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Jiang M, Li H, Zhang Q, Xu T, Huang L, Zhang J, Yu H, Zhang J. The role of RGS12 in tissue repair and human diseases. Genes Dis 2025; 12:101480. [PMID: 40271194 PMCID: PMC12017852 DOI: 10.1016/j.gendis.2024.101480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 08/05/2024] [Accepted: 11/02/2024] [Indexed: 04/25/2025] Open
Abstract
Regulator of G protein signaling 12 (RGS12) belongs to the superfamily of RGS proteins defined by a conserved RGS domain that canonically binds and deactivates heterotrimeric G-proteins. As the largest family member, RGS12 is widely expressed in many cells and tissues. In the past few decades, it has been found that RGS12 affects the activity of various cells in the human body, participates in many physiological and pathological processes, and plays an important role in the pathogenesis of many diseases. Here, we set out to comprehensively review the role of RGS12 in human diseases and its mechanisms, highlighting the possibility of RGS12 as a therapeutic target for the treatment of human diseases.
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Affiliation(s)
- Min Jiang
- Department of Geriatric Oncology and Department of Palliative Care, Chongqing University Cancer Hospital, Chongqing 400030, China
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Hongmei Li
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Qiong Zhang
- Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Tongtong Xu
- General Department of Critical Care Medicine, Zhenjiang Traditional Chinese Medicine Hospital, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Zhenjiang, Jiangsu 212003, China
| | - Le Huang
- Army 72nd Group Military Hospital, Huzhou, Zhejiang 313000, China
| | - Jinghong Zhang
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Huiqing Yu
- Department of Geriatric Oncology and Department of Palliative Care, Chongqing University Cancer Hospital, Chongqing 400030, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Junhui Zhang
- Department of Geriatric Oncology and Department of Palliative Care, Chongqing University Cancer Hospital, Chongqing 400030, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China
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Chen X, Zhang Z, Wang K. Lactate released by lung adenocarcinoma (LUAD) cells promotes M2 macrophage polarization via the GPR132/cAMP/PKA pathway. Genes Genomics 2025; 47:521-531. [PMID: 40053234 DOI: 10.1007/s13258-025-01622-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Accepted: 01/31/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND Increasing evidence suggests that lactate is an essential compound in the tumor microenvironment, and especially for macrophage cells. However, the mechanism by which lactate affects macrophages remains unclear. OBJECTIVE This study investigated whether and how lactate affects macrophage polarization in lung adenocarcinoma (LUAD). METHODS Clinical samples of LUAD and paracancerous tissue were obtained for evaluation of lactate dehydrogenase A (LDHA) expression. LUAD cell lines and THP-1 induced macrophages were used in this study. Quantitative real-time PCR (QPCR), western blotting, and immunohistochemical (IHC) staining were performed to detect gene expression. Flow cytometry and ELISA assays were used to detect the levels of M1 macrophage and M2 macrophage biomarkers. RESULTS LDHA was highly expressed in the LUAD tissues. Culture medium supernatants derived from LUAD cells (CM) promoted macrophage M2 polarization, and lactate levels were elevated in the CM. Inhibition of LDHA in LUAD cells decreased lactate levels and suppressed M2 macrophage polarization. Moreover, overexpression of GPR132 in macrophages promoted, while GPR132 knockdown in macrophages suppressed M2 macrophage polarization and cAMP (Cyclic Adenosine 3',5'-Monophosphate)/PKA (Protein Kinase) pathway activation induced by lactate. The effect of GPR132 overexpression was reversed by a PKA inhibitor (H-89). CONCLUSION Collectively, our results confirmed that lactate released by LUAD cells promoted M2 macrophage polarization via the GPR132/cAMP/PKA pathway.
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Affiliation(s)
- Xiao Chen
- Department of Geriatrics, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Zhongzheng Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Bengbu Medical University, 287 Chang Huai Road, Bengbu, 233000, Anhui, China
| | - Kangwu Wang
- Department of Thoracic Surgery, The First Affiliated Hospital of Bengbu Medical University, 287 Chang Huai Road, Bengbu, 233000, Anhui, China.
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Behera P, Mishra M. Lipid Droplet in Lipodystrophy and Neurodegeneration. Biol Cell 2025; 117:e70009. [PMID: 40249069 DOI: 10.1111/boc.70009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 02/22/2025] [Accepted: 04/01/2025] [Indexed: 04/19/2025]
Abstract
Lipid droplets are ubiquitous yet distinct intracellular organelles that are gaining attention for their uses outside of energy storage. Their formation, role in the physiological function, and the onset of the pathology have been gaining attention recently. Their structure, synthesis, and turnover play dynamic roles in both lipodystrophy and neurodegeneration. Factors like development, aging, inflammation, and cellular stress regulate the synthesis of lipid droplets. The biogenesis of lipid droplets has a critical role in reducing cellular stress. Lipid droplets, in response to stress, sequester hazardous lipids into their neutral lipid core, preserving energy and redox balance while guarding against lipotoxicity. Thus, the maintenance of lipid droplet homeostasis in adipose tissue, CNS, and other body tissues is essential for maintaining organismal health. Insulin resistance, hypertriglyceridemia, and lipid droplet accumulation are the severe metabolic abnormalities that accompany lipodystrophy-related fat deficit. Accumulation of lipid droplets is detected in almost all neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and Hereditary spastic paraplegia. Hence, the regulation of lipid droplets can be used as an alternative approach to the treatment of several diseases. The current review summarizes the structure, composition, biogenesis, and turnover of lipid droplets, with an emphasis on the factors responsible for the accumulation and importance of lipid droplets in lipodystrophy and neurodegenerative disease.
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Affiliation(s)
- Priyatama Behera
- Neural Developmental Biology Lab, Department of Life Science, NIT Rourkela, Rourkela, Odisha, India
| | - Monalisa Mishra
- Neural Developmental Biology Lab, Department of Life Science, NIT Rourkela, Rourkela, Odisha, India
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Wang Z, Zhou L, Zhong X, Jiang Y, Zhang Z, Li W. Liquid-liquid separation in gut immunity. Front Immunol 2024; 15:1505123. [PMID: 39720729 PMCID: PMC11666445 DOI: 10.3389/fimmu.2024.1505123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 11/25/2024] [Indexed: 12/26/2024] Open
Abstract
Gut immunity is essential for maintaining intestinal health. Recent studies have identified that intracellular liquid-liquid phase separation (LLPS) may play a significant role in regulating gut immunity, however, the underlying mechanisms remain unclear. LLPS refers to droplet condensates formed through intracellular molecular interactions, which are crucial for the formation of membraneless organelles and biomolecules. LLPS can contribute to the formation of tight junctions between intestinal epithelial cells and influence the colonization of probiotics in the intestine, thereby protecting the intestinal immune system by maintaining the integrity of the intestinal barrier and the stability of the microbiota. Additionally, LLPS can affect the microclusters on the plasma membrane of T cells, resulting in increased density and reduced mobility, which in turn influences T cell functionality. The occurrence of intracellular LLPS is intricately associated with the initiation and progression of gut immunity. This review introduces the mechanism of LLPS in gut immunity and analyzes future research directions and potential applications of this phenomenon.
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Affiliation(s)
- Zhaoyang Wang
- Department of Gastrointestinal Surgery, Huadu District People’s Hospital, Guangzhou, China
- Biology, School of Public Health, Guangzhou Medical University, Guangzhou, China
| | - Lili Zhou
- Department of Cell Biology, Jinan University, Guangzhou, China
| | - Xiaolan Zhong
- Department of Gastroenterology, Huadu District People’s Hospital, Guangzhou, China
| | - Yiguo Jiang
- Biology, School of Public Health, Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Xinzao, Guangzhou, China
| | - Zhentao Zhang
- Obstetrics and Gynecology Department, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Wanglin Li
- Department of Gastrointestinal Surgery, Huadu District People’s Hospital, Guangzhou, China
- Department of Gastroenterology, Huadu District People’s Hospital, Guangzhou, China
- Guangzhou Key Laboratory of Digestive Diseases, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
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Peng Y, Chen L, Chen X, Lin J, Wei J, Cheng J, Zhou F, Ge L, Zhou R, Ding F, Wang X. NPSR1 promotes chronic colitis through regulating CD4 + T cell effector function in inflammatory bowel disease. Int Immunopharmacol 2024; 142:113252. [PMID: 39332092 DOI: 10.1016/j.intimp.2024.113252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 08/31/2024] [Accepted: 09/22/2024] [Indexed: 09/29/2024]
Abstract
BACKGROUND Neuropeptide S receptor 1 (NPSR1) has been implicated in the the onset of inflammatory bowel disease (IBD), though its exact mechanism remains unclear. This study investigates the role of NPSR1 in regulating CD4+ T cell effector function in IBD. METHODS Peripheral blood and colonic mucosal biopsies from IBD patients, as well as dextran sodium sulfate (DSS)-induced mouse colitis models, were analyzed to assess the effects of NPSR1 on colitis and CD4+ T cell-mediated immune responses. NPSR1 knockdown was conducted both in vitro and in vivo to elucidate underlying mechanisms. Expression of NPSR1 and CD4+ T cell-related factors was measured using quantitative real-time PCR, immunoblotting, cytometric bead array, immunofluorescence, and immunohistochemistry. CD4 + T cell effector functions were evaluated through flow cytometry, EdU incorporation assay, Annexin V-FITC/PI staining, and transwell assay. RESULTS NPSR1 expression was elevated in the intestinal tissues from IBD patients. Its downregulation provided protection in DSS-induced mouse colitis models. NPSR1 correlated positively with CD4 + T cell-mediated inflammation, and its knockdown reduced CD4+ T cell-mediated immune responses and inhibited CD4+ T cell differentiation. Additionally, NPSR1 knockdown decreased CD4+ T cell proliferation, increased apoptosis, and enhanced CCL2-induced migration in vitro, while significantly reducing Th1 cell chemotaxis in vivo. CONCLUSIONS This study demonstrates that NPSR1 promotes chronic colitis by regulating CD4 + T cell effector functions in IBD, offering potential new therapeutic strategies for IBD treatment.
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Affiliation(s)
- Yanan Peng
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Provincial Clinical Research Center for Intestinal and Colorectal Diseases, Hubei Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Liping Chen
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Provincial Clinical Research Center for Intestinal and Colorectal Diseases, Hubei Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Xiaojia Chen
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Provincial Clinical Research Center for Intestinal and Colorectal Diseases, Hubei Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Jun Lin
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Provincial Clinical Research Center for Intestinal and Colorectal Diseases, Hubei Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Jia Wei
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China
| | - Jie Cheng
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Provincial Clinical Research Center for Intestinal and Colorectal Diseases, Hubei Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Feng Zhou
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Provincial Clinical Research Center for Intestinal and Colorectal Diseases, Hubei Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Liuqing Ge
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Provincial Clinical Research Center for Intestinal and Colorectal Diseases, Hubei Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Rui Zhou
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Provincial Clinical Research Center for Intestinal and Colorectal Diseases, Hubei Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Feng Ding
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Provincial Clinical Research Center for Intestinal and Colorectal Diseases, Hubei Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Xiaobing Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Provincial Clinical Research Center for Intestinal and Colorectal Diseases, Hubei Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China.
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6
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Bauset C, Carda-Diéguez M, Cejudo-Garcés A, Buetas E, Seco-Cervera M, Macias-Ceja DC, Navarro-Vicente F, Esplugues JV, Calatayud S, Mira Á, Ortiz-Masiá D, Barrachina MD, Cosín-Roger J. A disturbed metabolite-GPCR axis is associated with microbial dysbiosis in IBD patients: Potential role of GPR109A in macrophages. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167489. [PMID: 39233260 DOI: 10.1016/j.bbadis.2024.167489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 06/20/2024] [Accepted: 08/26/2024] [Indexed: 09/06/2024]
Abstract
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract characterized by disrupted immune function. Indeed, gut microbiota dysbiosis and metabolomic profile alterations, are hallmarks of IBD. In this scenario, metabolite-sensing G-protein coupled receptors (GPCRs), involved in several biological processes, have emerged as pivotal players in the pathophysiology of IBD. The aim of this study was to characterize the axis microbiota-metabolite-GPCR in intestinal surgical resections from IBD patients. Results showed that UC patients had a lower microbiota richness and bacterial load, with a higher proportion of the genus Cellulosimicrobium and a reduced proportion of Escherichia, whereas CD patients showed a decreased abundance of Enterococcus. Furthermore, metabolomic analysis revealed alterations in carboxylic acids, fatty acids, and amino acids in UC and CD samples. These patients also exhibited upregulated expression of most metabolite-sensing GPCRs analysed, which positively correlated with pro-inflammatory and pro-fibrotic markers. The role of GPR109A was studied in depth and increased expression of this receptor was detected in epithelial cells and cells from lamina propria, including CD68+ macrophages, in IBD patients. The treatment with β-hydroxybutyrate increased gene expression of GPR109A, CD86, IL1B and NOS2 in U937-derived macrophages. Besides, when GPR109A was transiently silenced, the mRNA expression and secretion of IL-1β, IL-6 and TNF-α were impaired in M1 macrophages. Finally, the secretome from siGPR109A M1 macrophages reduced the gene and protein expression of COL1A1 and COL3A1 in intestinal fibroblasts. A better understanding of metabolite-sensing GPCRs, such as GPR109A, could establish their potential as therapeutic targets for managing IBD.
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Affiliation(s)
- Cristina Bauset
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
| | | | - Andrea Cejudo-Garcés
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
| | - Elena Buetas
- Genomics & Health Department, FISABIO Foundation, Valencia, Spain
| | | | | | | | - Juan Vicente Esplugues
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; CIBERehd (Centro de Investigaciones en Red Enfermedad Hepática y Digestiva), Madrid, Spain
| | - Sara Calatayud
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; CIBERehd (Centro de Investigaciones en Red Enfermedad Hepática y Digestiva), Madrid, Spain
| | - Álex Mira
- Genomics & Health Department, FISABIO Foundation, Valencia, Spain; CIBER Center for Epidemiology and Public Health, Madrid, Spain
| | - Dolores Ortiz-Masiá
- CIBERehd (Centro de Investigaciones en Red Enfermedad Hepática y Digestiva), Madrid, Spain; Departamento de Medicina, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
| | - María Dolores Barrachina
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; CIBERehd (Centro de Investigaciones en Red Enfermedad Hepática y Digestiva), Madrid, Spain.
| | - Jesús Cosín-Roger
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; CIBERehd (Centro de Investigaciones en Red Enfermedad Hepática y Digestiva), Madrid, Spain
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7
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He K, Cheng H, McClements DJ, Xu Z, Meng M, Zou Y, Chen G, Chen L. Utilization of diverse probiotics to create human health promoting fatty acids: A review. Food Chem 2024; 458:140180. [PMID: 38964111 DOI: 10.1016/j.foodchem.2024.140180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 06/09/2024] [Accepted: 06/19/2024] [Indexed: 07/06/2024]
Abstract
Many probiotics produce functional lipids with health-promoting properties, such as short-chain fatty acids, linoleic acid and omega-3 fatty acids. They have been shown to maintain gut health, strengthen the intestinal barrier, and have anti-inflammatory and antioxidant effects. In this article, we provide an up-to-date review of the various functional lipids produced by probiotics. These probiotics can be incorporated into foods, supplements, or pharmaceuticals to produce these functional lipids in the human colon, or they can be used in industrial biotechnology processes to generate functional lipids, which are then isolated and used as ingredients. We then highlight the different physiological functions for which they may be beneficial to human health, in addition to discussing some of the challenges of incorporating probiotics into commercial products and some potential solutions to address these challenges. Finally, we highlight the importance of testing the efficacy and safety of the new generation of probiotic-enhanced products, as well as the great potential for the marketization of related products.
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Affiliation(s)
- Kuang He
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
| | - Hao Cheng
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
| | | | - Zhenlin Xu
- School of Food Science and Technology, South China Agricultural University, Guangzhou 510642, China
| | - Man Meng
- Licheng Detection & Certification Group Co., Ltd., Zhongshan 528400, China
| | - Yidong Zou
- Skystone Feed Co., Ltd., Wuxi 214258, China
| | | | - Long Chen
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China; State Key Lab of Food Science and Resources, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China; Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China; School of Food Science and Technology, South China Agricultural University, Guangzhou 510642, China.
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8
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Hurtado-Lorenzo A, Swantek JL. The landscape of new therapeutic opportunities for IBD. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2024; 101:1-83. [PMID: 39521596 DOI: 10.1016/bs.apha.2024.10.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
This chapter presents an overview of the emerging strategies to address the unmet needs in the management of inflammatory bowel diseases (IBD). IBD poses significant challenges, as over half of patients experience disease progression despite interventions, leading to irreversible complications, and a substantial proportion do not respond to existing therapies, such as biologics. To overcome these limitations, we describe a diverse array of novel therapeutic approaches. In the area of immune homeostasis restoration, the focus is on targeting cytokine networks, leukocyte trafficking, novel immune pathways, and cell therapies involving regulatory T cells and mesenchymal stem cells (MSC). Recognizing the critical role of impaired intestinal barrier integrity in IBD, we highlight therapies aimed at restoring barrier function and promoting mucosal healing, such as those targeting cell proliferation, tight junctions, and lipid mediators. Addressing the challenges posed by fibrosis and fistulas, we describe emerging targets for reversing fibrosis like kinase and cytokine inhibitors and nuclear receptor agonists, as well as the potential of MSC for fistulas. The restoration of a healthy gut microbiome, through strategies like fecal microbiota transplantation, rationally defined bacterial consortia, and targeted antimicrobials, is also highlighted. We also describe innovative approaches to gut-targeted drug delivery to enhance efficacy and minimize side effects. Reinforcing these advancements is the critical role of precision medicine, which emphasizes the use of multiomics analysis for the discovery of biomarkers to enable personalized IBD care. Overall, the emerging landscape of therapeutic opportunities for IBD holds great potential to surpass the therapeutic ceiling of current treatments.
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Affiliation(s)
- Andrés Hurtado-Lorenzo
- Translational Research & IBD Ventures, Research Department, Crohn's & Colitis Foundation, New York, NY, United States.
| | - Jennifer L Swantek
- Translational Research & IBD Ventures, Research Department, Crohn's & Colitis Foundation, New York, NY, United States
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9
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Zhang Y, Thomas JP, Korcsmaros T, Gul L. Integrating multi-omics to unravel host-microbiome interactions in inflammatory bowel disease. Cell Rep Med 2024; 5:101738. [PMID: 39293401 PMCID: PMC11525031 DOI: 10.1016/j.xcrm.2024.101738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 08/11/2024] [Accepted: 08/21/2024] [Indexed: 09/20/2024]
Abstract
The gut microbiome is crucial for nutrient metabolism, immune regulation, and intestinal homeostasis with changes in its composition linked to complex diseases like inflammatory bowel disease (IBD). Although the precise host-microbial mechanisms in disease pathogenesis remain unclear, high-throughput sequencing have opened new ways to unravel the role of interspecies interactions in IBD. Systems biology-a holistic computational framework for modeling complex biological systems-is critical for leveraging multi-omics datasets to identify disease mechanisms. This review highlights the significance of multi-omics data in IBD research and provides an overview of state-of-the-art systems biology resources and computational tools for data integration. We explore gaps, challenges, and future directions in the research field aiming to uncover novel biomarkers and therapeutic targets, ultimately advancing personalized treatment strategies. While focusing on IBD, the proposed approaches are applicable for other complex diseases, like cancer, and neurodegenerative diseases, where the microbiome has also been implicated.
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Affiliation(s)
- Yiran Zhang
- Department of Surgery & Cancer, Imperial College London, London W12 0NN, UK; Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK
| | - John P Thomas
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK; UKRI MRC Laboratory of Medical Sciences, Hammersmith Hospital Campus, London W12 0HS, UK
| | - Tamas Korcsmaros
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK; NIHR Imperial BRC Organoid Facility, Imperial College London, London W12 0NN, UK; Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK.
| | - Lejla Gul
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK; Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK
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10
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Li L, Cheng R, Wu Y, Lin H, Gan H, Zhang H. Diagnosis and management of inflammatory bowel disease. J Evid Based Med 2024; 17:409-433. [PMID: 38934234 DOI: 10.1111/jebm.12626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 06/10/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024]
Abstract
Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disease of the gastrointestinal tract with a gradually increasing global incidence and prevalence. A prolonged course of IBD leads to a decline in patient quality of life and the creation of a substantial economic burden on society. Owing to the lack of specific diagnostic markers, the diagnosis of IBD still needs a gold standard based on a combination of clinical manifestations, imaging, laboratory, and endoscopic results. Accordingly, the current goals of IBD treatment are to alleviate clinical symptoms and reduce recurrence rates. Therefore, it is imperative to develop a standard set of procedures to diagnose and treat IBD. In this review, we summarize prominent and emerging studies, outline classical and contemporary approaches to diagnosing and managing IBD, and integrate multiple guidelines. Furthermore, we propose the possibility of establishing an early and comprehensive diagnostic workflow and personalized management strategy in the future. We aim to enhance the quality and standardization of diagnostic and treatment procedures for IBD.
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Affiliation(s)
- Lili Li
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Cheng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yushan Wu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Hao Lin
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Huatian Gan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- The Center of Gerontology and Geriatrics, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
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11
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Lee DH, Kim MT, Han JH. GPR41 and GPR43: From development to metabolic regulation. Biomed Pharmacother 2024; 175:116735. [PMID: 38744220 DOI: 10.1016/j.biopha.2024.116735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 05/06/2024] [Accepted: 05/07/2024] [Indexed: 05/16/2024] Open
Abstract
G-protein-coupled receptors are a diverse class of cell surface receptors that orchestrate numerous physiological functions. The G-protein-coupled receptors, GPR41 and GPR43, sense short-chain fatty acids (SCFAs), which are metabolites of dietary fermentation by the host's intestinal bacteria. These receptors have gained attention as potential therapeutic targets against various diseases because of their SCFA-mediated beneficial effects on the host's intestinal health. Mounting evidence has associated the activity of these receptors with chronic metabolic diseases, including obesity, diabetes, inflammation, and cardiovascular disease. However, despite intensive research using various strategies, including gene knockout (KO) mouse models, evidence about the precise roles of GPR41 and GPR43 in disease treatment remains inconsistent. Here, we comprehensively review the latest findings from functional studies of the signaling mechanisms that underlie the activities of GPR41 and GPR43, as well as highlight their multifaceted roles in health and disease. We anticipate that this knowledge will guide future research priorities and the development of effective therapeutic interventions.
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Affiliation(s)
- Do-Hyung Lee
- College of Pharmacy, Chungnam National University, Daejeon 34134, the Republic of Korea
| | - Min-Tae Kim
- Department of Pharmaceutical Research, KyongBo Pharmaceutical Co., Ltd, 174, Sirok-ro, Asan-si, Chungcheongnam-do 31501, the Republic of Korea
| | - Joo-Hui Han
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Woosuk University, Wanju 55338, the Republic of Korea.
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12
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Duraisamy K, Kumar M, Nawabjan A, Lo EKK, Hui Lin M, Lefranc B, Bonnafé E, Treilhou M, El-Nezami H, Leprince J, Chow BKC. MRGPRB2/X2 and the analogous effects of its agonist and antagonist in DSS-induced colitis in mice. Biomed Pharmacother 2024; 174:116471. [PMID: 38547764 DOI: 10.1016/j.biopha.2024.116471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 03/08/2024] [Accepted: 03/18/2024] [Indexed: 05/01/2024] Open
Abstract
The mast cell receptor Mrgprb2, a mouse orthologue of human Mrgprx2, is known as an inflammatory receptor and its elevated expression is associated with various diseases such as ulcerative colitis. We aimed to elucidate the role of Mrgprb2/x2 and the effect of its ligands on a chemically induced murine colitis model. We showed that in Mrgprb2-/- mice, there is a differential regulation of cytokine releases in the blood plasma and severe colonic damages after DSS treatment. Unexpectedly, we demonstrated that known Mrgprb2/x2 agonists (peptide P17, P17 analogues and CST-14) and antagonist (GE1111) similarly increased the survival rate of WT mice subjected to 4% DSS-induced colitis, ameliorated the colonic damages of 2.5% DSS-induced colitis, restored major protein mRNA expression involved in colon integrity, reduced CD68+ and F4/80+ immune cell infiltration and restored cytokine levels. Collectively, our findings highlight the eminent role of Mrpgrb2/x2 in conferring a beneficial effect in the colitis model, and this significance is demonstrated by the heightened severity of colitis with altered cytokine releases and inflammatory immune cell infiltration observed in the Mrgprb2 knockout mice. Elevated expression of Mrgprb2 in WT colitis murine models may represent the organism's adaptive protective mechanism since Mrgprb2 knockout results in severe colitis. On the other hand, both agonist and antagonist of Mrgprb2 analogously mitigated the severity of colitis in DSS-induced colitis model by altering Mrgprb2 expression, immune cell infiltration and inflammatory cytokine releases.
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Affiliation(s)
- Karthi Duraisamy
- School of Biological Sciences, The University of Hong Kong, Hong Kong, China; INSERM U1239 NorDiC, PRIMACEN, Université Rouen Normandie, Rouen, France
| | - Mukesh Kumar
- School of Biological Sciences, The University of Hong Kong, Hong Kong, China
| | - Abdullah Nawabjan
- School of Biological Sciences, The University of Hong Kong, Hong Kong, China
| | - Emily Kwun Kwan Lo
- School of Biological Sciences, The University of Hong Kong, Hong Kong, China
| | - Ming Hui Lin
- School of Biological Sciences, The University of Hong Kong, Hong Kong, China
| | - Benjamin Lefranc
- INSERM U1239 NorDiC, PRIMACEN, Université Rouen Normandie, Rouen, France
| | - Elsa Bonnafé
- EA7417 BTSB, Université Fédérale Toulouse Midi-Pyrénées, INU Champollion, Albi, France
| | - Michel Treilhou
- EA7417 BTSB, Université Fédérale Toulouse Midi-Pyrénées, INU Champollion, Albi, France
| | - Hani El-Nezami
- School of Biological Sciences, The University of Hong Kong, Hong Kong, China; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Jérôme Leprince
- INSERM U1239 NorDiC, PRIMACEN, Université Rouen Normandie, Rouen, France.
| | - Billy K C Chow
- School of Biological Sciences, The University of Hong Kong, Hong Kong, China.
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13
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Chung YK, Chan HY, Lee TY, Wong YH. Inhibition of adenylyl cyclase by GTPase-deficient Gα i is mechanistically different from that mediated by receptor-activated Gα i. Cell Commun Signal 2024; 22:218. [PMID: 38581012 PMCID: PMC10996109 DOI: 10.1186/s12964-024-01572-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 03/16/2024] [Indexed: 04/07/2024] Open
Abstract
Signal transduction through G protein-coupled receptors (GPCRs) has been a major focus in cell biology for decades. Numerous disorders are associated with GPCRs that utilize Gi proteins to inhibit adenylyl cyclase (AC) as well as regulate other effectors. Several early studies have successfully defined the AC-interacting domains of several members of Gαi by measuring the loss of activity upon homologous replacements of putative regions of constitutive active Gαi mutants. However, whether such findings can indeed be translated into the context of a receptor-activated Gαi have not been rigorously verified. To address this issue, an array of known and new chimeric mutations was introduced into GTPase-deficient Q204L (QL) and R178C (RC) mutants of Gαi1, followed by examinations on their ability to inhibit AC. Surprisingly, most chimeras failed to abolish the constitutive activity brought on by the QL mutation, while some were able to eliminate the inhibitory activity of RC mutants. Receptor-mediated inhibition of AC was similarly observed in the same chimeric constructs harbouring the pertussis toxin (PTX)-resistant C351I mutation. Moreover, RC-bearing loss-of-function chimeras appeared to be hyper-deactivated by endogenous RGS protein. Molecular docking revealed a potential interaction between AC and the α3/β5 loop of Gαi1. Subsequent cAMP assays support a cooperative action of the α3/β5 loop, the α4 helix, and the α4/β6 loop in mediating AC inhibition by Gαi1-i3. Our results unveiled a notable functional divergence between constitutively active mutants and receptor-activated Gαi1 to inhibit AC, and identified a previously unknown AC-interacting domain of Gαi subunits. These results collectively provide valuable insights on the mechanism of AC inhibition in the cellular environment.
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Affiliation(s)
- Yin Kwan Chung
- Division of Life Science and Biotechnology Research Institute, Hong Kong University of Science and Technology, Hong Kong, China
- Rudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig University, Johannisallee 30, 04103, Leipzig, Germany
| | - Ho Yung Chan
- Division of Life Science and Biotechnology Research Institute, Hong Kong University of Science and Technology, Hong Kong, China
| | - Tung Yeung Lee
- Division of Life Science and Biotechnology Research Institute, Hong Kong University of Science and Technology, Hong Kong, China
| | - Yung Hou Wong
- Division of Life Science and Biotechnology Research Institute, Hong Kong University of Science and Technology, Hong Kong, China.
- State Key Laboratory of Molecular Neuroscience, and the Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
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14
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Glitsch MD. Recent advances in acid sensing by G protein coupled receptors. Pflugers Arch 2024; 476:445-455. [PMID: 38340167 PMCID: PMC11006784 DOI: 10.1007/s00424-024-02919-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 01/30/2024] [Accepted: 01/30/2024] [Indexed: 02/12/2024]
Abstract
Changes in extracellular proton concentrations occur in a variety of tissues over a range of timescales under physiological conditions and also accompany virtually all pathologies, notably cancers, stroke, inflammation and trauma. Proton-activated, G protein coupled receptors are already partially active at physiological extracellular proton concentrations and their activity increases with rising proton concentrations. Their ability to monitor and report changes in extracellular proton concentrations and hence extracellular pH appears to be involved in a variety of processes, and it is likely to mirror and in some cases promote disease progression. Unsurprisingly, therefore, these pH-sensing receptors (pHR) receive increasing attention from researchers working in an expanding range of research areas, from cellular neurophysiology to systemic inflammatory processes. This review is looking at progress made in the field of pHRs over the past few years and also highlights outstanding issues.
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Affiliation(s)
- Maike D Glitsch
- Medical School Hamburg, Am Sandtorkai 1, 20457, Hamburg, Germany.
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15
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Tak J, An Q, Lee SG, Lee CH, Kim SG. Gα12 and endoplasmic reticulum stress-mediated pyroptosis in a single cycle of dextran sulfate-induced mouse colitis. Sci Rep 2024; 14:6335. [PMID: 38491049 PMCID: PMC10943197 DOI: 10.1038/s41598-024-56685-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 03/09/2024] [Indexed: 03/18/2024] Open
Abstract
Inflammatory bowel disease (IBD) pathogenesis involves complex inflammatory events and cell death. Although IBD involves mainly necrosis in the digestive tract, pyroptosis has also been recognized. Nonetheless, the underlying basis is elusive. Gα12/13 overexpression may affect endoplasmic reticulum (ER) stress. This study examined how Gα12/13 and ER stress affect pyroptosis using dextran sulfate sodium (DSS)-induced colitis models. Gα12/13 levels were increased in the distal and proximal colons of mice exposed to a single cycle of DSS, as accompanied by increases of IRE1α, ATF6, and p-PERK. Moreover, Il-6, Il-1β, Ym1, and Arg1 mRNA levels were increased with caspase-1 and IL-1β activation, supportive of pyroptosis. In the distal colon, RIPK1/3 levels were enhanced to a greater degree, confirming necroptosis. By contrast, the mice subjected to three cycles of DSS treatments showed decreases of Gα12/13, as accompanied by IRE1α and ATF6 suppression, but increases of RIPK1/3 and c-Cas3. AZ2 treatment, which inhibited Gα12, has an anti-pyroptotic effect against a single cycle of colitis. These results show that a single cycle of DSS-induced colitis may cause ER stress-induced pyroptosis as mediated by Gα12 overexpression in addition to necroptosis, but three cycles model induces only necroptosis, and that AZ2 may have an anti-pyroptotic effect.
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Affiliation(s)
- Jihoon Tak
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do, 10326, Republic of Korea
| | - Quanxi An
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do, 10326, Republic of Korea
| | - Sang Gil Lee
- Research and Development Institute, A Pharma Inc, Goyang-si, Gyeonggi-do, 10326, Republic of Korea
| | - Chang Hoon Lee
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do, 10326, Republic of Korea
| | - Sang Geon Kim
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do, 10326, Republic of Korea.
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16
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Xu Y, Fang X, Zhao Z, Wu H, Fan H, Zhang Y, Meng Q, Rong Q, Fukunaga K, Guo Q, Liu Q. GPR124 induces NLRP3 inflammasome-mediated pyroptosis in endothelial cells during ischemic injury. Eur J Pharmacol 2024; 962:176228. [PMID: 38042462 DOI: 10.1016/j.ejphar.2023.176228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 11/25/2023] [Accepted: 11/27/2023] [Indexed: 12/04/2023]
Abstract
OBJECTIVE G protein-coupled receptor 124 (GPR124) regulates central nervous system angiogenesis and blood-brain barrier (BBB) integrity, and its deficiency aggravates BBB breakdown and hemorrhagic transformation in ischemic mice. However, excessive GPR124 expression promotes inflammation in atherosclerotic mice. In this study, we aimed to elucidate the role of GPR124 in hypoxia/ischemia-induced cerebrovascular endothelial cell injury. METHODS bEnd.3 cells were exposed to oxygen-glucose deprivation (OGD), and time-dependent changes in GPR124 mRNA and protein expression were evaluated using reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. The effects of GPR124 overexpression or knockdown on the expression of pyroptosis-related genes were assessed at the mRNA and protein levels. Tadehaginoside (TA) was screened as a potential small molecule targeting GPR124, and its effects on pyroptosis-related signaling pathways were investigated. Finally, the therapeutic efficacy of TA was evaluated using a rat model of transient middle cerebral artery occlusion/reperfusion (tMCAO/R). RESULTS During OGD, the expression of GPR124 initially increased and then decreased over time, with the highest levels observed 1 h after OGD. The overexpression of GPR124 enhanced the OGD-induced expression of NLRP3, Caspase-1, and Gasdermin D (GSDMD) in bEnd.3 cells, whereas GPR124 knockdown reduced pyroptosis. Additionally, TA exhibited a high targeting ability to GPR124, significantly inhibiting its function and expression and suppressing the expression of pyroptosis-related proteins during OGD. Furthermore, TA treatment significantly reduced the cerebral infarct volume and pyroptotic signaling in tMCAO/R rats. CONCLUSIONS Our findings suggest that GPR124 mediates pyroptotic signaling in endothelial cells during the early stages of hypoxia/ischemia, thereby exacerbating ischemic injury.
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Affiliation(s)
- Yiqian Xu
- Department of Pharmacy & Engineering Research Center of Tropical Medicine Innovation and Transformation, Ministry of Education, The First Affiliated Hospital of Hainan Medical University, Haikou 570102, China
| | - Xingyue Fang
- Department of Pharmacy & Engineering Research Center of Tropical Medicine Innovation and Transformation, Ministry of Education, The First Affiliated Hospital of Hainan Medical University, Haikou 570102, China
| | - Zhenqiang Zhao
- Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province, Hainan Medical University, Haikou 571199, China
| | - Haolin Wu
- Department of Pharmacy & Engineering Research Center of Tropical Medicine Innovation and Transformation, Ministry of Education, The First Affiliated Hospital of Hainan Medical University, Haikou 570102, China
| | - Haofei Fan
- Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province, Hainan Medical University, Haikou 571199, China
| | - Ya Zhang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou 571199, China
| | - Qingwen Meng
- Department of Pharmacology, School of Basic and Life Science, Hainan Medical University, Haikou 571199, China
| | - Qiongwen Rong
- Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province, Hainan Medical University, Haikou 571199, China
| | - Kohji Fukunaga
- Department of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan
| | - Qingyun Guo
- Department of Pharmacology, School of Basic and Life Science, Hainan Medical University, Haikou 571199, China; Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province, Hainan Medical University, Haikou 571199, China.
| | - Qibing Liu
- Department of Pharmacy & Engineering Research Center of Tropical Medicine Innovation and Transformation, Ministry of Education, The First Affiliated Hospital of Hainan Medical University, Haikou 570102, China; Department of Pharmacology, School of Basic and Life Science, Hainan Medical University, Haikou 571199, China.
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17
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Zeng Z, Jiang M, Li X, Yuan J, Zhang H. Precision medicine in inflammatory bowel disease. PRECISION CLINICAL MEDICINE 2023; 6:pbad033. [PMID: 38638127 PMCID: PMC11025389 DOI: 10.1093/pcmedi/pbad033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 12/13/2023] [Indexed: 04/20/2024] Open
Abstract
Inflammatory bowel disease (IBD) is an incurable disease characterized by remission-relapse cycles throughout its course. Both Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of IBD, exhibit tendency to develop complications and substantial heterogeneity in terms of frequency and severity of relapse, thus posing great challenges to the clinical management for IBD. Current treatment strategies are effective in different ways in induction and maintenance therapies for IBD. Recent advances in studies of genetics, pharmacogenetics, proteomics and microbiome provide a strong driving force for identifying molecular markers of prognosis and treatment response, which should help clinicians manage IBD patients more effectively, and then, improve clinical outcomes and reduce treatment costs of patients. In this review, we summarize and discuss precision medicine in IBD, focusing on predictive markers of disease course and treatment response, and monitoring indices during therapeutic drug monitoring.
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Affiliation(s)
- Zhen Zeng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Mingshan Jiang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xi Li
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jing Yuan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
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18
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Budu-Aggrey A, Kilanowski A, Sobczyk MK, Shringarpure SS, Mitchell R, Reis K, Reigo A, Mägi R, Nelis M, Tanaka N, Brumpton BM, Thomas LF, Sole-Navais P, Flatley C, Espuela-Ortiz A, Herrera-Luis E, Lominchar JVT, Bork-Jensen J, Marenholz I, Arnau-Soler A, Jeong A, Fawcett KA, Baurecht H, Rodriguez E, Alves AC, Kumar A, Sleiman PM, Chang X, Medina-Gomez C, Hu C, Xu CJ, Qi C, El-Heis S, Titcombe P, Antoun E, Fadista J, Wang CA, Thiering E, Wu B, Kress S, Kothalawala DM, Kadalayil L, Duan J, Zhang H, Hadebe S, Hoffmann T, Jorgenson E, Choquet H, Risch N, Njølstad P, Andreassen OA, Johansson S, Almqvist C, Gong T, Ullemar V, Karlsson R, Magnusson PKE, Szwajda A, Burchard EG, Thyssen JP, Hansen T, Kårhus LL, Dantoft TM, Jeanrenaud ACSN, Ghauri A, Arnold A, Homuth G, Lau S, Nöthen MM, Hübner N, Imboden M, Visconti A, Falchi M, Bataille V, Hysi P, Ballardini N, Boomsma DI, Hottenga JJ, Müller-Nurasyid M, Ahluwalia TS, Stokholm J, Chawes B, Schoos AMM, Esplugues A, Bustamante M, Raby B, Arshad S, German C, Esko T, Milani LA, Metspalu A, Terao C, Abuabara K, Løset M, Hveem K, Jacobsson B, Pino-Yanes M, Strachan DP, Grarup N, Linneberg A, et alBudu-Aggrey A, Kilanowski A, Sobczyk MK, Shringarpure SS, Mitchell R, Reis K, Reigo A, Mägi R, Nelis M, Tanaka N, Brumpton BM, Thomas LF, Sole-Navais P, Flatley C, Espuela-Ortiz A, Herrera-Luis E, Lominchar JVT, Bork-Jensen J, Marenholz I, Arnau-Soler A, Jeong A, Fawcett KA, Baurecht H, Rodriguez E, Alves AC, Kumar A, Sleiman PM, Chang X, Medina-Gomez C, Hu C, Xu CJ, Qi C, El-Heis S, Titcombe P, Antoun E, Fadista J, Wang CA, Thiering E, Wu B, Kress S, Kothalawala DM, Kadalayil L, Duan J, Zhang H, Hadebe S, Hoffmann T, Jorgenson E, Choquet H, Risch N, Njølstad P, Andreassen OA, Johansson S, Almqvist C, Gong T, Ullemar V, Karlsson R, Magnusson PKE, Szwajda A, Burchard EG, Thyssen JP, Hansen T, Kårhus LL, Dantoft TM, Jeanrenaud ACSN, Ghauri A, Arnold A, Homuth G, Lau S, Nöthen MM, Hübner N, Imboden M, Visconti A, Falchi M, Bataille V, Hysi P, Ballardini N, Boomsma DI, Hottenga JJ, Müller-Nurasyid M, Ahluwalia TS, Stokholm J, Chawes B, Schoos AMM, Esplugues A, Bustamante M, Raby B, Arshad S, German C, Esko T, Milani LA, Metspalu A, Terao C, Abuabara K, Løset M, Hveem K, Jacobsson B, Pino-Yanes M, Strachan DP, Grarup N, Linneberg A, Lee YA, Probst-Hensch N, Weidinger S, Jarvelin MR, Melén E, Hakonarson H, Irvine AD, Jarvis D, Nijsten T, Duijts L, Vonk JM, Koppelmann GH, Godfrey KM, Barton SJ, Feenstra B, Pennell CE, Sly PD, Holt PG, Williams LK, Bisgaard H, Bønnelykke K, Curtin J, Simpson A, Murray C, Schikowski T, Bunyavanich S, Weiss ST, Holloway JW, Min JL, Brown SJ, Standl M, Paternoster L. European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation. Nat Commun 2023; 14:6172. [PMID: 37794016 PMCID: PMC10550990 DOI: 10.1038/s41467-023-41180-2] [Show More Authors] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 08/24/2023] [Indexed: 10/06/2023] Open
Abstract
Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.
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Affiliation(s)
- Ashley Budu-Aggrey
- Medical Research Council Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, England
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England
| | - Anna Kilanowski
- Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
- Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, University of Munich Medical Center, Munich, Germany
- Pettenkofer School of Public Health, Ludwig-Maximilians University Munich, Munich, Germany
| | - Maria K Sobczyk
- Medical Research Council Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, England
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England
| | | | - Ruth Mitchell
- Medical Research Council Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, England
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England
| | - Kadri Reis
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Anu Reigo
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Reedik Mägi
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Mari Nelis
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
- Core Facility of Genomics, University of Tartu, Tartu, Estonia
| | - Nao Tanaka
- Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Ben M Brumpton
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, 7030, Norway
- HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, 7600, Norway
- Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, 7030, Norway
| | - Laurent F Thomas
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, 7030, Norway
- Department of Clinical and Molecular Medicine, NTNU Norwegian University of Science and Technology, Trondheim, Norway
- BioCore - Bioinformatics Core Facility, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- Clinic of Laboratory Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Pol Sole-Navais
- Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Christopher Flatley
- Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Antonio Espuela-Ortiz
- Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, La Laguna, Tenerife, Spain
| | - Esther Herrera-Luis
- Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, La Laguna, Tenerife, Spain
| | - Jesus V T Lominchar
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, København, Denmark
| | - Jette Bork-Jensen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, København, Denmark
| | - Ingo Marenholz
- Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
- Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Aleix Arnau-Soler
- Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
- Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Ayoung Jeong
- Swiss Tropical and Public Health Institute, CH-4123, Basel, Switzerland
- University of Basel, CH-4001, Basel, Switzerland
| | - Katherine A Fawcett
- Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK
| | - Hansjorg Baurecht
- Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany
| | - Elke Rodriguez
- Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany
| | | | - Ashish Kumar
- Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Solna, Sweden
| | - Patrick M Sleiman
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
- Rhythm Pharmaceuticals, 222 Berkley Street, Boston, 02116, USA
| | - Xiao Chang
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Carolina Medina-Gomez
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Chen Hu
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Dermatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Cheng-Jian Xu
- University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergy, Beatrix Children's Hospital, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands
- Centre for Individualized Infection Medicine, CiiM, a joint venture between Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
- TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
| | - Cancan Qi
- University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergy, Beatrix Children's Hospital, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands
| | - Sarah El-Heis
- MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK
| | - Philip Titcombe
- MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK
| | - Elie Antoun
- Faculty of Medicine, University of Southampton, Southampton, UK
- Institute of Developmental Sciences, University of Southampton, Southampton, UK
| | - João Fadista
- Department of Bioinformatics & Data Mining, Måløv, Denmark
- Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
- Department of Clinical Sciences, Lund University Diabetes Centre, Malmö, Sweden
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Carol A Wang
- School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, Newcastle, NSW, Australia
| | - Elisabeth Thiering
- Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
- Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, University of Munich Medical Center, Munich, Germany
| | - Baojun Wu
- Center for Individualized and Genomic Medicine Research (CIGMA), Department of Medicine, Henry Ford Health, Detroit, MI, 48104, USA
| | - Sara Kress
- Environmental Epidemiology of Lung, Brain and Skin Aging, IUF - Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany
| | - Dilini M Kothalawala
- Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK
| | - Latha Kadalayil
- Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Jiasong Duan
- Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA
| | - Hongmei Zhang
- Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA
| | - Sabelo Hadebe
- Division of Immunology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Thomas Hoffmann
- Institute for Human Genetics, UCSF, San Francisco, CA, 94143, USA
- Department of Epidemiology and Biostatistics, UCSF, San Francisco, CA, 94158, USA
| | | | - Hélène Choquet
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Neil Risch
- Institute for Human Genetics, UCSF, San Francisco, CA, 94143, USA
- Department of Epidemiology and Biostatistics, UCSF, San Francisco, CA, 94158, USA
| | - Pål Njølstad
- Center for Diabetes Research, Department of Clinical Science, University of Bergen, NO-5020, Bergen, Norway
- Children and Youth Clinic, Haukeland University Hospital, NO-5021, Bergen, Norway
| | - Ole A Andreassen
- NORMENT Centre, Institute of Clinical Medicine, University of Oslo, 0450, Oslo, Norway
- Division of Mental Health and Addiction, Oslo University Hospital, 0450, Oslo, Norway
| | - Stefan Johansson
- Center for Diabetes Research, Department of Clinical Science, University of Bergen, NO-5020, Bergen, Norway
- Department of Medical Genetics, Haukeland University Hospital, NO-5021, Bergen, Norway
| | - Catarina Almqvist
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Pediatric Lung and Allergy Unit, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
| | - Tong Gong
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Vilhelmina Ullemar
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Robert Karlsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Patrik K E Magnusson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Agnieszka Szwajda
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Esteban G Burchard
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
| | - Jacob P Thyssen
- Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, København, Denmark
| | - Line L Kårhus
- Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark
| | - Thomas M Dantoft
- Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark
| | - Alexander C S N Jeanrenaud
- Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
- Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Ahla Ghauri
- Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
- Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Andreas Arnold
- Clinic and Polyclinic of Dermatology, University Medicine Greifswald, Greifswald, Germany
| | - Georg Homuth
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Susanne Lau
- Department of Pediatric Respiratory Medicine, Immunology, and Critical Care Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Markus M Nöthen
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Norbert Hübner
- Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
- Charite-Universitätsmedizin Berlin, Berlin, Germany
| | - Medea Imboden
- Swiss Tropical and Public Health Institute, CH-4123, Basel, Switzerland
- University of Basel, CH-4001, Basel, Switzerland
| | - Alessia Visconti
- Department of Twin Research & Genetics Epidemiology, Kings College London, London, UK
| | - Mario Falchi
- Department of Twin Research & Genetics Epidemiology, Kings College London, London, UK
| | - Veronique Bataille
- Department of Twin Research & Genetics Epidemiology, Kings College London, London, UK
- Dermatology Department, West Herts NHS Trust, Watford, UK
| | - Pirro Hysi
- Department of Twin Research & Genetics Epidemiology, Kings College London, London, UK
| | - Natalia Ballardini
- Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Solna, Sweden
| | - Dorret I Boomsma
- Dept Biological Psychology, Netherlands Twin Register, VU University, Amsterdam, the Netherlands
- Institute for Health and Care Research (EMGO), VU University, Amsterdam, the Netherlands
| | - Jouke J Hottenga
- Dept Biological Psychology, Netherlands Twin Register, VU University, Amsterdam, the Netherlands
| | - Martina Müller-Nurasyid
- Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
- IBE, Faculty of Medicine, LMU Munich, Munich, Germany
- Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University, Mainz, Germany
| | - Tarunveer S Ahluwalia
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Jakob Stokholm
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Pediatrics, Slagelse Hospital, Slagelse, Denmark
| | - Bo Chawes
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Ann-Marie M Schoos
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Pediatrics, Slagelse Hospital, Slagelse, Denmark
| | - Ana Esplugues
- Nursing School, University of Valencia, FISABIO-University Jaume I-University of Valencia, Valencia, Spain
- Joint Research Unit of Epidemiology and Environmental Health, CIBERESP, Valencia, Spain
| | - Mariona Bustamante
- ISGlobal, Institute for Global Health, Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CIBER Epidemiología y Salud Pública, Madrid, Spain
| | - Benjamin Raby
- Channing Division of Network Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Syed Arshad
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
- David Hide Asthma and Allergy Research Centre, Isle of Wight, UK
| | | | - Tõnu Esko
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Lili A Milani
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Andres Metspalu
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Chikashi Terao
- Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan
- Department of Applied Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Katrina Abuabara
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Mari Løset
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, 7030, Norway
- Department of Dermatology, Clinic of Orthopaedy, Rheumatology and Dermatology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Kristian Hveem
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, 7030, Norway
- HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway
| | - Bo Jacobsson
- Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Genetics and Bioinformatics, Norwegian Institute of Public Health, Oslo, Norway
| | - Maria Pino-Yanes
- Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, La Laguna, Tenerife, Spain
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain
| | - David P Strachan
- Population Health Research Institute, St George's, University of London, Cranmer Terrace, London, SW17 0RE, UK
| | - Niels Grarup
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, København, Denmark
| | - Allan Linneberg
- Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Young-Ae Lee
- Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
- Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Nicole Probst-Hensch
- Swiss Tropical and Public Health Institute, CH-4123, Basel, Switzerland
- University of Basel, CH-4001, Basel, Switzerland
| | - Stephan Weidinger
- Department of Dermatology, Allergology and Venereology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Marjo-Riitta Jarvelin
- Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health,Imperial College London, London, UK
- Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
- Biocenter Oulu, University of Oulu, Oulu, Finland
| | - Erik Melén
- Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Solna, Sweden
| | - Hakon Hakonarson
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- Department of Pediatrics, Divisions of Human Genetics and Pulmonary Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Faculty of Medicine, University of Iceland, 101, Reykjavík, Iceland
| | - Alan D Irvine
- Department of Clinical Medicine, Trinity College, Dublin, Ireland
| | - Deborah Jarvis
- Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London, United Kingdom
- Medical Research Council and Public Health England Centre for Environment and Health, London, United Kingdom
| | - Tamar Nijsten
- Department of Dermatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Liesbeth Duijts
- Department of Pediatrics, division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Pediatrics, division of Neonatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Judith M Vonk
- University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands
| | - Gerard H Koppelmann
- University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergy, Beatrix Children's Hospital, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands
| | - Keith M Godfrey
- MRC Lifecourse Epidemiology Centre and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Sheila J Barton
- MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK
| | - Bjarke Feenstra
- Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
| | - Craig E Pennell
- School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, Newcastle, NSW, Australia
| | - Peter D Sly
- Children's Health and Environment Program, Child Health Research Centre, The University of Queensland, South Brisbane, 4101, Queensland, Australia
- Australian Infectious Diseases Research Centre, The University of Queensland, St Lucia, 4072, QLD, Australia
| | - Patrick G Holt
- Telethon Kids Institute, University of Western Australia, Perth, WA, Australia
| | - L Keoki Williams
- Center for Individualized and Genomic Medicine Research (CIGMA), Department of Medicine, Henry Ford Health, Detroit, MI, 48104, USA
| | - Hans Bisgaard
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Klaus Bønnelykke
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - John Curtin
- Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester Academic Health Science Centre, and Manchester University NHS Foundation Trust, Manchester, England
| | - Angela Simpson
- Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester Academic Health Science Centre, and Manchester University NHS Foundation Trust, Manchester, England
| | - Clare Murray
- Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester Academic Health Science Centre, and Manchester University NHS Foundation Trust, Manchester, England
| | - Tamara Schikowski
- Environmental Epidemiology of Lung, Brain and Skin Aging, Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany
| | - Supinda Bunyavanich
- Division of Allergy and Immunology, Department of Pediatrics, and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Scott T Weiss
- Channing Division of Network Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - John W Holloway
- Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Josine L Min
- Medical Research Council Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, England
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England
| | - Sara J Brown
- Centre for Genomics and Experimental Medicine, Institute for Genetics and Cancer, University of Edinburgh, Crewe Road, Edinburgh, UK EH4 2XU, Scotland
| | - Marie Standl
- Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
- German Center for Lung Research (DZL), Munich, Germany
| | - Lavinia Paternoster
- Medical Research Council Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, England.
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England.
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19
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Mukorako P, St-Pierre DH, Flamand N, Biertho L, Lebel S, Lemoine N, Plamondon J, Roy MC, Tchernof A, Varin TV, Marette A, Silvestri C, Di Marzo V, Richard D. Hypoabsorptive surgeries cause limb-dependent changes in the gut endocannabinoidome and microbiome in association with beneficial metabolic effects. Int J Obes (Lond) 2023:10.1038/s41366-023-01307-3. [PMID: 37142736 DOI: 10.1038/s41366-023-01307-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 03/27/2023] [Accepted: 04/03/2023] [Indexed: 05/06/2023]
Abstract
OBJECTIVE To determine whether the metabolic benefits of hypoabsorptive surgeries are associated with changes in the gut endocannabinoidome (eCBome) and microbiome. METHODS Biliopancreatic diversion with duodenal switch (BPD-DS) and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) were performed in diet-induced obese (DIO) male Wistar rats. Control groups fed a high-fat diet (HF) included sham-operated (SHAM HF) and SHAM HF-pair-weighed to BPD-DS (SHAM HF-PW). Body weight, fat mass gain, fecal energy loss, HOMA-IR, and gut-secreted hormone levels were measured. The levels of eCBome lipid mediators and prostaglandins were quantified in different intestinal segments by LC-MS/MS, while expression levels of genes encoding eCBome metabolic enzymes and receptors were determined by RT-qPCR. Metataxonomic (16S rRNA) analysis was performed on residual distal jejunum, proximal jejunum, and ileum contents. RESULTS BPD-DS and SADI-S reduced fat gain and HOMA-IR, while increasing glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) levels in HF-fed rats. Both surgeries induced potent limb-dependent alterations in eCBome mediators and in gut microbial ecology. In response to BPD-DS and SADI-S, changes in gut microbiota were significantly correlated with those of eCBome mediators. Principal component analyses revealed connections between PYY, N-oleoylethanolamine (OEA), N-linoleoylethanolamine (LEA), Clostridium, and Enterobacteriaceae_g_2 in the proximal and distal jejunum and in the ileum. CONCLUSIONS BPD-DS and SADI-S caused limb-dependent changes in the gut eCBome and microbiome. The present results indicate that these variables could significantly influence the beneficial metabolic outcome of hypoabsorptive bariatric surgeries.
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Affiliation(s)
- Paulette Mukorako
- Department of Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada
- Québec Heart and Lung Institute, Chemin Sainte-Foy, Québec, QC, Canada
| | - David H St-Pierre
- Institute of Nutrition and Functional Foods, Centre NUTRISS, Québec, QC, Canada
- Department of Exercise Sciences, Université du Québec à Montréal (UQAM), Québec, QC, Canada
- School of Nutrition, Faculty of Agriculture and Food Sciences, Québec, QC, Canada
| | - Nicolas Flamand
- Department of Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada
- Québec Heart and Lung Institute, Chemin Sainte-Foy, Québec, QC, Canada
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, QC, Canada
| | - Laurent Biertho
- Department of Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada
- Québec Heart and Lung Institute, Chemin Sainte-Foy, Québec, QC, Canada
| | - Stéfane Lebel
- Department of Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada
- Québec Heart and Lung Institute, Chemin Sainte-Foy, Québec, QC, Canada
| | - Natacha Lemoine
- Québec Heart and Lung Institute, Chemin Sainte-Foy, Québec, QC, Canada
| | - Julie Plamondon
- Québec Heart and Lung Institute, Chemin Sainte-Foy, Québec, QC, Canada
| | - Marie-Claude Roy
- Québec Heart and Lung Institute, Chemin Sainte-Foy, Québec, QC, Canada
| | - André Tchernof
- Québec Heart and Lung Institute, Chemin Sainte-Foy, Québec, QC, Canada
- School of Nutrition, Faculty of Agriculture and Food Sciences, Québec, QC, Canada
| | - Thibault V Varin
- Institute of Nutrition and Functional Foods, Centre NUTRISS, Québec, QC, Canada
| | - André Marette
- Department of Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada
- Québec Heart and Lung Institute, Chemin Sainte-Foy, Québec, QC, Canada
- Institute of Nutrition and Functional Foods, Centre NUTRISS, Québec, QC, Canada
| | - Cristoforo Silvestri
- Department of Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada.
- Québec Heart and Lung Institute, Chemin Sainte-Foy, Québec, QC, Canada.
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, QC, Canada.
| | - Vincenzo Di Marzo
- Department of Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada.
- Québec Heart and Lung Institute, Chemin Sainte-Foy, Québec, QC, Canada.
- Institute of Nutrition and Functional Foods, Centre NUTRISS, Québec, QC, Canada.
- School of Nutrition, Faculty of Agriculture and Food Sciences, Québec, QC, Canada.
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, QC, Canada.
| | - Denis Richard
- Department of Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada.
- Québec Heart and Lung Institute, Chemin Sainte-Foy, Québec, QC, Canada.
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20
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Bandara Y, Priestnall SL, Chang YM, Kathrani A. Characterization of intestinal fibrosis in cats with chronic inflammatory enteropathy. J Vet Intern Med 2023; 37:936-947. [PMID: 37052621 DOI: 10.1111/jvim.16688] [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: 09/30/2022] [Accepted: 03/10/2023] [Indexed: 04/14/2023] Open
Abstract
BACKGROUND Intestinal fibrosis (IF) is commonly identified on histopathology of intestinal biopsy specimens (IBSp) from cats with chronic inflammatory enteropathy (CIE) however, its clinical relevance is unknown. OBJECTIVES Characterize and determine the clinical relevance of IF in cats with CIE. ANIMALS Sixty-five client-owned cats diagnosed with CIE after gastrointestinal histopathology from a single referral hospital in the United Kingdom. METHODS Medical records were retrospectively searched for cases of CIE on the basis of histopathology of IBSp. The IBSp from eligible cats were re-reviewed by a single board-certified veterinary pathologist for inclusion. Masson's trichrome (MT) stain and immunohistochemical labeling using antivimentin and anticollagen I antibodies to identify IF. For each case, various variables at the time of diagnostic investigation were recorded and referring veterinarians were contacted for follow-up information. RESULTS Mucosal fibrosis was identified in 51% of duodenal and 76% of colonic hematoxylin and eosin (HE)-stained IBSp. Vimentin labeling and MT staining identified additional cases of IF in 65% and 58% of the duodenal biopsy specimens, respectively. Vimentin labeling detected IF in 79% of the colonic biopsy specimens. Positive vimentin labeling and MT staining of the colonic mucosa were associated with decreased likelihood of attaining clinical remission and increased risk of death because of CIE (P < .05). CONCLUSIONS AND CLINICAL IMPORTANCE Additional stains at initial histopathologic examination of IBSp allow for better identification of IF compared to routine HE staining. Identification of IF in colonic biopsy specimens by vimentin immunolabeling and MT staining may provide prognostic information in cats with CIE.
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Affiliation(s)
- Yuvani Bandara
- Royal Veterinary College, University of London, London, UK
| | | | - Yu-Mei Chang
- Royal Veterinary College, University of London, London, UK
| | - Aarti Kathrani
- Royal Veterinary College, University of London, London, UK
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21
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Roy A. Advances in the molecular level understanding of G-protein coupled receptor. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 196:1-13. [PMID: 36813353 DOI: 10.1016/bs.pmbts.2022.07.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
G-protein coupled receptors (GPCRs) represent largest family of plasma membrane-bound receptor proteins that are involved in numerous cellular and physiological functions. Many extracellular stimuli such as hormones, lipids and chemokines activate these receptors. Aberrant expression and genetic alteration in GPCR are associated with many human diseases including cancer and cardiovascular disease. GPCRs have emerged as potential therapeutic target and numerous drugs are either approved by FDA or under clinical trial. This chapter provides an update on GPCR research and its significance as a promising therapeutic target.
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Affiliation(s)
- Adhiraj Roy
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University, Noida, Uttar Pradesh, India.
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22
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Li K, Lai C, Hei S, Liu C, Li Z, Xu K. Identification of a potential structure-based GPCR drug for interstitial cystitis/bladder pain syndrome: in silico protein structure analysis and molecular docking. Int Urogynecol J 2022:10.1007/s00192-022-05424-x. [PMID: 36576541 DOI: 10.1007/s00192-022-05424-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 11/12/2022] [Indexed: 12/29/2022]
Abstract
INTRODUCTION AND HYPOTHESIS There is currently no effective treatment for interstitial cystitis / bladder pain syndrome (IC/BPS) and thus seriously reduces the quality of life of patients. The purpose of this study is to analyze the structure and function of G protein coupled receptors related to IC/BPS by integrating bioinformatics and provide basis for the development of new drugs for IC/BPS. METHODS We used ProtParam and DNAMAN to analyze the physical and chemical properties of GPR18 and GPR183 proteins. The secondary and tertiary structure, conservative domain, phosphorylation site of both proteins were predicted by ProtScale, PredictProtein, SWISS-MODEL and GPS5.0 respectively. Multiple sequence alignment of the proteins were carried out by DNAMAN and the phylogenetic tree was constructed by MEGA. Further, the molecular docking verification of cannabidiol and both proteins were carried out by using AutoDock Vin. RESULTS GPR18 and GPR183 proteins were composed of 331 and 361 amino acids respectively. α-helix is the highest in the secondary structure of the two proteins. Both proteins contain seven transmembrane domains specific to G protein coupled receptors. And homology analysis showed that the two proteins had high homology. In terms of molecular docking, cannabidiol, a non psychoactive component extracted from the cannabis, can form effective molecular binding with GPR18 and GPR183 proteins. CONCLUSIONS We identified the structures of GPR18 and GPR183 proteins and their highly homologous evolutionary properties. Furthermore, both proteins can form effective binding with cannabidiol which provides new insights for the development of IC/BPS drugs by targeting G protein coupled receptors.
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Affiliation(s)
- Kuiqing Li
- Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 Yan Jiang West Road, Guangzhou, 510120, China
| | - Cong Lai
- Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 Yan Jiang West Road, Guangzhou, 510120, China
| | - Shangyan Hei
- Traditional Chinese Medicine Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Cheng Liu
- Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 Yan Jiang West Road, Guangzhou, 510120, China
| | - Zhuohang Li
- Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 Yan Jiang West Road, Guangzhou, 510120, China
| | - Kewei Xu
- Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 Yan Jiang West Road, Guangzhou, 510120, China.
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Dinarvand M, Koch FC, Al Mouiee D, Vuong K, Vijayan A, Tanzim AF, Azad AKM, Penesyan A, Castaño-Rodríguez N, Vafaee F. dRNASb: a systems biology approach to decipher dynamics of host-pathogen interactions using temporal dual RNA-seq data. Microb Genom 2022; 8. [PMID: 36136078 DOI: 10.1099/mgen.0.000862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Infection triggers a dynamic cascade of reciprocal events between host and pathogen wherein the host activates complex mechanisms to recognise and kill pathogens while the pathogen often adjusts its virulence and fitness to avoid eradication by the host. The interaction between the pathogen and the host results in large-scale changes in gene expression in both organisms. Dual RNA-seq, the simultaneous detection of host and pathogen transcripts, has become a leading approach to unravelling complex molecular interactions between the host and the pathogen and is particularly informative for intracellular organisms. The amount of in vitro and in vivo dual RNA-seq data is rapidly growing, which demands computational pipelines to effectively analyse such data. In particular, holistic, systems-level, and temporal analyses of dual RNA-seq data are essential to enable further insights into the host-pathogen transcriptional dynamics and potential interactions. Here, we developed an integrative network-driven bioinformatics pipeline, dRNASb, a systems biology-based computational pipeline to analyse temporal transcriptional clusters, incorporate molecular interaction networks (e.g. protein-protein interactions), identify topologically and functionally key transcripts in host and pathogen, and associate host and pathogen temporal transcriptome to decipher potential between-species interactions. The pipeline is applicable to various dual RNA-seq data from different species and experimental conditions. As a case study, we applied dRNASb to analyse temporal dual RNA-seq data of Salmonella-infected human cells, which enabled us to uncover genes contributing to the infection process and their potential functions and to identify putative associations between host and pathogen genes during infection. Overall, dRNASb has the potential to identify key genes involved in bacterial growth or host defence mechanisms for future uses as therapeutic targets.
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Affiliation(s)
- Mojdeh Dinarvand
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Forrest C Koch
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Daniel Al Mouiee
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
- Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia
- UNSW Data Science Hub, University of New South Wales, Sydney, NSW, Australia
| | - Kaylee Vuong
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Abhishek Vijayan
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Afia Fariha Tanzim
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
| | - A K M Azad
- ProCan®, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia
| | - Anahit Penesyan
- School of Natural Sciences, Faculty of Science and Engineering, Macquarie University, Sydney, NSW, Australia
| | - Natalia Castaño-Rodríguez
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Fatemeh Vafaee
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
- UNSW Data Science Hub, University of New South Wales, Sydney, NSW, Australia
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Akhtar M, Chen Y, Ma Z, Zhang X, Shi D, Khan JA, Liu H. Gut microbiota-derived short chain fatty acids are potential mediators in gut inflammation. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2022; 8:350-360. [PMID: 35510031 PMCID: PMC9040132 DOI: 10.1016/j.aninu.2021.11.005] [Citation(s) in RCA: 142] [Impact Index Per Article: 47.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 02/07/2023]
Abstract
Gut inflammation is a challenging concern in humans and animals, which disturbs normal growth and leads to severe bowel diseases. Short chain fatty acids (SCFA) are the gut microbiota metabolites produced from fermentation of non-digestible carbohydrates, and have been reported to modulate gut inflammation. SCFA have been implicated as the potential therapeutic bioactive molecules for gut inflammatory diseases, and could be an alternative to antibiotic growth promoters (AGP). In this review, the existing knowledge about the types of SCFA, the related gut microbes producing SCFA, the roles of SCFA in maintaining gut homeostasis, and how SCFA modulate gut inflammation is summarized. The therapeutic application of SCFA in the treatment of inflammatory bowel disease (IBD) is also highlighted.
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Affiliation(s)
- Muhammad Akhtar
- Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
| | - Yan Chen
- Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
| | - Ziyu Ma
- Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
| | - Xiaolong Zhang
- Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
| | - Deshi Shi
- Department of Preventive Veterinary Medicine, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
| | - Jawaria A. Khan
- Department of Veterinary Medicine, Faculty of Veterinary Science, University of Veterinary and Animal Sciences, Lahore, 54000, Pakistan
| | - Huazhen Liu
- Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
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IBD-associated G protein-coupled receptor 65 variant compromises signalling and impairs key functions involved in inflammation. Cell Signal 2022; 93:110294. [PMID: 35218908 PMCID: PMC9536022 DOI: 10.1016/j.cellsig.2022.110294] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/06/2022] [Accepted: 02/21/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Inflammatory bowel diseases (IBD) result in chronic inflammation of the gastrointestinal tract. Genetic studies have shown that the GPR65 gene, as well as its missense coding variant, GPR65*Ile231Leu, is associated with IBD. We aimed to define the signalling and biological pathways downstream of GPR65 activation and evaluate the impact of GPR65*231Leu on these. METHODS We used HEK 293 cells stably expressing GPR65 and deficient for either Gαs, Gαq/11 or Gα12/13, to define GPR65 signalling pathways, IBD patient biopsies and a panel of human tissues, primary immune cells and cell lines to determine biologic context, and genetic modulation of human THP-1-derived macrophages to examine the impact of GPR65 in bacterial phagocytosis and NLRP3 inflammasome activation. RESULTS We confirmed that GPR65 signals via the Gαs pathway, leading to cAMP accumulation. GPR65 can also signal via the Gα12/13 pathway leading to formation of stress fibers, actin remodeling and RhoA activation; all impaired by the IBD-associated GPR65*231Leu allele. Gene expression profiling revealed greater expression of GPR65 in biopsies from inflamed compared to non-inflamed tissues from IBD patients or control individuals, potentially explained by infiltration of inflammatory immune cells. Decreased GPR65 expression in THP-1-derived macrophages leads to impaired bacterial phagocytosis, increased NLRP3 inflammasome activation and IL-1β secretion in response to an inflammatory stimulus. CONCLUSIONS We demonstrate that GPR65 exerts its effects through Gαs- and Gα12/13-mediated pathways, that the IBD-associated GPR65*231Leu allele has compromised interactions with Gα12/13 and that KD of GPR65 leads to impaired bacterial phagocytosis and increased inflammatory signalling via the NLRP3 inflammasome. This work identifies a target for development of small molecule therapies.
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26
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Li Y, Gao H, Yu R, Zhang Y, Feng F, Tang J, Li B. Identification and characterization of G protein-coupled receptors in Spodoptera frugiperda (Insecta: Lepidoptera). Gen Comp Endocrinol 2022; 317:113976. [PMID: 35016911 DOI: 10.1016/j.ygcen.2022.113976] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/23/2021] [Accepted: 01/05/2022] [Indexed: 12/13/2022]
Abstract
Spodoptera frugiperda (Insecta: Lepidoptera) is a destructive invasive pest feeding on various plants and causing serious damage to several economically-important crops. G protein-coupled receptors (GPCRs) are cellular receptors that coordinate diverse signaling processes, associated with many physiological processes and disease states. However, less information about GPCRs had been reported in S. frugiperda, limiting the recognition of signaling system and in-depth studies of this pest. Here, a total of 167 GPCRs were identified in S. frugiperda. Compared with other insects, the GPCRs of S. frugiperda were significantly expanded. A large of tandem duplication and segmental duplication events were observed, which may be the key factor to increase the size of GPCR family. In detail, these expansion events mainly concentrate on biogenic amine receptors, neuropeptide and protein hormone receptors, which may be involved in feeding, reproduction, life span, and tolerance of S. frugiperda. Additionally, 17 Mth/Mthl members were identified in S. frugiperda, which may be similar to the evolutionary pattern of 16 Mth/Mthl members in Drosophila. Moreover, the expression patterns across different developmental stages of all GPCR genes were also analyzed. Among these, most of the GPCR genes are poorly expressed in S. frugiperda and some highly expressed GPCR genes help S. frugiperda adapt to the environment better, such as Rh6 and AkhR. In this study, all GPCRs in S. frugiperda were identified for the first time, which provided a basis for further revealing the role of these receptors in the physiological and behavioral regulation of this pest.
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Affiliation(s)
- Yanxiao Li
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China
| | - Han Gao
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China
| | - Runnan Yu
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China
| | - Yonglei Zhang
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China
| | - Fan Feng
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China
| | - Jing Tang
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China
| | - Bin Li
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China.
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Abstract
Inflammatory bowel diseases (IBD) arise from a convergence of genetic risk, environmental factors, and gut microbiota, where each is necessary but not sufficient to cause disease. Emerging evidence supports a bidirectional relationship between disease progression and changes in microbiota membership and function. Thus, the study of the gut microbiome and host-microbe interactions should provide critical insights into disease pathogenesis as well as leads for developing microbiome-based diagnostics and interventions for IBD. In this article, we review the most recent advances in understanding the relationship between the gut microbiota and IBD and highlight the importance of going beyond establishing description and association to gain mechanistic insights into causes and consequences of IBD. The review aims to contextualize recent findings to form conceptional frameworks for understanding the etiopathogenesis of IBD and for the future development of microbiome-based diagnostics and interventions.
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Affiliation(s)
- Yue Shan
- Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA;
| | - Mirae Lee
- Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA; .,Committee on Microbiology, University of Chicago, Chicago, Illinois 60637, USA
| | - Eugene B Chang
- Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA; .,Committee on Microbiology, University of Chicago, Chicago, Illinois 60637, USA
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28
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GPR75: An exciting new target in metabolic syndrome and related disorders. Biochimie 2022; 195:19-26. [DOI: 10.1016/j.biochi.2022.01.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 01/08/2022] [Accepted: 01/13/2022] [Indexed: 12/31/2022]
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29
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Hryhorowicz S, Kaczmarek-Ryś M, Zielińska A, Scott RJ, Słomski R, Pławski A. Endocannabinoid System as a Promising Therapeutic Target in Inflammatory Bowel Disease - A Systematic Review. Front Immunol 2021; 12:790803. [PMID: 35003109 PMCID: PMC8727741 DOI: 10.3389/fimmu.2021.790803] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 11/29/2021] [Indexed: 12/20/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a general term used to describe a group of chronic inflammatory conditions of the gastrointestinal tract of unknown etiology, including two primary forms: Crohn's disease (CD) and ulcerative colitis (UC). The endocannabinoid system (ECS) plays an important role in modulating many physiological processes including intestinal homeostasis, modulation of gastrointestinal motility, visceral sensation, or immunomodulation of inflammation in IBD. It consists of cannabinoid receptors (CB1 and CB2), transporters for cellular uptake of endocannabinoid ligands, endogenous bioactive lipids (Anandamide and 2-arachidonoylglycerol), and the enzymes responsible for their synthesis and degradation (fatty acid amide hydrolase and monoacylglycerol lipase), the manipulation of which through agonists and antagonists of the system, shows a potential therapeutic role for ECS in inflammatory bowel disease. This review summarizes the role of ECS components on intestinal inflammation, suggesting the advantages of cannabinoid-based therapies in inflammatory bowel disease.
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MESH Headings
- Animals
- Anti-Inflammatory Agents/pharmacology
- Anti-Inflammatory Agents/therapeutic use
- Cannabinoid Receptor Agonists/pharmacology
- Cannabinoid Receptor Agonists/therapeutic use
- Cannabinoid Receptor Antagonists/pharmacology
- Cannabinoid Receptor Antagonists/therapeutic use
- Colitis, Ulcerative/drug therapy
- Colitis, Ulcerative/immunology
- Colitis, Ulcerative/pathology
- Crohn Disease/drug therapy
- Crohn Disease/immunology
- Crohn Disease/pathology
- Disease Models, Animal
- Drug Evaluation, Preclinical
- Endocannabinoids/agonists
- Endocannabinoids/antagonists & inhibitors
- Endocannabinoids/metabolism
- Gastrointestinal Motility/drug effects
- Humans
- Intestinal Mucosa/drug effects
- Intestinal Mucosa/immunology
- Intestinal Mucosa/pathology
- Randomized Controlled Trials as Topic
- Receptor, Cannabinoid, CB1/agonists
- Receptor, Cannabinoid, CB1/antagonists & inhibitors
- Receptor, Cannabinoid, CB1/metabolism
- Receptor, Cannabinoid, CB2/agonists
- Receptor, Cannabinoid, CB2/antagonists & inhibitors
- Receptor, Cannabinoid, CB2/metabolism
- Signal Transduction/drug effects
- Signal Transduction/immunology
- Treatment Outcome
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Affiliation(s)
| | | | | | - Rodney J. Scott
- Discipline of Medical Genetics and Centre for Information-Based Medicine, The University of Newcastle and Hunter Medical Research Institute, Newcastle, NSW, Australia
- Division of Molecular Medicine, New South Wales Health Pathology North, Newcastle, NSW, Australia
| | - Ryszard Słomski
- Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland
| | - Andrzej Pławski
- Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland
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30
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Zeng Z, Ma C, Chen K, Jiang M, Vasu R, Liu R, Zhao Y, Zhang H. Roles of G Protein-Coupled Receptors (GPCRs) in Gastrointestinal Cancers: Focus on Sphingosine 1-Shosphate Receptors, Angiotensin II Receptors, and Estrogen-Related GPCRs. Cells 2021; 10:2988. [PMID: 34831211 PMCID: PMC8616429 DOI: 10.3390/cells10112988] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 10/19/2021] [Accepted: 10/20/2021] [Indexed: 02/05/2023] Open
Abstract
It is well established that gastrointestinal (GI) cancers are common and devastating diseases around the world. Despite the significant progress that has been made in the treatment of GI cancers, the mortality rates remain high, indicating a real need to explore the complex pathogenesis and develop more effective therapeutics for GI cancers. G protein-coupled receptors (GPCRs) are critical signaling molecules involved in various biological processes including cell growth, proliferation, and death, as well as immune responses and inflammation regulation. Substantial evidence has demonstrated crucial roles of GPCRs in the development of GI cancers, which provided an impetus for further research regarding the pathophysiological mechanisms and drug discovery of GI cancers. In this review, we mainly discuss the roles of sphingosine 1-phosphate receptors (S1PRs), angiotensin II receptors, estrogen-related GPCRs, and some other important GPCRs in the development of colorectal, gastric, and esophageal cancer, and explore the potential of GPCRs as therapeutic targets.
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Affiliation(s)
- Zhen Zeng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 410061, China; (Z.Z.); (C.M.); (K.C.); (M.J.)
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 410061, China
| | - Chunxiang Ma
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 410061, China; (Z.Z.); (C.M.); (K.C.); (M.J.)
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 410061, China
| | - Kexin Chen
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 410061, China; (Z.Z.); (C.M.); (K.C.); (M.J.)
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 410061, China
| | - Mingshan Jiang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 410061, China; (Z.Z.); (C.M.); (K.C.); (M.J.)
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 410061, China
| | - Reshma Vasu
- West China School of Medicine, Sichuan University, Chengdu 410061, China;
| | - Rui Liu
- Key Laboratory of Green Chemistry & Technology, College of Chemistry, Sichuan University, Chengdu 610064, China;
| | - Yinglan Zhao
- Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China;
| | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 410061, China; (Z.Z.); (C.M.); (K.C.); (M.J.)
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 410061, China
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Manoharan I, Prasad PD, Thangaraju M, Manicassamy S. Lactate-Dependent Regulation of Immune Responses by Dendritic Cells and Macrophages. Front Immunol 2021; 12:691134. [PMID: 34394085 PMCID: PMC8358770 DOI: 10.3389/fimmu.2021.691134] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 07/14/2021] [Indexed: 12/28/2022] Open
Abstract
For decades, lactate has been considered an innocuous bystander metabolite of cellular metabolism. However, emerging studies show that lactate acts as a complex immunomodulatory molecule that controls innate and adaptive immune cells’ effector functions. Thus, recent advances point to lactate as an essential and novel signaling molecule that shapes innate and adaptive immune responses in the intestine and systemic sites. Here, we review these recent advances in the context of the pleiotropic effects of lactate in regulating diverse functions of immune cells in the tissue microenvironment and under pathological conditions.
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Affiliation(s)
- Indumathi Manoharan
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States.,Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Puttur D Prasad
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Muthusamy Thangaraju
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Santhakumar Manicassamy
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States.,Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United States.,Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States
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32
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The Intestinal Fatty Acid-Enteroendocrine Interplay, Emerging Roles for Olfactory Signaling and Serotonin Conjugates. Molecules 2021; 26:molecules26051416. [PMID: 33807994 PMCID: PMC7961910 DOI: 10.3390/molecules26051416] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/19/2021] [Accepted: 02/25/2021] [Indexed: 12/11/2022] Open
Abstract
Intestinal enteroendocrine cells (EECs) respond to fatty acids from dietary and microbial origin by releasing neurotransmitters and hormones with various paracrine and endocrine functions. Much has become known about the underlying signaling mechanisms, including the involvement of G-protein coupled receptors (GPCRs), like free fatty acids receptors (FFARs). This review focusses on two more recently emerging research lines: the roles of odorant receptors (ORs), and those of fatty acid conjugates in gut. Odorant receptors belong to a large family of GPCRs with functional roles that only lately have shown to reach beyond the nasal-oral cavity. In the intestinal tract, ORs are expressed on serotonin (5-HT) and glucagon-like-peptide-1 (GLP-1) producing enterochromaffin and enteroendocrine L cells, respectively. There, they appear to function as chemosensors of microbiologically produced short-, and branched-chain fatty acids. Another mechanism of fatty acid signaling in the intestine occurs via their conjugates. Among them, conjugates of unsaturated long chain fatty acids and acetate with 5-HT, N-acyl serotonins have recently emerged as mediators with immune-modulatory effects. In this review, novel findings in mechanisms and molecular players involved in intestinal fatty acid biology are highlighted and their potential relevance for EEC-mediated signaling to the pancreas, immune system, and brain is discussed.
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33
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Yang M, Zhang CY. G protein-coupled receptors as potential targets for nonalcoholic fatty liver disease treatment. World J Gastroenterol 2021; 27:677-691. [PMID: 33716447 PMCID: PMC7934005 DOI: 10.3748/wjg.v27.i8.677] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/24/2020] [Accepted: 01/21/2021] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a broad-spectrum disease, ranging from simple hepatic steatosis to nonalcoholic steatohepatitis, which can progress to cirrhosis and liver cancer. Abnormal hepatic lipid accumulation is the major manifestation of this disease, and lipotoxicity promotes NAFLD progression. In addition, intermediate metabolites such as succinate can stimulate the activation of hepatic stellate cells to produce extracellular matrix proteins, resulting in progression of NAFLD to fibrosis and even cirrhosis. G protein-coupled receptors (GPCRs) have been shown to play essential roles in metabolic disorders, such as NAFLD and obesity, through their function as receptors for bile acids and free fatty acids. In addition, GPCRs link gut microbiota-mediated connections in a variety of diseases, such as intestinal diseases, hepatic steatosis, diabetes, and cardiovascular diseases. The latest findings show that gut microbiota-derived acetate contributes to liver lipogenesis by converting dietary fructose into hepatic acetyl-CoA and fatty acids. GPCR agonists, including peptides and natural products like docosahexaenoic acid, have been applied to investigate their role in liver diseases. Therapies such as probiotics and GPCR agonists may be applied to modulate GPCR function to ameliorate liver metabolism syndrome. This review summarizes the current findings regarding the role of GPCRs in the development and progression of NAFLD and describes some preclinical and clinical studies of GPCR-mediated treatment. Overall, understanding GPCR-mediated signaling in liver disease may provide new therapeutic options for NAFLD.
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Affiliation(s)
- Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
| | - Chun-Ye Zhang
- Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65212, United States
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Hu S, Uniken Venema WT, Westra HJ, Vich Vila A, Barbieri R, Voskuil MD, Blokzijl T, Jansen BH, Li Y, Daly MJ, Xavier RJ, Dijkstra G, Festen EA, Weersma RK. Inflammation status modulates the effect of host genetic variation on intestinal gene expression in inflammatory bowel disease. Nat Commun 2021; 12:1122. [PMID: 33602935 PMCID: PMC7892863 DOI: 10.1038/s41467-021-21458-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 01/22/2021] [Indexed: 12/12/2022] Open
Abstract
More than 240 genetic risk loci have been associated with inflammatory bowel disease (IBD), but little is known about how they contribute to disease development in involved tissue. Here, we hypothesized that host genetic variation affects gene expression in an inflammation-dependent way, and investigated 299 snap-frozen intestinal biopsies from inflamed and non-inflamed mucosa from 171 IBD patients. RNA-sequencing was performed, and genotypes were determined using whole exome sequencing and genome wide genotyping. In total, 28,746 genes and 6,894,979 SNPs were included. Linear mixed models identified 8,881 independent intestinal cis-expression quantitative trait loci (cis-eQTLs) (FDR < 0.05) and interaction analysis revealed 190 inflammation-dependent intestinal cis-eQTLs (FDR < 0.05), including known IBD-risk genes and genes encoding immune-cell receptors and antibodies. The inflammation-dependent cis-eQTL SNPs (eSNPs) mainly interact with prevalence of immune cell types. Inflammation-dependent intestinal cis-eQTLs reveal genetic susceptibility under inflammatory conditions that can help identify the cell types involved in and the pathways underlying inflammation, knowledge that may guide future drug development and profile patients for precision medicine in IBD.
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Affiliation(s)
- Shixian Hu
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Werna T Uniken Venema
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Harm-Jan Westra
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Arnau Vich Vila
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Ruggero Barbieri
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Michiel D Voskuil
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Tjasso Blokzijl
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Bernadien H Jansen
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Yanni Li
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Mark J Daly
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
- Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Ramnik J Xavier
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
- Center for Microbiome Informatics and Therapeutic, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Eleonora A Festen
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
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