Health Sciences Drive, Davis, CA, USA 95616
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia P.O. Box 80203, Jeddah, Saudi Arabia 21589
| | - Sonia Michail
- Keck School of Medicine of the University of Southern California, Department of Pediatrics, Los Angeles, CA, USA 1975 Zonal Ave, Los Angeles, CA, USA 90033
| | - Katrine Whiteson
- Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA 3315 McGaugh Hall, Irvine, CA, USA 92697
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23
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Jiang P, Trimigno A, Stanstrup J, Khakimov B, Viereck N, Engelsen SB, Sangild PT, Dragsted LO. Antibiotic Treatment Preventing Necrotising Enterocolitis Alters Urinary and Plasma Metabolomes in Preterm Pigs. J Proteome Res 2017; 16:3547-3557. [PMID: 28871782 DOI: 10.1021/acs.jproteome.7b00263] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Necrotising enterocolitis (NEC) is a serious gut inflammatory condition in premature neonates, onset and development of which depend on the gut microbiome. Attenuation of the gut microbiome by antibiotics can reduce NEC incidence and severity. However, how the antibiotics-suppressed gut microbiome affects the whole-body metabolism in NEC-sensitive premature neonates is unknown. In formula-fed preterm pigs, used as a model for preterm infants, plasma and urinary metabolomes were investigated by LC-MS and 1H NMR, with and without antibiotic treatment immediately after birth. While it reduced the gut microbiome density and NEC lesions as previously reported, the antibiotic treatment employed in the current study affected the abundance of 44 metabolites in different metabolic pathways. In antibiotics-treated pigs, tryptophan metabolism favored the kynurenine pathway, relative to the serotonin pathway, as shown by specific metabolites. Metabolites associated with the gut microbiome, including 3-phenyllactic acid, 4-hydroxyphenylacetic acid, and phenylacetylglycine, all from phenylalanine, and three bile acids showed lower levels in the antibiotics-treated pigs where the gut microbiome was extensively attenuated. Findings in the current study warrant further investigation of metabolic and developmental consequences of antibiotic treatment in preterm neonates.
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Affiliation(s)
| | - Alessia Trimigno
- Department of Agricultural and Food Sciences, University of Bologna , Campus di Scienze degli Alimenti, Cesena, Italy
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Glymenaki M, Barnes A, O'Hagan S, Warhurst G, McBain AJ, Wilson ID, Kell DB, Else KJ, Cruickshank SM. Stability in metabolic phenotypes and inferred metagenome profiles before the onset of colitis-induced inflammation. Sci Rep 2017; 7:8836. [PMID: 28821731 PMCID: PMC5562868 DOI: 10.1038/s41598-017-08732-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 07/12/2017] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) is associated with altered microbiota composition and metabolism, but it is unclear whether these changes precede inflammation or are the result of it since current studies have mainly focused on changes after the onset of disease. We previously showed differences in mucus gut microbiota composition preceded colitis-induced inflammation and stool microbial differences only became apparent at colitis onset. In the present study, we aimed to investigate whether microbial dysbiosis was associated with differences in both predicted microbial gene content and endogenous metabolite profiles. We examined the functional potential of mucus and stool microbial communities in the mdr1a -/- mouse model of colitis and littermate controls using PICRUSt on 16S rRNA sequencing data. Our findings indicate that despite changes in microbial composition, microbial functional pathways were stable before and during the development of mucosal inflammation. LC-MS-based metabolic phenotyping (metabotyping) in urine samples confirmed that metabolite profiles in mdr1a -/- mice were remarkably unaffected by development of intestinal inflammation and there were no differences in previously published metabolic markers of IBD. Metabolic profiles did, however, discriminate the colitis-prone mdr1a -/- genotype from controls. Our results indicate resilience of the metabolic network irrespective of inflammation. Importantly as metabolites differentiated genotype, genotype-differentiating metabolites could potentially predict IBD risk.
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Affiliation(s)
- M Glymenaki
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - A Barnes
- Shimadzu Corporation, Manchester, UK
| | - S O'Hagan
- School of Chemistry, University of Manchester, Manchester, UK; Manchester Institute of Biotechnology, University of Manchester, Manchester, UK
| | - G Warhurst
- Infection, Injury and Inflammation Research Group, Division of Medicine and Neurosciences, University of Manchester and Salford Royal Hospitals NHS Trust, Salford, UK
| | - A J McBain
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - I D Wilson
- Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College, London, UK
| | - D B Kell
- School of Chemistry, University of Manchester, Manchester, UK; Manchester Institute of Biotechnology, University of Manchester, Manchester, UK
| | - K J Else
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - S M Cruickshank
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
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25
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Shui S, Shen S, Huang R, Xiao B, Yang J. Metabonomic analysis of biochemical changes in the plasma and urine of carrageenan-induced rats after treatment with Yi-Guan-Jian decoction. J Chromatogr B Analyt Technol Biomed Life Sci 2016; 1033-1034:80-90. [DOI: 10.1016/j.jchromb.2016.08.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 08/01/2016] [Accepted: 08/02/2016] [Indexed: 11/16/2022]
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Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice. Proc Natl Acad Sci U S A 2016; 113:E3130-9. [PMID: 27185913 DOI: 10.1073/pnas.1600324113] [Citation(s) in RCA: 159] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The prevalence of inflammatory diseases is increasing in modern urban societies. Inflammation increases risk of stress-related pathology; consequently, immunoregulatory or antiinflammatory approaches may protect against negative stress-related outcomes. We show that stress disrupts the homeostatic relationship between the microbiota and the host, resulting in exaggerated inflammation. Repeated immunization with a heat-killed preparation of Mycobacterium vaccae, an immunoregulatory environmental microorganism, reduced subordinate, flight, and avoiding behavioral responses to a dominant aggressor in a murine model of chronic psychosocial stress when tested 1-2 wk following the final immunization. Furthermore, immunization with M. vaccae prevented stress-induced spontaneous colitis and, in stressed mice, induced anxiolytic or fear-reducing effects as measured on the elevated plus-maze, despite stress-induced gut microbiota changes characteristic of gut infection and colitis. Immunization with M. vaccae also prevented stress-induced aggravation of colitis in a model of inflammatory bowel disease. Depletion of regulatory T cells negated protective effects of immunization with M. vaccae on stress-induced colitis and anxiety-like or fear behaviors. These data provide a framework for developing microbiome- and immunoregulation-based strategies for prevention of stress-related pathologies.
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27
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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: 14] [Impact Index Per Article: 1.6] [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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Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut-brain pathways. CNS Spectr 2016; 21:184-98. [PMID: 26307347 DOI: 10.1017/s1092852915000449] [Citation(s) in RCA: 137] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The nature of depression has recently been reconceptualized, being conceived as the clinical expression of activated immune-inflammatory, oxidative, and nitrosative stress (IO&NS) pathways, including tryptophan catabolite (TRYCAT), autoimmune, and gut-brain pathways. IO&NS pathways are similarly integral to the pathogenesis of inflammatory bowel disease (IBD). The increased depression prevalence in IBD associates with a lower quality of life and increased morbidity in IBD, highlighting the role of depression in modulating the pathophysiology of IBD.This review covers data within such a wider conceptualization that better explains the heightened co-occurrence of IBD and depression. Common IO&NS underpinning between both disorders is evidenced by increased pro-inflammatory cytokine levels, eg, interleukin-1 (IL-1) and tumor necrosis factor-α, IL-6 trans-signalling; Th-1- and Th-17-like responses; neopterin and soluble IL-2 receptor levels; positive acute phase reactants (haptoglobin and C-reactive protein); lowered levels of negative acute phase reactants (albumin, transferrin, zinc) and anti-inflammatory cytokines (IL-10 and transforming growth factor-β); increased O&NS with damage to lipids, proteinsm and DNA; increased production of nitric oxide (NO) and inducible NO synthase; lowered plasma tryptophan but increased TRYCAT levels; autoimmune responses; and increased bacterial translocation. As such, heightened IO&NS processes in depression overlap with the biological underpinnings of IBD, potentially explaining their increased co-occurrence. This supports the perspective that there is a spectrum of IO&NS disorders that includes depression, both as an emergent comorbidity and as a contributor to IO&NS processes. Such a frame of reference has treatment implications for IBD when "comorbid" with depression.
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29
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Barnett MPG, Dommels YEM, Butts CA, Zhu S, McNabb WC, Roy NC. Inoculation with enterococci does not affect colon inflammation in the multi-drug resistance 1a-deficient mouse model of IBD. BMC Gastroenterol 2016; 16:31. [PMID: 26940566 PMCID: PMC4778357 DOI: 10.1186/s12876-016-0447-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 02/24/2016] [Indexed: 01/08/2023] Open
Abstract
Background Intestinal bacteria are thought to play a role in the pathogenesis of human inflammatory bowel disease (IBD). We investigated whether oral inoculation with specific intestinal bacteria increased colon inflammation in the multi-drug resistance 1a-deficient (Mdr1a–/–) mouse model of IBD. Methods Five-week-old Mdr1a–/– mice (FVB background) and FVB mice were randomly assigned to one of two treatment groups (Control or Inoculation, n = 12 per group). All mice were fed AIN-76A rodent diet, and mice in the Inoculation groups also received a single oral bacterial inoculation consisting of twelve cultured Enterococcus species combined with conventional intestinal flora obtained from the gastrointestinal tract of healthy mice (EF.CIF). Body weight, food intake, and disease activity index (DAI) were assessed throughout the study, and at 21 or 24 weeks of age, inflammation was assessed post-mortem by determining colon length and histological injury score (HIS), and plasma serum amyloid A (SAA). Results Mdr1a–/– mice consumed more food than FVB mice at 13 weeks of age (P < 0.05). There was also a significant effect of genotype on body weight, with Mdr1a–/– mice weighing less than FVB mice throughout the study (P < 0.05) regardless of treatment, but there was no effect of inoculation on body weight (P > 0.25). Colon HIS of Mdr1a–/– mice was significantly higher than that of FVB mice in the Control (9.3 ± 4.7 (mean ± SD) vs. 0.58 ± 0.51; P < 0.001) and Inoculation (6.7 ± 5.1 vs. 0.92 ± 0.39; P < 0.001) groups. There was no difference in colon HIS of Mdr1a–/– mice in the Control group compared with Mdr1a–/– mice in the Inoculation group (P = 0.25), nor was there any difference in within-group variation of colon HIS in these two Mdr1a–/– groups. DAI was higher in Mdr1a–/– mice than in FVB mice, but there was no effect of treatment in either strain, nor were there any differences in colon length or plasma SAA. Conclusions Inoculation of Mdr1a–/– mice with the EF.CIF inoculum described here does not increase colon inflammation or reduce the observed variability of inflammation. Electronic supplementary material The online version of this article (doi:10.1186/s12876-016-0447-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Matthew P G Barnett
- Food Nutrition & Health Team, Food & Bio-based Products Group, AgResearch, Palmerston North, 4474, New Zealand. .,Gravida: National Centre for Growth and Development, Private Bag 92019, Auckland, 1142, New Zealand.
| | - Yvonne E M Dommels
- Food and Nutrition, Food Innovation, Plant & Food Research, Palmerston North, 4474, New Zealand.
| | - Christine A Butts
- Food and Nutrition, Food Innovation, Plant & Food Research, Palmerston North, 4474, New Zealand.
| | - Shuotun Zhu
- Discipline of Nutrition, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, 1023, New Zealand.
| | - Warren C McNabb
- AgResearch, Palmerston North, 4474, New Zealand. .,Riddet Institute, Massey University, Palmerston North, 4474, New Zealand.
| | - Nicole C Roy
- Food Nutrition & Health Team, Food & Bio-based Products Group, AgResearch, Palmerston North, 4474, New Zealand. .,Gravida: National Centre for Growth and Development, Private Bag 92019, Auckland, 1142, New Zealand. .,Riddet Institute, Massey University, Palmerston North, 4474, New Zealand.
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Buttó LF, Schaubeck M, Haller D. Mechanisms of Microbe-Host Interaction in Crohn's Disease: Dysbiosis vs. Pathobiont Selection. Front Immunol 2015; 6:555. [PMID: 26635787 PMCID: PMC4652232 DOI: 10.3389/fimmu.2015.00555] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 10/16/2015] [Indexed: 12/11/2022] Open
Abstract
Crohn’s disease (CD) is a systemic chronic inflammatory condition mainly characterized by discontinuous transmural pathology of the gastrointestinal tract and frequent extraintestinal manifestations with intermittent episodes of remission and relapse. Genome-wide association studies identified a number of risk loci that, catalyzed by environmental triggers, result in the loss of tolerance toward commensal bacteria based on dysregulated innate effector functions and antimicrobial defense, leading to exacerbated adaptive immune responses responsible for chronic immune-mediated tissue damage. In this review, we discuss the inter-related role of changes in the intestinal microbiota, epithelial barrier integrity, and immune cell functions on the pathogenesis of CD, describing the current approaches available to investigate the molecular mechanisms underlying the disease. Substantial effort has been dedicated to define disease-associated changes in the intestinal microbiota (dysbiosis) and to link pathobionts to the etiology of inflammatory bowel diseases. A cogent definition of dysbiosis is lacking, as well as an agreement of whether pathobionts or complex shifts in the microbiota trigger inflammation in the host. Among the rarely available animal models, SAMP/Yit and TNFdeltaARE mice are the best known displaying a transmural CD-like phenotype. New hypothesis-driven mouse models, e.g., epithelial-specific Caspase8−/−, ATG16L1−/−, and XBP1−/− mice, validate pathway-focused function of specific CD-associated risk genes highlighting the role of Paneth cells in antimicrobial defense. To study the causal role of bacteria in initiating inflammation in the host, the use of germ-free mouse models is indispensable. Unraveling the interactions of genes, immune cells and microbes constitute a criterion for the development of safe, reliable, and effective treatment options for CD.
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Affiliation(s)
- Ludovica F Buttó
- Chair of Nutrition and Immunology, Technische Universität München , Freising-Weihenstephan , Germany
| | - Monika Schaubeck
- Chair of Nutrition and Immunology, Technische Universität München , Freising-Weihenstephan , Germany
| | - Dirk Haller
- Chair of Nutrition and Immunology, Technische Universität München , Freising-Weihenstephan , Germany
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31
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Identification of phosphatidylcholine and lysophosphatidylcholine as novel biomarkers for cervical cancers in a prospective cohort study. Tumour Biol 2015; 37:5485-92. [DOI: 10.1007/s13277-015-4164-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 09/27/2015] [Indexed: 10/22/2022] Open
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Ferguson LR. Nutritional Modulation of Gene Expression: Might This be of Benefit to Individuals with Crohn's Disease? Front Immunol 2015; 6:467. [PMID: 26441972 PMCID: PMC4566049 DOI: 10.3389/fimmu.2015.00467] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Accepted: 08/27/2015] [Indexed: 12/18/2022] Open
Abstract
The incidence of inflammatory bowel diseases (IBD), including Crohn's disease (CD), is increasing worldwide, especially in young children and adolescents. Although hospitalized patients are usually provided with enteral or parenteral support, continuing care typically requires a trial-and-error approach to suppressing symptoms and maintaining disease remission. Current nutritional advice does not differ from general population guidelines. International collaborative studies have revealed 163 distinct genetic loci affecting susceptibility to IBD, in some of which host-microbe interactions can be seen to play an important role. The nature of these loci enables a rationale for predicting nutritional requirements that may not be evident through standard therapeutic approaches. Certain recognized nutrients, such as vitamin D and long-chain omega-3 polyunsaturated fatty acids, may be required at higher than anticipated levels. Various phytochemicals, not usually considered in the same class as classic nutrients, could play an important role. Prebiotics and probiotics may also be beneficial. Genomic approaches enable proof of principle of nutrient optimization rather than waiting for disease symptoms to appear and/or progress. We suggest a paradigm shift in diagnostic tools and nutritional therapy for CD, involving a systems biology approach for implementation.
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Affiliation(s)
- Lynnette R Ferguson
- Discipline of Nutrition and Dietetics, Faculty of Medical and Health Sciences, The University of Auckland , Auckland , New Zealand ; Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland , Auckland , New Zealand
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Barnett M, Young W, Cooney J, Roy N. Metabolomics and Proteomics, and What to Do with All These 'Omes': Insights from Nutrigenomic Investigations in New Zealand. JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS 2015; 7:274-82. [PMID: 25997469 DOI: 10.1159/000381349] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 03/03/2015] [Indexed: 12/29/2022]
Abstract
BACKGROUND/AIMS Nutrigenomics New Zealand has invested considerable effort researching the role of nutrient-gene interactions in human inflammatory bowel disease (IBD). This research has utilised a number of 'omics' techniques, including proteomics and metabolomics. METHODS Mouse models of intestinal inflammation have been used to investigate the mechanisms underlying IBD and to test foods or food components for potential beneficial effects. Proteomics combining two-dimensional gel electrophoresis with liquid chromatography-mass spectrometry (LC-MS) analysis of peptides, and metabolomics using both gas chromatography-MS and LC-MS have been combined with transcriptomics and microbiome analyses to comprehensively assess samples derived from these models. RESULTS Across several independent studies, we have identified key proteins and metabolites which are involved in chronic inflammation. We have also identified food compounds such as polyphenols (green tea polyphenols or curcumin) and polyunsaturated fatty acids, or whole foods such as salmon and broccoli, that reduce inflammation by regulating the activity of these proteins and metabolites. CONCLUSIONS Omics techniques, including proteomics and metabolomics, have deepened our insight into the mechanisms underlying intestinal inflammation, and how nutrient-gene interactions may influence these. However, challenges remain in dealing with the enormous quantity of data generated by these techniques, and in utilising these data to improve the outcome for people with IBD.
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Affiliation(s)
- Matthew Barnett
- Food Nutrition and Health Team, AgResearch Ltd., Grasslands Research Centre, Palmerston North, New Zealand
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Zhang Y, Zhao F, Deng Y, Zhao Y, Ren H. Metagenomic and metabolomic analysis of the toxic effects of trichloroacetamide-induced gut microbiome and urine metabolome perturbations in mice. J Proteome Res 2015; 14:1752-61. [PMID: 25609144 DOI: 10.1021/pr5011263] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Disinfection byproducts (DBPs) in drinking water have been linked to various diseases, including colon, colorectal, rectal, and bladder cancer. Trichloroacetamide (TCAcAm) is an emerging nitrogenous DBP, and our previous study found that TCAcAm could induce some changes associated with host-gut microbiota co-metabolism. In this study, we used an integrated approach combining metagenomics, based on high-throughput sequencing, and metabolomics, based on nuclear magnetic resonance (NMR), to evaluate the toxic effects of TCAcAm exposure on the gut microbiome and urine metabolome. High-throughput sequencing revealed that the gut microbiome's composition and function were significantly altered after TCAcAm exposure for 90 days in Mus musculus mice. In addition, metabolomic analysis showed that a number of gut microbiota-related metabolites were dramatically perturbed in the urine of the mice. These results may provide novel insight into evaluating the health risk of environmental pollutants as well as revealing the potential mechanism of TCAcAm's toxic effects.
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Affiliation(s)
- Yan Zhang
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, Jiangsu 210023, China
| | - Fuzheng Zhao
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, Jiangsu 210023, China
| | - Yongfeng Deng
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, Jiangsu 210023, China
| | - Yanping Zhao
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, Jiangsu 210023, China
| | - Hongqiang Ren
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, Jiangsu 210023, China
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35
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Kohashi M, Nishiumi S, Ooi M, Yoshie T, Matsubara A, Suzuki M, Hoshi N, Kamikozuru K, Yokoyama Y, Fukunaga K, Nakamura S, Azuma T, Yoshida M. A novel gas chromatography mass spectrometry-based serum diagnostic and assessment approach to ulcerative colitis. J Crohns Colitis 2014; 8:1010-21. [PMID: 24582087 DOI: 10.1016/j.crohns.2014.01.024] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Revised: 01/29/2014] [Accepted: 01/29/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS To improve the clinical course of ulcerative colitis (UC), more accurate serum diagnostic and assessment methods are required. We used serum metabolomics to develop diagnostic and assessment methods for UC. METHODS Sera from UC patients, Crohn's disease (CD) patients, and healthy volunteers (HV) were collected at multiple institutions. The UC and HV were randomly allocated to the training or validation set, and their serum metabolites were analyzed by gas chromatography mass spectrometry (GC/MS). Using the training set, diagnostic and assessment models for UC were established by multiple logistic regression analysis. Then, the models were assessed using the validation set. Additionally, to establish a diagnostic model for discriminating UC from CD, the CD patients' data were used. RESULTS The diagnostic model for discriminating UC from HV demonstrated an AUC of 0.988, 93.33% sensitivity, and 95.00% specificity in the training set and 95.00% sensitivity and 98.33% specificity in the validation set. Another model for discriminating UC from CD exhibited an AUC of 0.965, 85.00% sensitivity, and 97.44% specificity in the training set and 83.33% sensitivity in the validation set. The model for assessing UC showed an AUC of 0.967, 84.62% sensitivity, and 88.23% specificity in the training set and 84.62% sensitivity, 91.18% specificity, and a significant correlation with the clinical activity index (rs=0.7371, P<0.0001) in the validation set. CONCLUSIONS Our models demonstrated high performance and might lead to the development of a novel treatment selection method based on UC condition.
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Affiliation(s)
- Michitaka Kohashi
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chu-o-ku, Kobe, Hyogo 650-0017, Japan
| | - Shin Nishiumi
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chu-o-ku, Kobe, Hyogo 650-0017, Japan
| | - Makoto Ooi
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chu-o-ku, Kobe, Hyogo 650-0017, Japan
| | - Tomoo Yoshie
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chu-o-ku, Kobe, Hyogo 650-0017, Japan
| | - Atsuki Matsubara
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chu-o-ku, Kobe, Hyogo 650-0017, Japan
| | - Makoto Suzuki
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chu-o-ku, Kobe, Hyogo 650-0017, Japan
| | - Namiko Hoshi
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chu-o-ku, Kobe, Hyogo 650-0017, Japan
| | - Koji Kamikozuru
- Division of Lower Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
| | - Yoko Yokoyama
- Division of Lower Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
| | - Ken Fukunaga
- Division of Lower Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
| | - Shiro Nakamura
- Division of Lower Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
| | - Takeshi Azuma
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chu-o-ku, Kobe, Hyogo 650-0017, Japan
| | - Masaru Yoshida
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chu-o-ku, Kobe, Hyogo 650-0017, Japan; The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chu-o-ku, Kobe, Hyogo 650-0017, Japan; Division of Metabolomics Research, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chu-o-ku, Kobe, Hyogo 650-0017, Japan.
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Venkatesh M, Mukherjee S, Wang H, Li H, Sun K, Benechet AP, Qiu Z, Maher L, Redinbo MR, Phillips RS, Fleet JC, Kortagere S, Mukherjee P, Fasano A, Le Ven J, Nicholson JK, Dumas ME, Khanna KM, Mani S. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity 2014; 41:296-310. [PMID: 25065623 DOI: 10.1016/j.immuni.2014.06.014] [Citation(s) in RCA: 716] [Impact Index Per Article: 65.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Accepted: 05/30/2014] [Indexed: 02/07/2023]
Abstract
Intestinal microbial metabolites are conjectured to affect mucosal integrity through an incompletely characterized mechanism. Here we showed that microbial-specific indoles regulated intestinal barrier function through the xenobiotic sensor, pregnane X receptor (PXR). Indole 3-propionic acid (IPA), in the context of indole, is a ligand for PXR in vivo, and IPA downregulated enterocyte TNF-α while it upregulated junctional protein-coding mRNAs. PXR-deficient (Nr1i2(-/-)) mice showed a distinctly "leaky" gut physiology coupled with upregulation of the Toll-like receptor (TLR) signaling pathway. These defects in the epithelial barrier were corrected in Nr1i2(-/-)Tlr4(-/-) mice. Our results demonstrate that a direct chemical communication between the intestinal symbionts and PXR regulates mucosal integrity through a pathway that involves luminal sensing and signaling by TLR4.
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Affiliation(s)
- Madhukumar Venkatesh
- Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Subhajit Mukherjee
- Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Hongwei Wang
- Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Hao Li
- Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Katherine Sun
- Department of Pathology, Montefiore Medical Center, Bronx, NY 10467, USA
| | - Alexandre P Benechet
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA
| | - Zhijuan Qiu
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA
| | - Leigh Maher
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA
| | - Matthew R Redinbo
- Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Robert S Phillips
- Department of Chemistry, University of Georgia, Athens, GA 30602, USA
| | - James C Fleet
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA
| | - Sandhya Kortagere
- Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA
| | - Paromita Mukherjee
- Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Alessio Fasano
- Department of Pediatrics, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA 02114, USA
| | - Jessica Le Ven
- Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Exhibition Road, South Kensington, London SW7 2AZ, UK
| | - Jeremy K Nicholson
- Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Exhibition Road, South Kensington, London SW7 2AZ, UK
| | - Marc E Dumas
- Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Exhibition Road, South Kensington, London SW7 2AZ, UK
| | - Kamal M Khanna
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
| | - Sridhar Mani
- Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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Zhang H, Fu P, Ke B, Wang S, Li M, Han L, Peng C, Zhang W, Liu R. Metabolomic analysis of biochemical changes in the plasma and urine of collagen-induced arthritis in rats after treatment with Huang-Lian-Jie-Du-Tang. JOURNAL OF ETHNOPHARMACOLOGY 2014; 154:55-64. [PMID: 24709313 DOI: 10.1016/j.jep.2014.03.007] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2013] [Revised: 02/10/2014] [Accepted: 03/01/2014] [Indexed: 06/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Huang-Lian-Jie-Du-Tang (HLJDT oren-gedoku-to in Japanese), a classical traditional Chinese medicine (TCM) formula, is well known for the treatment of inflammatory-related diseases such as gastritis, dermatitis, and ulcerative colitis. Our previous studies have indicated that HLJDT has therapeutic potential in rheumatoid arthritis treatment. To investigate the therapeutic mechanism of a traditional Chinese medicine formula Huang-Lian-Jie-Du-Tang (HLJDT oren-gedoku-to in Japanese) and its constituents combination for collagen-induced arthritis in rats using a metabolomics approach. MATERIALS AND METHODS Rats were divided into 9 groups, and drugs were administered from on the day after the onset of arthritis (day 12) until day 31 of the experiment once daily continuously. Urine and plasma were analyzed by reversed-phase liquid chromatography/quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS). Partial least-squares discriminate analysis (PLS-DA) models were built to evaluate the therapeutic effects of HLJDT and its constituents combination. 15 identified CIA biomarkers were investigated to explain its therapeutic mechanism. RESULTS Administration of HLJDT and its constituents combination in CIA rats not only significantly reduced arthritic scores and serum levels of IL-1β but also improved histopathologic changes in joint architecture. Urinary and plasma metabolic profiling revealed that perturbation of energy metabolism, lipid metabolism, oxidative injury and some amino acids metabolism occurred in collagen-induced arthritis (CIA). Our results also indicated that the disturbed urinary levels of succinic acid, citric acid, creatine, uridine, pantothenic acid, carnitine, phenylacetylglycine, allantoin and plasma levels of phenylpyruvic acid in model rats were gradually restored to normal after administration of HLJDT. The treatment of constituents combination of HLJDT group was able to restore to normal the disturbed urinary levels of citric acid, creatine, pantothenic acid, carnitine, pantothenic acid, phenylacetylglycine and plasma levels of uric acid, L-histidine, and l-phenylalanine in model rats. CONCLUSIONS Our study indicates that HLJDT and its constituents combination treatment can ameliorate CIA through partially regulating the perturbed energy metabolism. Our work demonstrated that metabonomics-based approach is a promising new tool to evaluate the therapeutic effects and mechanism of complex TCM prescriptions.
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MESH Headings
- Animals
- Anti-Inflammatory Agents/pharmacology
- Anti-Inflammatory Agents/therapeutic use
- Arthritis, Experimental/blood
- Arthritis, Experimental/drug therapy
- Arthritis, Experimental/pathology
- Arthritis, Experimental/urine
- Arthritis, Rheumatoid/blood
- Arthritis, Rheumatoid/drug therapy
- Arthritis, Rheumatoid/pathology
- Arthritis, Rheumatoid/urine
- Biomarkers/blood
- Biomarkers/urine
- Drugs, Chinese Herbal/pharmacology
- Drugs, Chinese Herbal/therapeutic use
- Energy Metabolism/drug effects
- Interleukin-1beta/blood
- Knee Joint/drug effects
- Knee Joint/pathology
- Male
- Metabolomics
- Rats, Wistar
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Affiliation(s)
- Huawei Zhang
- School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, PR China
| | - Peng Fu
- Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai 200433, PR China
| | - Beilei Ke
- School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, PR China
| | - Shuping Wang
- School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, PR China
| | - Min Li
- School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, PR China
| | - Lin Han
- School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, PR China
| | - Chengcheng Peng
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200030, PR China
| | - Weidong Zhang
- School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, PR China; School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200030, PR China; King Saud University, Riyadh 11451, Saudi Arabia.
| | - Runhui Liu
- School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, PR China.
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Wen T, Gao L, Wen Z, Wu C, Tan CS, Toh WZ, Ong CN. Exploratory investigation of plasma metabolomics in human lung adenocarcinoma. MOLECULAR BIOSYSTEMS 2014; 9:2370-8. [PMID: 23857124 DOI: 10.1039/c3mb70138g] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Globally lung cancer is common among males and recently also noted with increasing incidences in females, especially adenocarcinoma. Further, most lung cancers are not easily detected until the late stage. Metabolic profiling of plasma low molecular weight metabolites may help unveil the complex pathophysiological changes during early lung adenocarcinoma development. Here we used a combination of gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) methods to investigate the metabolic signatures in the plasma of 31 stage I human lung adenocarcinoma patients and 28 healthy controls. The metabolic profiles were assayed using orthogonal projections to latent structures discriminant analysis (OPLS-DA), and were further analyzed to identify the associated marker metabolites. The OPLS-DA models derived from both GC-MS and LC-MS showed significant discriminations in metabolic profiles between cases and healthy controls. It was found that around 37 metabolites contributed to the differences. The alterations of these metabolites implied disturbances in amino acids, lipids, fatty acids and glutaminolysis metabolism in human lung adenocarcinoma, even after removal of influencing factors such as age, gender and smoking habits. Of particular interest, the sex hormone metabolic pathway involving the sulfate conjugate of testosterone, androsterone and pregnenolone was found to be disturbed considerably. All these metabolic perturbations occur at an early stage of lung adenocarcinoma and thus could act as biomarkers for its early diagnosis. These exploratory findings suggest that integration of two sensitive and complementary metabolomic approaches enables a comprehensive metabolite profiling for human lung adenocarcinoma, although a more extensive study is needed to confirm the findings.
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Affiliation(s)
- Tao Wen
- Saw Swee Hock School of Public Health, National University of Singapore, 16 Medical Drive, Singapore 117597, Singapore
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39
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Rueedi R, Ledda M, Nicholls AW, Salek RM, Marques-Vidal P, Morya E, Sameshima K, Montoliu I, Da Silva L, Collino S, Martin FP, Rezzi S, Steinbeck C, Waterworth DM, Waeber G, Vollenweider P, Beckmann JS, Le Coutre J, Mooser V, Bergmann S, Genick UK, Kutalik Z. Genome-wide association study of metabolic traits reveals novel gene-metabolite-disease links. PLoS Genet 2014; 10:e1004132. [PMID: 24586186 PMCID: PMC3930510 DOI: 10.1371/journal.pgen.1004132] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Accepted: 12/10/2013] [Indexed: 12/15/2022] Open
Abstract
Metabolic traits are molecular phenotypes that can drive clinical phenotypes and may predict disease progression. Here, we report results from a metabolome- and genome-wide association study on (1)H-NMR urine metabolic profiles. The study was conducted within an untargeted approach, employing a novel method for compound identification. From our discovery cohort of 835 Caucasian individuals who participated in the CoLaus study, we identified 139 suggestively significant (P<5×10(-8)) and independent associations between single nucleotide polymorphisms (SNP) and metabolome features. Fifty-six of these associations replicated in the TasteSensomics cohort, comprising 601 individuals from São Paulo of vastly diverse ethnic background. They correspond to eleven gene-metabolite associations, six of which had been previously identified in the urine metabolome and three in the serum metabolome. Our key novel findings are the associations of two SNPs with NMR spectral signatures pointing to fucose (rs492602, P = 6.9×10(-44)) and lysine (rs8101881, P = 1.2×10(-33)), respectively. Fine-mapping of the first locus pinpointed the FUT2 gene, which encodes a fucosyltransferase enzyme and has previously been associated with Crohn's disease. This implicates fucose as a potential prognostic disease marker, for which there is already published evidence from a mouse model. The second SNP lies within the SLC7A9 gene, rare mutations of which have been linked to severe kidney damage. The replication of previous associations and our new discoveries demonstrate the potential of untargeted metabolomics GWAS to robustly identify molecular disease markers.
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Affiliation(s)
- Rico Rueedi
- Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Mirko Ledda
- Department of Food-Consumer Interaction, Nestlé Research Center, Lausanne, Switzerland
| | - Andrew W. Nicholls
- Investigative Preclinical Toxicology, GlaxoSmithKline R&D, Ware, Herts, United Kingdom
| | - Reza M. Salek
- European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom
- Department of Biochemistry & Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom
| | - Pedro Marques-Vidal
- Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Lausanne, Switzerland
| | - Edgard Morya
- Sensonomic Laboratory of Alberto Santos Dumont Research Support Association and IEP Sirio, Libanes Hospital, São Paulo, Brazil
- Edmond and Lily Safra International Institute of Neuroscience of Natal, Natal, Brazil
| | - Koichi Sameshima
- Department of Radiology and Oncology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Ivan Montoliu
- Department of Bioanalytical Sciences, Nestlé Research Center, Lausanne, Switzerland
| | - Laeticia Da Silva
- Department of Bioanalytical Sciences, Nestlé Research Center, Lausanne, Switzerland
| | - Sebastiano Collino
- Department of Bioanalytical Sciences, Nestlé Research Center, Lausanne, Switzerland
| | | | - Serge Rezzi
- Department of Bioanalytical Sciences, Nestlé Research Center, Lausanne, Switzerland
| | - Christoph Steinbeck
- European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom
| | - Dawn M. Waterworth
- Medical Genetics, GlaxoSmithKline, Philadelphia, Pennsylvania, United States of America
| | - Gérard Waeber
- Department of Medicine, Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
| | - Peter Vollenweider
- Department of Medicine, Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
| | - Jacques S. Beckmann
- Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
| | - Johannes Le Coutre
- Department of Food-Consumer Interaction, Nestlé Research Center, Lausanne, Switzerland
- Organization for Interdisciplinary Research Projects, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Vincent Mooser
- Department of Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
| | - Sven Bergmann
- Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Ulrich K. Genick
- Department of Food-Consumer Interaction, Nestlé Research Center, Lausanne, Switzerland
| | - Zoltán Kutalik
- Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Lausanne, Switzerland
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Mani S, Boelsterli UA, Redinbo MR. Understanding and modulating mammalian-microbial communication for improved human health. Annu Rev Pharmacol Toxicol 2013; 3. [PMID: 27942535 PMCID: PMC5145265 DOI: 10.11131/2016/101199] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The molecular basis for the regulation of the intestinal barrier is a very fertile research area. A growing body of knowledge supports the targeting of various components of intestinal barrier function as means to treat a variety of diseases, including the inflammatory bowel diseases. Herein, we will summarize the current state of knowledge of key xenobiotic receptor regulators of barrier function, highlighting recent advances, such that the field and its future are succinctly reviewed. We posit that these receptors confer an additional dimension of host-microbe interaction in the gut, by sensing and responding to metabolites released from the symbiotic microbiota, in innate immunity and also in host drug metabolism. The scientific evidence for involvement of the receptors and its molecular basis for the control of barrier function and innate immunity regulation would serve as a rationale towards development of non-toxic probes and ligands as drugs.
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Affiliation(s)
- Sridhar Mani
- Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York 10461
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41
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Collino S, Martin FPJ, Rezzi S. Clinical metabolomics paves the way towards future healthcare strategies. Br J Clin Pharmacol 2013; 75:619-29. [PMID: 22348240 DOI: 10.1111/j.1365-2125.2012.04216.x] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Metabolomics is recognized as a powerful top-down system biological approach to understand genetic-environment-health paradigms paving new avenues to identify clinically relevant biomarkers. It is nowadays commonly used in clinical applications shedding new light on physiological regulatory processes of complex mammalian systems with regard to disease aetiology, diagnostic stratification and, potentially, mechanism of action of therapeutic solutions. A key feature of metabolomics lies in its ability to underpin the complex metabolic interactions of the host with its commensal microbial partners providing a new way to define individual and population phenotypes. This review aims at describing recent applications of metabolomics in clinical fields with insight into diseases, diagnostics/monitoring and improvement of homeostatic metabolic regulation.
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Affiliation(s)
- Sebastiano Collino
- Nestec Ltd, Nestlé Research Center, BioAnalytical Science, Metabolomics and Biomarkers, PO Box 44, CH-1000 Lausanne 26, Switzerland
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Abstract
PURPOSE OF REVIEW Several gastrointestinal diseases including the inflammatory bowel diseases (IBDs) and malignancy are associated with elevated expression of indoleamine 2,3 dioxygenase-1 (IDO1). IDO1 initiates tryptophan catabolism along a pathway that generates several bioactive kynurenine-based metabolites. Promotion of T-cell-mediated tolerance and antimicrobial effects are among the variety of functions attributed to IDO1 activity. Recent advances addressing the diverse implications of gut-associated IDO1 expression are herein reviewed. RECENT FINDINGS In active IBD, IDO1 is highly expressed both in the cells of the lamina propria and epithelium. Experimental models demonstrate that IDO1 promotes gut immune homeostasis by limiting inflammatory responses and protecting the epithelium. In human colon cancer, high expression of IDO1 by the neoplastic epithelium correlates with poor prognosis. The serum kynurenine : tryptophan ratio is elevated in both active Crohn's disease and in colon cancer, suggesting this measurement may prove useful as a disease biomarker. IDO1 inhibitors have moved to clinical trials providing new hope as immunotherapy for advanced malignancy. SUMMARY IDO1 activity significantly shapes gastrointestinal disease pathophysiology and severity. Measures of IDO1 activity may be useful as a disease biomarker. Manipulation of IDO1 activity has great potential as a treatment for both inflammatory and malignancy associated gastrointestinal disease.
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43
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Schicho R, Shaykhutdinov R, Ngo J, Nazyrova A, Schneider C, Panaccione R, Kaplan GG, Vogel HJ, Storr M. Quantitative metabolomic profiling of serum, plasma, and urine by (1)H NMR spectroscopy discriminates between patients with inflammatory bowel disease and healthy individuals. J Proteome Res 2012; 11:3344-57. [PMID: 22574726 PMCID: PMC3558013 DOI: 10.1021/pr300139q] [Citation(s) in RCA: 192] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
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Serologic biomarkers for inflammatory bowel disease (IBD)
have
yielded variable differentiating ability. Quantitative analysis of
a large number of metabolites is a promising method to detect IBD
biomarkers. Human subjects with active Crohn’s disease (CD)
and active ulcerative colitis (UC) were identified, and serum, plasma,
and urine specimens were obtained. We characterized 44 serum, 37 plasma,
and 71 urine metabolites by use of 1H NMR spectroscopy
and “targeted analysis” to differentiate between diseased
and non-diseased individuals, as well as between the CD and UC cohorts.
We used multiblock principal component analysis and hierarchical OPLS-DA
for comparing several blocks derived from the same “objects”
(e.g., subject) to examine differences in metabolites. In serum and
plasma of IBD patients, methanol, mannose, formate, 3-methyl-2-oxovalerate,
and amino acids such as isoleucine were the metabolites most prominently
increased, whereas in urine, maximal increases were observed for mannitol,
allantoin, xylose, and carnitine. Both serum and plasma of UC and
CD patients showed significant decreases in urea and citrate, whereas
in urine, decreases were observed, among others, for betaine and hippurate.
Quantitative metabolomic profiling of serum, plasma, and urine discriminates
between healthy and IBD subjects. However, our results show that the
metabolic differences between the CD and UC cohorts are less pronounced.
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Affiliation(s)
- Rudolf Schicho
- Division of Gastroenterology and Snyder Institute of Infection, Immunity and Inflammation, Department of Medicine and §Department of Biological Sciences, Metabolomics Research Centre, University of Calgary , Alberta, Canada
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44
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Martin FPJ, Collino S, Rezzi S, Kochhar S. Metabolomic applications to decipher gut microbial metabolic influence in health and disease. Front Physiol 2012; 3:113. [PMID: 22557976 PMCID: PMC3337463 DOI: 10.3389/fphys.2012.00113] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Accepted: 04/05/2012] [Indexed: 12/22/2022] Open
Abstract
Dietary preferences and nutrients composition have been shown to influence human and gut microbial metabolism, which ultimately has specific effects on health and diseases’ risk. Increasingly, results from molecular biology and microbiology demonstrate the key role of the gut microbiota metabolic interface to the overall mammalian host’s health status. There is therefore raising interest in nutrition research to characterize the molecular foundations of the gut microbial–mammalian cross talk at both physiological and biochemical pathway levels. Tackling these challenges can be achieved through systems biology approaches, such as metabolomics, to underpin the highly complex metabolic exchanges between diverse biological compartments, including organs, systemic biofluids, and microbial symbionts. By the development of specific biomarkers for prediction of health and disease, metabolomics is increasingly used in clinical applications as regard to disease etiology, diagnostic stratification, and potentially mechanism of action of therapeutical and nutraceutical solutions. Surprisingly, an increasing number of metabolomics investigations in pre-clinical and clinical studies based on proton nuclear magnetic resonance (1H NMR) spectroscopy and mass spectrometry provided compelling evidence that system wide and organ-specific biochemical processes are under the influence of gut microbial metabolism. This review aims at describing recent applications of metabolomics in clinical fields where main objective is to discern the biochemical mechanisms under the influence of the gut microbiota, with insight into gastrointestinal health and diseases diagnostics and improvement of homeostasis metabolic regulation.
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Affiliation(s)
- François-Pierre J Martin
- Metabolomics and Biomarkers, Department of BioAnalytical Science, Nestlé Research Center, Nestec Ltd. Lausanne, Switzerland
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45
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Iskandar HN, Ciorba MA. Biomarkers in inflammatory bowel disease: current practices and recent advances. Transl Res 2012; 159:313-25. [PMID: 22424434 PMCID: PMC3308116 DOI: 10.1016/j.trsl.2012.01.001] [Citation(s) in RCA: 146] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2011] [Revised: 12/30/2011] [Accepted: 01/03/2012] [Indexed: 02/07/2023]
Abstract
Crohn's disease and ulcerative colitis represent the two main forms of the idiopathic chronic inflammatory bowel diseases (IBD). Currently available blood and stool based biomarkers provide reproducible, quantitative tools that can complement clinical assessment to aid clinicians in IBD diagnosis and management. C-reactive protein and fecal based leukocyte markers can help the clinician distinguish IBD from noninflammatory diarrhea and assess disease activity. The ability to differentiate between forms of IBD and predict risk for disease complications is specific to serologic tests including antibodies against Saccharomyces cerevisiae and perinuclear antineutrophil cytoplasmic proteins. Advances in genomic, proteomic, and metabolomic array based technologies are facilitating the development of new biomarkers for IBD. The discovery of novel biomarkers, which can correlate with mucosal healing or predict long-term disease course has the potential to significantly improve patient care. This article reviews the uses and limitations of currently available biomarkers and highlights recent advances in IBD biomarker discovery.
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Affiliation(s)
- Heba N Iskandar
- Division of Gastroenterology, Washington University in Saint Louis School of Medicine, Saint Louis, MO, USA
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46
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Abstract
Crohn's disease is a chronic relapsing condition that has no certain cure. Both genetic susceptibility and nutrition have key roles, but their level of involvement varies between patients. Interacting gene pathways influence the probability of disease development, but these are affected by stress and various environmental factors, including diet. In addition, the role of the gut microbiome must not be underestimated, as it is substantially altered in patients with Crohn's disease. Although an elemental diet might lead to disease remission, reintroducing real foods and sustainable diets in patients with Crohn's disease is currently difficult, and would benefit from the sensitivity and rapid feedback provided by the field of nutrigenomics. Nutrigenomics utilizes high-throughput genomics technologies to reveal changes in gene and protein expression that are modulated by the patient's nutrition. The most widely used technique thus far is transcriptomics, which permits measurement of changes in the expression of thousands of genes simultaneously in one sample. Given the volume of numbers generated in such studies, data-basing and bioinformatics are essential to ensure the correct application of nutrigenomics at the population level. These methods have been successfully applied to animal models of Crohn's disease, and the time is right to move them to human studies.
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Affiliation(s)
- Lynnette R Ferguson
- Discipline of Nutrition, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
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47
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Yoshida M, Hatano N, Nishiumi S, Irino Y, Izumi Y, Takenawa T, Azuma T. Diagnosis of gastroenterological diseases by metabolome analysis using gas chromatography-mass spectrometry. J Gastroenterol 2012; 47:9-20. [PMID: 22041921 DOI: 10.1007/s00535-011-0493-8] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2011] [Accepted: 10/05/2011] [Indexed: 02/04/2023]
Abstract
Recently, metabolome analysis has been increasingly applied to biomarker detection and disease diagnosis in medical studies. Metabolome analysis is a strategy for studying the characteristics and interactions of low molecular weight metabolites under a specific set of conditions and is performed using mass spectrometry and nuclear magnetic resonance spectroscopy. There is a strong possibility that changes in metabolite levels reflect the functional status of a cell because alterations in their levels occur downstream of DNA, RNA, and protein. Therefore, the metabolite profile of a cell is more likely to represent the current status of a cell than DNA, RNA, or protein. Thus, owing to the rapid development of mass spectrometry analytical techniques metabolome analysis is becoming an important experimental method in life sciences including the medical field. Here, we describe metabolome analysis using liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry (GC-MS), capillary electrophoresis-mass spectrometry, and matrix assisted laser desorption ionization-mass spectrometry. Then, the findings of studies about GC-MS-based metabolome analysis of gastroenterological diseases are summarized, and our research results are also introduced. Finally, we discuss the realization of disease diagnosis by metabolome analysis. The development of metabolome analysis using mass spectrometry will aid the discovery of novel biomarkers, hopefully leading to the early detection of various diseases.
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Affiliation(s)
- Masaru Yoshida
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chu-o-ku, Kobe, Hyogo 650-0017, Japan.
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Baur P, Martin FP, Gruber L, Bosco N, Brahmbhatt V, Collino S, Guy P, Montoliu I, Rozman J, Klingenspor M, Tavazzi I, Thorimbert A, Rezzi S, Kochhar S, Benyacoub J, Kollias G, Haller D. Metabolic phenotyping of the Crohn's disease-like IBD etiopathology in the TNF(ΔARE/WT) mouse model. J Proteome Res 2011; 10:5523-35. [PMID: 22029571 DOI: 10.1021/pr2007973] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The underlying biochemical consequences of inflammatory bowel disease (IBD) on the systemic and gastrointestinal metabolism have not yet been fully elucidated but could help to better understand the disease pathogenesis and to identify tissue-specific markers associated with the different disease stages. Here, we applied a metabonomic approach to monitor metabolic events associated with the gradual development of Crohn's disease (CD)-like ileitis in the TNF(ΔARE/WT) mouse model. Metabolic profiles of different intestinal compartments from the age of 4 up to 24 weeks were generated by combining proton nuclear magnetic resonance ((1)H NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS). From 8 weeks onward, mice developed CD similar to the immune and tissue-related phenotype of human CD with ileal involvement, including ileal histological abnormalities, reduced fat mass and body weight, as well as hallmarks of malabsorption with higher energy wasting. The metabonomic approach highlighted shifts in the intestinal lipid metabolism concomitant to the histological onset of inflammation. Moreover, the advanced disease status was characterized by a significantly altered metabolism of cholesterol, triglycerides, phospholipids, plasmalogens, and sphingomyelins in the inflamed tissue (ileum) and the adjacent intestinal parts (proximal colon). These results describe different biological processes associated with the disease onset, including modifications of the general cell membrane composition, alteration of energy homeostasis, and finally the generation of inflammatory lipid mediators. Taken together, this provides novel insights into IBD-related alterations of specific lipid-dependant processes during inflammatory states.
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Affiliation(s)
- Pia Baur
- ZIEL-Research Center for Nutrition and Food Science, CDD-Center for Diet and Disease, Technische Universität München, Gregor-Mendel-Strasse 2, 85350 Freising-Weihenstephan, Germany
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Lin HM, Edmunds SJ, Zhu S, Helsby NA, Ferguson LR, Rowan DD. Metabolomic analysis reveals differences in urinary excretion of kiwifruit-derived metabolites in a mouse model of inflammatory bowel disease. Mol Nutr Food Res 2011; 55:1900-4. [PMID: 21957058 DOI: 10.1002/mnfr.201100302] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2011] [Revised: 06/23/2011] [Accepted: 07/15/2011] [Indexed: 01/23/2023]
Abstract
The interleukin-10-deficient (IL-10(-/-)) mouse, a model of inflammatory bowel disease (IBD), develops intestinal inflammation unless raised in germ-free conditions. The metabolic effects of consuming extracts from the fruits of yellow (Actinidia chinensis) or green-fleshed (A. deliciosa) kiwifruit that displayed in vitro anti-inflammatory activity were investigated in IL-10(-/-) mice by metabolomic analysis of urine samples. Kiwifruit-derived metabolites were detected at significantly higher levels in urine of IL-10(-/-) mice relative to those of wild-type mice, indicating that the metabolism of these metabolites was affected by IL-10(-/-)-wild-type genotypic differences. Urinary metabolites previously associated with inflammation were not altered by the kiwifruit extracts. This study demonstrates the use of metabolomic analysis to study dietary effects and the influence of genotype on food metabolism, which may have implications on the development of functional foods for the treatment of IBD.
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Affiliation(s)
- Hui-Ming Lin
- School of Medical Sciences, University of Auckland, Auckland, New Zealand
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50
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Qi Y, Qu L, Wu Y, Fan G. A plasma metabonomic investigation into the intervention of volatile oil of Magnolia biondii Pamp on rat model of acute inflammation. JOURNAL OF ETHNOPHARMACOLOGY 2011; 137:487-494. [PMID: 21771651 DOI: 10.1016/j.jep.2011.05.045] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2011] [Revised: 05/24/2011] [Accepted: 05/30/2011] [Indexed: 05/31/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The dried flower buds of Magnolia biondii Pamp (Magnoliaceae) possesses significant anti-inflammatory activities. AIM OF THE STUDY Volatile oil in Magnolia biondii Pamp (VOMbP) is considered to be important pharmacologically active individuals against acute inflammation, but its exact anti-inflammatory mechanism remains elusive. In this study, we aimed to investigate the intervention of VOMbP on rats with acute inflammation and explore the possible anti-inflammatory mechanisms of VOMbP with metabonomic strategy. MATERIALS AND METHODS Acute inflammation was induced by subcutaneously injection of carrageenan in the rats. Plasma was analyzed using gas chromatography-mass spectrometry (GC-MS), based on which the principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA) models were established for metabonomic analysis. RESULTS It was revealed that the pretreatment of VOMbP in acute inflammatory rats induces a substantial and characteristic change in their metabolic profiles. Some significantly changed metabolites, including hexadecanoic acid, linoleic acid, oleic acid, stearic acid, and cholesterol, were found to be reasonable in explaining the anti-inflammatory mechanism of VOMbP. CONCLUSIONS In all, it is likely that VOMbP intervenes the metabolic process of inflammatory rats by affecting the fatty acid and cholesterol metabolism. Our work also indicated that the metabonomics method is a promising tool for performing intervention and mechanism research of traditional Chinese medicines.
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Affiliation(s)
- Yunpeng Qi
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, PR China
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