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Xiong L, Huang YX, Mao L, Xu Y, Deng YQ. Targeting gut microbiota and its associated metabolites as a potential strategy for promoting would healing in diabetes. World J Diabetes 2025; 16:98788. [DOI: 10.4239/wjd.v16.i5.98788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 01/03/2025] [Accepted: 03/05/2025] [Indexed: 04/25/2025] Open
Abstract
Impaired healing of diabetic wounds is one of the most important complications of diabetes, often leading to lower limb amputations and incurring significant economic and psychosocial costs. Unfortunately, there are currently no effective prevention or treatment strategies available. Recent research has reported that an imbalance in the gut microbiota, known as dysbiosis, was linked to the onset of type 2 diabetes, as well as the development and progression of diabetic complications. Indeed, the gut microbiota has emerged as a promising therapeutic approach for treating type 2 diabetes and related diseases. However, there is few of literatures specifically discussing the relationship between gut microbiota and diabetic wounds. This review aims to explore the potential role of the gut microbiota, especially probiotics, and its associated byproducts such as short chain fatty acids, bile acids, hydrogen sulfide, and tryptophan metabolites on wound healing to provide fresh insights and novel perspectives for the treatment of chronic wounds in diabetes.
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Affiliation(s)
- Ling Xiong
- Department of Dermatology & STD, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Ya-Xin Huang
- Department of Dermatology & STD, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Lan Mao
- Department of Dermatology & STD, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Yong Xu
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Yong-Qiong Deng
- Department of Dermatology & STD, Chengdu Integrated TCM & Western Medicine Hospital, Chengdu 610000, Sichuan Province, China
- Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, Sichuan Province, China
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Chen J, Qu B, Yang D, Wang Y, Zhu H, Wang Z, Zhang X, Ma H, Zhao N, Zhao L, Zhou L, He X, Li P. Combined metabolomics and network pharmacology to elucidate the mechanisms of Huiyang Shengji decoction in treating diabetic skin ulcer mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 141:156569. [PMID: 40120541 DOI: 10.1016/j.phymed.2025.156569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/17/2025] [Accepted: 02/24/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUND Diabetic skin ulcer is a clinical disorder of glucose metabolism that has a long treatment period and is prone to recurrent episodes. Huiyang Shengji decoction (HYSJD) is an effective traditional Chinese medicine for its clinical treatment, but its metabolic effects in patients with diabetic skin ulcers have not been well studied. PURPOSE Our study aimed to investigate the mechanism of pharmacological treatment of HYSJD in treating diabetic skin ulcers. METHODS The potential mechanism underlying diabetic wound treatment by HYSJD was screened using network pharmacology. Ultra-high performance liquid chromatography-MS/MS metabolomics analysis and correlation analysis were performed to investigate potential target pathways and genes. Furthermore, the db/db diabetic wound tissues and RAW264.7 macrophage inflammation model verified the mechanism using molecular biology experiments. RESULTS In network pharmacology, HYSJD played a mainly therapeutic effect by regulating PI3K/AKT signaling pathway, EGFR tyrosine kinase inhibitor resistance, metabolic pathway, and other related metabolic-related pathways. Metabolomics analysis disclosed that L-lysine content increased, while those of linoleic and deoxycholic acids decreased in plasma between the HYSJD-treated group and the control group, participating in biotin metabolism. Among them, PPARγ played an important role. The experiments conducted in db/db mice indicated that HYSJD facilitates VEGF secretion and PPARγ expression. In vitro experiments have revealed that HYSJD inhibits macrophage ROS production, augments mitochondrial ATP production, elevates mitochondrial membrane potential, and diminishes the mitochondrial ECAR rate. Furthermore, these effects culminate in promoting M2 macrophage polarization through PPARγ activation. The molecular docking results revealed that the active compounds from HYSJD were capable of binding to PPARγ protein primarily through hydrogen bonding interactions. Notably, all binding energies were found to be lower than -3 kcal/mol, indicating strong and favorable interactions between the active compounds and the target receptor. CONCLUSIONS The findings suggested that HYSJD regulates biotin metabolism by reducing excess levels of linoleic and deoxycholic acids and increasing levels of L-lysine, which in turn promotes diabetic wound healing by promoting M2 macrophage polarization through PPARγ up-regulation. These findings indicated that HYSJD is a decoction that can effectively treat diabetic skin ulcers.
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Affiliation(s)
- Jia Chen
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China; Wuhan Hospital of Traditional Chinese and Western Medicine, Wuhan, 430022, China
| | - Baoquan Qu
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Danyang Yang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Yazhuo Wang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Haoyue Zhu
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Zhengchun Wang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Xiawei Zhang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Huike Ma
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Ning Zhao
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Li Zhao
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China; Wuhan Hospital of Traditional Chinese and Western Medicine, Wuhan, 430022, China
| | - Lijiaming Zhou
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Xiujuan He
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China.
| | - Ping Li
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China.
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Pan S, Yan H, Zhu J, Ma Y, Wang P, Liu Y, Chen Z. GYY4137, as a slow-releasing H 2S donor, ameliorates sodium deoxycholate-induced chronic intestinal barrier injury and gut microbiota dysbiosis. Front Pharmacol 2024; 15:1476407. [PMID: 39508040 PMCID: PMC11539038 DOI: 10.3389/fphar.2024.1476407] [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: 08/05/2024] [Accepted: 10/09/2024] [Indexed: 11/08/2024] Open
Abstract
Introduction Numerous studies have revealed that a long-term high-fat diet can raise intestinal deoxycholate acid concentration, which can harm intestinal mucosal barrier function in several ways. This study aims to verify the protective effect of GYY4137, as a slow-releasing H2S donor, on microbiome disturbance and the chronic injury of the intestinal mucosal barrier function caused by sodium deoxycholate. Methods Caco-2 monolayer and mouse models were treated with a relatively high concentration of sodium deoxycholate (1.0 mM and 0.2%, respectively) for longer periods (32 h and 12 weeks, respectively) to understand the effects of GYY4137 on sodium deoxycholate-induced chronic intestinal barrier dysfunction and its fundamental mechanisms. Results A relatively long period of sodium deoxycholate treatment can remarkably increase the intestinal barrier permeability, alter the distribution and expression of tight junction proteins and generate the production of pro-inflammatory cytokines (TNF-α and IL-1β) in the Caco-2 monolayers and mouse models. Moreover, it can activate the MLCK-P-MLC2 pathway in the Caco-2 monolayers, which was further confirmed using RNA sequencing. The body weight, intestinal barrier histological score, and TUNEL index of sodium deoxycholate-treated mice worsened. In addition, an induced microbiome imbalance was observed in these mice. The above variations can be reversed with the administration of GYY4137. Conclusion This study demonstrates that GYY4137 ameliorates sodium deoxycholate-induced chronic intestinal barrier injury by restricting the MLCK-P-MLC2 pathway while elevating the expression level of tight junction proteins, anti-apoptosis and maintaining the microbiome's homeostasis.
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Affiliation(s)
- Shaorong Pan
- Department of Gastrointestinal Surgery, Peking University First Hospital, Peking University, Beijing, China
| | - Han Yan
- Department of Gastrointestinal Surgery, Peking University First Hospital, Peking University, Beijing, China
| | - Jing Zhu
- Department of Gastrointestinal Surgery, Peking University First Hospital, Peking University, Beijing, China
| | - Yuanyuan Ma
- Animal Experiment Center, Peking University First Hospital, Peking University, Beijing, China
| | - Pengyuan Wang
- Department of Gastrointestinal Surgery, Peking University First Hospital, Peking University, Beijing, China
| | - Yucun Liu
- Department of Gastrointestinal Surgery, Peking University First Hospital, Peking University, Beijing, China
| | - Zeyang Chen
- Department of Gastrointestinal Surgery, Peking University First Hospital, Peking University, Beijing, China
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Rojas CA, Park B, Scarsella E, Jospin G, Entrolezo Z, Jarett JK, Martin A, Ganz HH. Species-level characterization of the core microbiome in healthy dogs using full-length 16S rRNA gene sequencing. Front Vet Sci 2024; 11:1405470. [PMID: 39286595 PMCID: PMC11404154 DOI: 10.3389/fvets.2024.1405470] [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: 03/22/2024] [Accepted: 08/09/2024] [Indexed: 09/19/2024] Open
Abstract
Despite considerable interest and research in the canine fecal microbiome, our understanding of its species-level composition remains incomplete, as the majority of studies have only provided genus-level resolution. Here, we used full-length 16S rRNA gene sequencing to characterize the fecal microbiomes of 286 presumed healthy dogs living in homes in North America who are devoid of clinical signs, physical conditions, medication use, and behavioral problems. We identified the bacterial species comprising the core microbiome and investigated whether a dog's sex & neuter status, age, body weight, diet, and geographic region predicted microbiome variation. Our analysis revealed that 23 bacterial species comprised the core microbiome, among them Collinsella intestinalis, Megamonas funiformis, Peptacetobacter hiranonis, Prevotella copri, and Turicibacter sanguinis. The 23 taxa comprised 75% of the microbiome on average. Sterilized females, dogs of intermediate body sizes, and those exclusively fed kibble tended to harbor the most core taxa. Host diet category, geographic region, and body weight predicted microbiome beta-diversity, but the effect sizes were modest. Specifically, the fecal microbiomes of dogs fed kibble were enriched in several core taxa, including C. intestinalis, P. copri, and Holdemanella biformis, compared to those fed raw or cooked food. Conversely, dogs on a raw food diet exhibited higher abundances of Bacteroides vulgatus, Caballeronia sordicola, and Enterococcus faecium, among others. In summary, our study provides novel insights into the species-level composition and drivers of the fecal microbiome in healthy dogs living in homes; however, extrapolation of our findings to different dog populations will require further study.
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Feng Y, Pan M, Li R, He W, Chen Y, Xu S, Chen H, Xu H, Lin Y. Recent developments and new directions in the use of natural products for the treatment of inflammatory bowel disease. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 132:155812. [PMID: 38905845 DOI: 10.1016/j.phymed.2024.155812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 05/13/2024] [Accepted: 06/06/2024] [Indexed: 06/23/2024]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) represents a significant global health challenge, and there is an urgent need to explore novel therapeutic interventions. Natural products have demonstrated highly promising effectiveness in the treatment of IBD. PURPOSE This study systematically reviews the latest research advancements in leveraging natural products for IBD treatment. METHODS This manuscript strictly adheres to the PRISMA guidelines. Relevant literature on the effects of natural products on IBD was retrieved from the PubMed, Web of Science and Cochrane Library databases using the search terms "natural product," "inflammatory bowel disease," "colitis," "metagenomics", "target identification", "drug delivery systems", "polyphenols," "alkaloids," "terpenoids," and so on. The retrieved data were then systematically summarized and reviewed. RESULTS This review assessed the different effects of various natural products, such as polyphenols, alkaloids, terpenoids, quinones, and others, in the treatment of IBD. While these natural products offer promising avenues for IBD management, they also face challenges in terms of clinical translation and drug discovery. The advent of metagenomics, single-cell sequencing, target identification techniques, drug delivery systems, and other cutting-edge technologies heralds a new era in overcoming these challenges. CONCLUSION This paper provides an overview of current research progress in utilizing natural products for the treatment of IBD, exploring how contemporary technological innovations can aid in discovering and harnessing bioactive natural products for the treatment of IBD.
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Affiliation(s)
- Yaqian Feng
- Fujian-Macao Science and Technology Cooperation Base of Traditional Chinese Medicine-Oriented Chronic Disease Prevention and Treatment, Innovation and Transformation Center, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China
| | - Mengting Pan
- Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China
| | - Ruiqiong Li
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China
| | - Weishen He
- Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Yangyang Chen
- Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China
| | - Shaohua Xu
- Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Hui Chen
- Department of Gastroenterology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350004, China.
| | - Huilong Xu
- Institute of Structural Pharmacology & TCM Chemical Biology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
| | - Yao Lin
- Fujian-Macao Science and Technology Cooperation Base of Traditional Chinese Medicine-Oriented Chronic Disease Prevention and Treatment, Innovation and Transformation Center, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China.
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Medina-Rodríguez EM, Martínez-Raga J, Sanz Y. Intestinal Barrier, Immunity and Microbiome: Partners in the Depression Crime. Pharmacol Rev 2024; 76:956-969. [PMID: 39084934 DOI: 10.1124/pharmrev.124.001202] [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: 01/30/2024] [Revised: 05/28/2024] [Accepted: 05/29/2024] [Indexed: 08/02/2024] Open
Abstract
Depression is a highly prevalent disorder and a leading cause of disability worldwide. It has a major impact on the affected individual and on society as a whole. Regrettably, current available treatments for this condition are insufficient in many patients. In recent years, the gut microbiome has emerged as a promising alternative target for treating and preventing depressive disorders. However, the microbes that form this ecosystem do not act alone but are part of a complicated network connecting the gut and the brain that influences our mood. Host cells that are in intimate contact with gut microbes, such as the epithelial cells forming the gut barrier and the immune cells in their vicinity, play a key role in the process. These cells continuously shape immune responses to maintain healthy communication between gut microbes and the host. In this article, we review how the interplay among epithelial cells, the immune system, and gut microbes mediates gut-brain communication to influence mood. We also discuss how advances in our knowledge of the mechanisms underlying the gut-brain axis could contribute to addressing depression. SIGNIFICANCE STATEMENT: This review does not aim to systematically describe intestinal microbes that might be beneficial or detrimental for depression. We have adopted a novel point of view by focusing on potential mechanisms underlying the crosstalk between gut microbes and their intestinal environment to control mood. These pathways could be targeted by well defined and individually tailored dietary interventions, microbes, or microbial metabolites to ameliorate depression and decrease its important social and economic impact.
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Affiliation(s)
- Eva M Medina-Rodríguez
- Psychiatry Service, Doctor Peset University Hospital, FISABIO, Valencia, Spain (E.M.M.-R., J.M.-R.); Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain (E.M.M.-R., Y.S.); and University of Valencia, Valencia, Spain (J.M.-R.)
| | - José Martínez-Raga
- Psychiatry Service, Doctor Peset University Hospital, FISABIO, Valencia, Spain (E.M.M.-R., J.M.-R.); Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain (E.M.M.-R., Y.S.); and University of Valencia, Valencia, Spain (J.M.-R.)
| | - Yolanda Sanz
- Psychiatry Service, Doctor Peset University Hospital, FISABIO, Valencia, Spain (E.M.M.-R., J.M.-R.); Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain (E.M.M.-R., Y.S.); and University of Valencia, Valencia, Spain (J.M.-R.)
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Srimai N, Tonum K, Soodvilai S. Activation of farnesoid X receptor retards expansion of renal collecting duct cell-derived cysts via inhibition of CFTR-mediated Cl - secretion. Am J Physiol Renal Physiol 2024; 326:F600-F610. [PMID: 38299213 DOI: 10.1152/ajprenal.00363.2023] [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: 11/07/2023] [Revised: 01/12/2024] [Accepted: 01/29/2024] [Indexed: 02/02/2024] Open
Abstract
The transcription factor farnesoid X receptor (FXR) regulates energy metabolism. Specifically, FXR functions to regulate cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl- secretion in intestinal epithelial cells. Therefore, this study aimed to investigate the role of FXR in CFTR-mediated Cl- secretion in renal tubular cells and to further elucidate its effects on renal cyst formation and growth. CFTR-mediated Cl- transport was evaluated via short-circuit current (ISC) measurements in Madin-Darby canine kidney (MDCK) cell monolayers and primary rat inner medullary collecting duct cells. The role of FXR in renal cyst formation and growth was determined by the MDCK cell-derived cyst model. Incubation with synthesized (GW4064) and endogenous (CDCA) FXR ligands reduced CFTR-mediated Cl- secretion in a concentration- and time-dependent manner. The inhibitory effect of FXR ligands was not due to the result of reduced cell viability and was attenuated by cotreatment with an FXR antagonist. FXR activation significantly decreased CFTR protein but not its mRNA. In addition, FXR activation inhibited CFTR-mediated Cl- secretion in primary renal collecting duct cells. FXR activation decreased ouabain-sensitive ISC without altering Na+-K+-ATPase mRNA and protein levels. Furthermore, FXR activation significantly reduced the number of cysts and renal cyst expansion. These inhibitory effects were correlated with a decrease in the expression of protein synthesis regulators mammalian target of rapamycin/S6 kinase. This study shows that FXR activation inhibits Cl- secretion in renal cells via inhibition of CFTR expression and retards renal cyst formation and growth. The discoveries point to a physiological role of FXR in the regulation of CFTR and a potential therapeutic application in polycystic kidney disease treatment.NEW & NOTEWORTHY The present study reveals that farnesoid X receptor (FXR) activation reduces microcyst formation and enlargement. This inhibitory effect of FXR activation is involved with decreased cell proliferation and cystic fibrosis transmembrane conductance regulator-mediated Cl- secretion in renal collecting duct cells. FXR might represent a novel target for the treatment of autosomal dominant polycystic kidney disease.
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Affiliation(s)
- Nipitpon Srimai
- Research Center of Transport Protein for Medical Innovation, Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Kanlayanee Tonum
- Department of Physiology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Sunhapas Soodvilai
- Research Center of Transport Protein for Medical Innovation, Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
- Excellent Center for Drug Discovery, Mahidol University, Bangkok, Thailand
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Jin L, Shi L, Huang W. The role of bile acids in human aging. MEDICAL REVIEW (2021) 2024; 4:154-157. [PMID: 38680685 PMCID: PMC11046569 DOI: 10.1515/mr-2024-0003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 02/20/2024] [Indexed: 05/01/2024]
Abstract
Bile acids are recognized as important signaling molecules that enable fine-tuned inter-communication from the liver, through the intestine, to virtually any organ, thus encouraging their pleiotropic physiological effects. Aging is a complex natural process defined as a progressive decline in cellular and organismal functions. A causal link between bile acids and the aging process is emerging. However, there are gaps in our understanding of the molecular mechanisms and precise targets responsible for the alteration of bile acid profiles and their role in the aging process. Intestinal barrier dysfunction leads to endotoxemia, systemic inflammation, insulin resistance, diabetes, lipid accumulation, obesity and fatty liver diseases, and health decline and death. In fact, intestinal barrier dysfunction is suggested to be an evolutionarily conserved hallmark of aging. Bile acids may modulate the aging process by regulating intestinal barrier integrity.
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Affiliation(s)
- Lihua Jin
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, institution-id-type="Ringgold" />City of Hope National Medical Center, Duarte, CA, USA
| | - Linsen Shi
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, institution-id-type="Ringgold" />City of Hope National Medical Center, Duarte, CA, USA
| | - Wendong Huang
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, institution-id-type="Ringgold" />City of Hope National Medical Center, Duarte, CA, USA
- Irell & Manella Graduate School of Biomedical Science, institution-id-type="Ringgold" />City of Hope National Medical Center, Duarte, CA, USA
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Kovacevic B, Ionescu CM, Jones M, Wagle SR, Foster T, Lewkowicz M, Wong EY, Ðanić M, Mikov M, Mooranian A, Al-Salami H. Novel polysaccharides-bile acid-cyclodextrin gel systems and effects on cellular viability and bioenergetic parameters. Ther Deliv 2024; 15:119-134. [PMID: 38180012 DOI: 10.4155/tde-2023-0063] [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] [Indexed: 01/06/2024] Open
Abstract
Aim: The novel hydrogel systems made from sodium alginate, pectin, beta-cyclodextrin and deoxycholic acid (DCA) were proposed as potential drug-delivery matrices. Materials & methods: To ensure biocompatibility, rheological parameters were examined and hydrogels' effects on bioenergetic parameters and cellular viability on murine hepatic, and muscle and pancreatic beta cells. Results & conclusion: All hydrogels show non-Newtonian, shear thinning behavior. Cells displayed various oxygen-dependent viability patterns, with the bile acid overall adversely affecting their biological activities. All cells performed best under normoxia, with pancreatic beta cells displaying the most profound oxygen-dependent viability behavior. The cells tolerated the addition of a moderate concentration of beta-cyclodextrin to the polymer matrix.
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Affiliation(s)
- Bozica Kovacevic
- The Biotechnology & Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, WA 6102, Australia
| | - Corina Mihaela Ionescu
- The Biotechnology & Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, WA 6102, Australia
| | - Melissa Jones
- The Biotechnology & Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, WA 6102, Australia
| | - Susbin Raj Wagle
- The Biotechnology & Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, WA 6102, Australia
| | - Thomas Foster
- The Biotechnology & Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, WA 6102, Australia
| | - Michael Lewkowicz
- The Biotechnology & Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, WA 6102, Australia
| | - Elaine Ym Wong
- Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Nedlands, Perth, WA 6009, Australia
| | - Maja Ðanić
- Department of Pharmacology, Toxicology & Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, 21101, Serbia
| | - Momir Mikov
- Department of Pharmacology, Toxicology & Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, 21101, Serbia
| | - Armin Mooranian
- The Biotechnology & Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, WA 6102, Australia
| | - Hani Al-Salami
- The Biotechnology & Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, WA 6102, Australia
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Huang RL, Huang WK, Xiao XY, Ma LF, Gu HZR, Yang GP. Diagnosis and treatment of post-cholecystectomy diarrhoea. World J Gastrointest Surg 2023; 15:2398-2405. [PMID: 38111762 PMCID: PMC10725554 DOI: 10.4240/wjgs.v15.i11.2398] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/22/2023] [Accepted: 09/22/2023] [Indexed: 11/26/2023] Open
Abstract
The incidence of cholecystitis is relatively high in developed countries and may usually be attributed to gallstones, the treatment for which involves complete surgical removal of the gallbladder (cholecystectomy). Bile acids produced following cholecystectomy continue to flow into the duodenum but are poorly absorbed by the colon. Excessive bile acids in the colon stimulate mucosal secretion of water and electrolytes leading, in severe cases, to diarrhoea. Bile acid diarrhoea (BAD) is difficult to diagnose, requiring a comprehensive medical history and physical examination in combination with laboratory evaluation. The current work reviews the diagnosis and treatment of BAD following cholecystectomy.
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Affiliation(s)
- Rang-Lang Huang
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of The Central South University, Changsha 410013, Hunan Province, China
| | - Wen-Kai Huang
- Department of General Medicine, The Third Xiangya Hospital of The Central South University, Changsha 410013, Hunan Province, China
| | - Xiang-Yi Xiao
- The Xiangya School of Medicine, The Central South University, Changsha 410013, Hunan Province, China
| | - Lin-Feng Ma
- The Xiangya School of Medicine, The Central South University, Changsha 410013, Hunan Province, China
| | - He-Zi-Rui Gu
- The Xiangya School of Medicine, The Central South University, Changsha 410013, Hunan Province, China
| | - Guo-Ping Yang
- Department of Clinical Pharmacy, The Third Hospital of The Central South University, Changsha 410013, Hunan Province, China
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Di Ciaula A, Bonfrate L, Khalil M, Portincasa P. The interaction of bile acids and gut inflammation influences the pathogenesis of inflammatory bowel disease. Intern Emerg Med 2023; 18:2181-2197. [PMID: 37515676 PMCID: PMC10635993 DOI: 10.1007/s11739-023-03343-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 06/08/2023] [Indexed: 07/31/2023]
Abstract
Bile acids (BA) are amphipathic molecules originating from cholesterol in the liver and from microbiota-driven biotransformation in the colon. In the gut, BA play a key role in fat digestion and absorption and act as potent signaling molecules on the nuclear farnesoid X receptor (FXR) and membrane-associated G protein-coupled BA receptor-1 (GPBAR-1). BA are, therefore, involved in the maintenance of gut barrier integrity, gene expression, metabolic homeostasis, and microbiota profile and function. Disturbed BA homeostasis can activate pro-inflammatory pathways in the gut, while inflammatory bowel diseases (IBD) can induce gut dysbiosis and qualitative and/or quantitative changes of the BA pool. These factors contribute to impaired repair capacity of the mucosal barrier, due to chronic inflammation. A better understanding of BA-dependent mechanisms paves the way to innovative therapeutic tools by administering hydrophilic BA and FXR agonists and manipulating gut microbiota with probiotics and prebiotics. We discuss the translational value of pathophysiological and therapeutic evidence linking BA homeostasis to gut inflammation in IBD.
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Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy
| | - Leonilde Bonfrate
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy.
| | - Mohamad Khalil
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy
| | - Piero Portincasa
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy
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12
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Long XQ, Liu MZ, Liu ZH, Xia LZ, Lu SP, Xu XP, Wu MH. Bile acids and their receptors: Potential therapeutic targets in inflammatory bowel disease. World J Gastroenterol 2023; 29:4252-4270. [PMID: 37545642 PMCID: PMC10401658 DOI: 10.3748/wjg.v29.i27.4252] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 05/19/2023] [Accepted: 06/21/2023] [Indexed: 07/13/2023] Open
Abstract
Chronic and recurrent inflammatory disorders of the gastrointestinal tract caused by a complex interplay between genetics and intestinal dysbiosis are called inflammatory bowel disease. As a result of the interaction between the liver and the gut microbiota, bile acids are an atypical class of steroids produced in mammals and traditionally known for their function in food absorption. With the development of genomics and metabolomics, more and more data suggest that the pathophysiological mechanisms of inflammatory bowel disease are regulated by bile acids and their receptors. Bile acids operate as signalling molecules by activating a variety of bile acid receptors that impact intestinal flora, epithelial barrier function, and intestinal immunology. Inflammatory bowel disease can be treated in new ways by using these potential molecules. This paper mainly discusses the increasing function of bile acids and their receptors in inflammatory bowel disease and their prospective therapeutic applications. In addition, we explore bile acid metabolism and the interaction of bile acids and the gut microbiota.
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Affiliation(s)
- Xiong-Quan Long
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Ming-Zhu Liu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Zi-Hao Liu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Lv-Zhou Xia
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Shi-Peng Lu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Xiao-Ping Xu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Ming-Hao Wu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
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13
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Shi L, Jin L, Huang W. Bile Acids, Intestinal Barrier Dysfunction, and Related Diseases. Cells 2023; 12:1888. [PMID: 37508557 PMCID: PMC10377837 DOI: 10.3390/cells12141888] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 07/11/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
The intestinal barrier is a precisely regulated semi-permeable physiological structure that absorbs nutrients and protects the internal environment from infiltration of pathological molecules and microorganisms. Bile acids are small molecules synthesized from cholesterol in the liver, secreted into the duodenum, and transformed to secondary or tertiary bile acids by the gut microbiota. Bile acids interact with bile acid receptors (BARs) or gut microbiota, which plays a key role in maintaining the homeostasis of the intestinal barrier. In this review, we summarize and discuss the recent studies on bile acid disorder associated with intestinal barrier dysfunction and related diseases. We focus on the roles of bile acids, BARs, and gut microbiota in triggering intestinal barrier dysfunction. Insights for the future prevention and treatment of intestinal barrier dysfunction and related diseases are provided.
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Affiliation(s)
- Linsen Shi
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Lihua Jin
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Wendong Huang
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
- Irell & Manella Graduate School of Biomedical Science, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
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14
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Tsai PL, Lin YW, Chen JS, Wu SI, Chiang MF, Chen MJ. Cholelithiasis, cholecystitis, cholecystectomy and the associated risk of colorectal cancer. FORMOSAN JOURNAL OF SURGERY 2023; 56:109-115. [DOI: 10.1097/fs9.0000000000000047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2025] Open
Abstract
Abstract
Background
Many studies have suggested that cholelithiasis or cholecystectomy may be associated with risk of colorectal cancer [CRC]. This study aimed to verify CRC risk among cholelithiasis patients who experienced cholecystitis or cholecystectomy or both.
Methods
Data of a cholelithiasis cohort (n = 28,267) and a noncholelithiasis cohort (n = 112,948) were retrieved (1:4 ratio) from the Longitudinal Health Insurance Database for comparison of CRC risk. Confounding factors were adjusted in multivariate analysis. A hospital-based cancer registry containing 8156 CRC patients was also examined. Data were statistically analyzed using χ2 test, t test, and Cox proportional-hazards model.
Results
Univariate and multivariate analysis showed that having cholelithiasis was associated with increased risk of CRC (crude hazard ratio: 1.533 [95% confidence interval {CI}: 1.423–1.652); adjusted HR: 1.481 [95% CI: 1.375–1.597], respectively, p < 0.001) relative to not having cholelithiasis. Increased CRC incidence among patients with cholelithiasis was higher in the right-sided colon (adjusted HR: 1.452 [95% CI: 1.234–1.709], p < 0.001), and higher in female patients. The trend of higher incidence of right-sided colon cancer was also seen in the hospital-based cancer registry. Of note, cholecystitis or cholecystectomy was associated with mildly increased CRC risk among cholelithiasis patients. Cholecystitis was associated with increased risk of left-sided CRC. Cholecystitis plus cholecystectomy was associated with increased risk of rectal cancer.
Conclusions
These results support that cholelithiasis is associated with increased risk of CRC especially in the right-sided colon and among female patients. Cholecystitis and cholecystectomy may shift cancer to the distal part of the large bowel.
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Affiliation(s)
- Po-Li Tsai
- Division of Colorectal Surgery, Department of Surgery, MacKay Memorial Hospital, Taipei, Taiwan
| | - Yu-Wen Lin
- Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan
| | - Jian-Syun Chen
- Division of Colorectal Surgery, Department of Surgery, MacKay Memorial Hospital, Taipei, Taiwan
| | | | - Mei-Feng Chiang
- Department of Nursing, MacKay Memorial Hospital, Taipei, Taiwan
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15
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Novel hydrogel comprising non-ionic copolymer with various concentrations of pharmacologically active bile acids for cellular injectable gel. Colloids Surf B Biointerfaces 2023; 222:113014. [PMID: 36427407 DOI: 10.1016/j.colsurfb.2022.113014] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/19/2022] [Accepted: 11/08/2022] [Indexed: 11/13/2022]
Abstract
Deoxycholic acid (DCA) is a bile acid capable of forming micelles and modifying the properties of hydrogels. We incorporated DCA in sodium alginate (SA) and poloxamer 407 matrices creating novel DCA-copolymer hydrogel for therapeutic delivery. Hydrogels were assessed for common rheological properties. Biocompatibility and biological effect were examined on various cell lines. Cell viability was determent in normal and various hypoxic conditions, and full mitochondrial bioenergetic parameters were assessed in cell lines in order to illustrate hydrogel effects on survival, and cell metabolic profile within the hydrogels. Obtained data suggest that a low dose of DCA in permeable, biocompatible hydrogels can be beneficial for cells to combat hypoxic conditions.
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16
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Zhou M, Wang D, Li X, Cao Y, Yi C, Wiredu Ocansey DK, Zhou Y, Mao F. Farnesoid-X receptor as a therapeutic target for inflammatory bowel disease and colorectal cancer. Front Pharmacol 2022; 13:1016836. [PMID: 36278234 PMCID: PMC9583386 DOI: 10.3389/fphar.2022.1016836] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 09/20/2022] [Indexed: 12/09/2022] Open
Abstract
Farnesoid-X receptor (FXR), as a nuclear receptor activated by bile acids, is a vital molecule involved in bile acid metabolism. Due to its expression in immune cells, FXR has a significant effect on the function of immune cells and the release of chemokines when immune cells sense changes in bile acids. In addition to its regulation by ligands, FXR is also controlled by post-translational modification (PTM) activities such as acetylation, SUMOylation, and methylation. Due to the high expression of FXR in the liver and intestine, it significantly influences intestinal homeostasis under the action of enterohepatic circulation. Thus, FXR protects the intestinal barrier, resists bacterial infection, reduces oxidative stress, inhibits inflammatory reactions, and also acts as a tumor suppressor to impair the multiplication and invasion of tumor cells. These potentials provide new perspectives on the treatment of intestinal conditions, including inflammatory bowel disease (IBD) and its associated colorectal cancer (CRC). Moreover, FXR agonists on the market have certain organizational heterogeneity and may be used in combination with other drugs to achieve a greater therapeutic effect. This review summarizes current data on the role of FXR in bile acid metabolism, regulation of immune cells, and effects of the PTM of FXR. The functions of FXR in intestinal homeostasis and potential application in the treatment of IBD and CRC are discussed.
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Affiliation(s)
- Mengjiao Zhou
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Danfeng Wang
- Nanjing Jiangning Hospital, Nanjing, Jiangsu, China
| | - Xiang Li
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Ying Cao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Chengxue Yi
- School of Medical Technology, Zhenjiang College, Zhenjiang, Jiangsu, China
| | - Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
- Directorate of University Health Services, University of Cape Coast, Cape Coast, Ghana
| | - Yuling Zhou
- Nanjing Jiangning Hospital, Nanjing, Jiangsu, China
- *Correspondence: Yuling Zhou, ; Fei Mao,
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
- *Correspondence: Yuling Zhou, ; Fei Mao,
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17
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Zhang D, Liu J, Cheng H, Wang H, Tan Y, Feng W, Peng C. Interactions between polysaccharides and gut microbiota: A metabolomic and microbial review. Food Res Int 2022; 160:111653. [DOI: 10.1016/j.foodres.2022.111653] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 07/05/2022] [Accepted: 07/06/2022] [Indexed: 12/17/2022]
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18
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Jiang X, Jiang Z, Cheng Q, Sun W, Jiang M, Sun Y. Cholecystectomy promotes the development of colorectal cancer by the alternation of bile acid metabolism and the gut microbiota. Front Med (Lausanne) 2022; 9:1000563. [PMID: 36213655 PMCID: PMC9540502 DOI: 10.3389/fmed.2022.1000563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 09/06/2022] [Indexed: 12/24/2022] Open
Abstract
The incidence and mortality of colorectal cancer (CRC) have been markedly increasing worldwide, causing a tremendous burden to the healthcare system. Therefore, it is crucial to investigate the risk factors and pathogenesis of CRC. Cholecystectomy is a gold standard procedure for treating symptomatic cholelithiasis and gallstone diseases. The rhythm of bile acids entering the intestine is altered after cholecystectomy, which leads to metabolic disorders. Nonetheless, emerging evidence suggests that cholecystectomy might be associated with the development of CRC. It has been reported that alterations in bile acid metabolism and gut microbiota are the two main reasons. However, the potential mechanisms still need to be elucidated. In this review, we mainly discussed how bile acid metabolism, gut microbiota, and the interaction between the two factors influence the development of CRC. Subsequently, we summarized the underlying mechanisms of the alterations in bile acid metabolism after cholecystectomy including cellular level, molecular level, and signaling pathways. The potential mechanisms of the alterations on gut microbiota contain an imbalance of bile acid metabolism, cellular immune abnormality, acid-base imbalance, activation of cancer-related pathways, and induction of toxin, inflammation, and oxidative stress.
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Affiliation(s)
- Xi Jiang
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zhongxiu Jiang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Qi Cheng
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Wei Sun
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Min Jiang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yan Sun
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
- *Correspondence: Yan Sun,
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19
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Chen L, Jiao T, Liu W, Luo Y, Wang J, Guo X, Tong X, Lin Z, Sun C, Wang K, He Y, Zhang Y, Xu H, Wang J, Zuo J, Ding Q, He S, Gonzalez FJ, Xie C. Hepatic cytochrome P450 8B1 and cholic acid potentiate intestinal epithelial injury in colitis by suppressing intestinal stem cell renewal. Cell Stem Cell 2022; 29:1366-1381.e9. [PMID: 36055192 PMCID: PMC10673678 DOI: 10.1016/j.stem.2022.08.008] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 06/08/2022] [Accepted: 08/11/2022] [Indexed: 11/03/2022]
Abstract
Although disrupted bile acid (BA) homeostasis is implicated in inflammatory bowel disease (IBD), the role of hepatic BA metabolism in the pathogenesis of colitis is poorly understood. Here, we found that cholic acid (CA) levels were increased in patients and mice. Cytochrome P450 8B1 (CYP8B1), which synthesizes CA, was induced in livers of colitic mice. CA-treated or liver Cyp8b1-overexpressing mice developed more severe colitis with compromised repair of the mucosal barrier, whereas Cyp8b1-knockout mice were resistant to colitis. Mechanistically, CA inhibited peroxisome proliferator-activated receptor alpha (PPARα), resulting in impeded fatty acid oxidation (FAO) and impaired Lgr5+ intestinal stem cell (ISC) renewal. A PPARα agonist restored FAO and improved Lgr5+ ISC function. Activation of the farnesoid X receptor (FXR) suppressed liver CYP8B1 expression and ameliorated colitis in mice. This study reveals a connection between the hepatic CYP8B1-CA axis and colitis via regulating intestinal epithelial regeneration, suggesting that BA-based strategies might be beneficial in IBD treatment.
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Affiliation(s)
- Li Chen
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Tingying Jiao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China
| | - Weiwei Liu
- Department of Laboratory Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China; Department of Laboratory Medicine and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200070, P.R. China
| | - Yuhong Luo
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jue Wang
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Xiaozhen Guo
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China
| | - Xiao Tong
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Zemin Lin
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China
| | - Chuying Sun
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210029, P.R. China
| | - Kanglong Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China
| | - Yifan He
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Yuwei Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China
| | - Hualing Xu
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210029, P.R. China
| | - Jiawen Wang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, P.R. China
| | - Jianping Zuo
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Qiurong Ding
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China
| | - Shijun He
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China.
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Cen Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. China.
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20
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Xing C, Du Y, Duan T, Nim K, Chu J, Wang HY, Wang RF. Interaction between microbiota and immunity and its implication in colorectal cancer. Front Immunol 2022; 13:963819. [PMID: 35967333 PMCID: PMC9373904 DOI: 10.3389/fimmu.2022.963819] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the world. Besides genetic causes, colonic inflammation is one of the major risk factors for CRC development, which is synergistically regulated by multiple components, including innate and adaptive immune cells, cytokine signaling, and microbiota. The complex interaction between CRC and the gut microbiome has emerged as an important area of current CRC research. Metagenomic profiling has identified a number of prominent CRC-associated bacteria that are enriched in CRC patients, linking the microbiota composition to colitis and cancer development. Some microbiota species have been reported to promote colitis and CRC development in preclinical models, while a few others are identified as immune modulators to induce potent protective immunity against colitis and CRC. Mechanistically, microbiota regulates the activation of different immune cell populations, inflammation, and CRC via crosstalk between innate and adaptive immune signaling pathways, including nuclear factor kappa B (NF-κB), type I interferon, and inflammasome. In this review, we provide an overview of the potential interactions between gut microbiota and host immunity and how their crosstalk could synergistically regulate inflammation and CRC, thus highlighting the potential roles and mechanisms of gut microbiota in the development of microbiota-based therapies to prevent or alleviate colitis and CRC.
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Affiliation(s)
- Changsheng Xing
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Yang Du
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Tianhao Duan
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Kelly Nim
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Junjun Chu
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Helen Y. Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Rong-Fu Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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21
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Wang Z, Li F, Liu J, Luo Y, Guo H, Yang Q, Xu C, Ma S, Chen H. Intestinal Microbiota - An Unmissable Bridge to Severe Acute Pancreatitis-Associated Acute Lung Injury. Front Immunol 2022; 13:913178. [PMID: 35774796 PMCID: PMC9237221 DOI: 10.3389/fimmu.2022.913178] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 05/11/2022] [Indexed: 11/28/2022] Open
Abstract
Severe acute pancreatitis (SAP), one of the most serious abdominal emergencies in general surgery, is characterized by acute and rapid onset as well as high mortality, which often leads to multiple organ failure (MOF). Acute lung injury (ALI), the earliest accompanied organ dysfunction, is the most common cause of death in patients following the SAP onset. The exact pathogenesis of ALI during SAP, however, remains unclear. In recent years, advances in the microbiota-gut-lung axis have led to a better understanding of SAP-associated lung injury (PALI). In addition, the bidirectional communications between intestinal microbes and the lung are becoming more apparent. This paper aims to review the mechanisms of an imbalanced intestinal microbiota contributing to the development of PALI, which is mediated by the disruption of physical, chemical, and immune barriers in the intestine, promotes bacterial translocation, and results in the activation of abnormal immune responses in severe pancreatitis. The pathogen-associated molecular patterns (PAMPs) mediated immunol mechanisms in the occurrence of PALI via binding with pattern recognition receptors (PRRs) through the microbiota-gut-lung axis are focused in this study. Moreover, the potential therapeutic strategies for alleviating PALI by regulating the composition or the function of the intestinal microbiota are discussed in this review. The aim of this study is to provide new ideas and therapeutic tools for PALI patients.
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Affiliation(s)
- Zhengjian Wang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Fan Li
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jin Liu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yalan Luo
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Haoya Guo
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Qi Yang
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Caiming Xu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, United States
| | - Shurong Ma
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- *Correspondence: Shurong Ma, ; Hailong Chen,
| | - Hailong Chen
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- *Correspondence: Shurong Ma, ; Hailong Chen,
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22
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Kovacevic B, Ionescu CM, Jones M, Wagle SR, Lewkowicz M, Đanić M, Mikov M, Mooranian A, Al-Salami H. The Effect of Deoxycholic Acid on Chitosan-Enabled Matrices for Tissue Scaffolding and Injectable Nanogels. Gels 2022; 8:gels8060358. [PMID: 35735702 PMCID: PMC9222767 DOI: 10.3390/gels8060358] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 05/20/2022] [Accepted: 05/27/2022] [Indexed: 02/07/2023] Open
Abstract
The pathophysiology of a multitude of diseases is influenced by bioenergetic dysfunction. Healthy mitochondria are presented as essential for the regulation and function of multiple cell types, including the cells of relevance for this research: pancreatic beta cells, muscle cells, and liver cells. Hence, effects of hydrogels (particularly nanogels) on bioenergetics needs to be taken into account when designing optimum delivery matrices. Several polymers have been suggested for use in hydrogels and nanogels, with focus on chitosan due to its range of beneficial properties. Bile acids have emerged as beneficial excipients, including deoxycholic acid, which can increase membrane permeability of cells. Nanogels were manufactured containing various concentrations of chitosan and deoxycholic acid in addition to the staple sodium alginate. Nanogels then underwent an array of analysis including rheological studies and in vitro cell work assessing viability, hypoxia, and the bioenergetic profiles. Overall, deoxycholic acid showed enhanced gel strength although this resulted in slightly lower cell viability and impacted bioenergetic profiles. Results from this study showed the benefits of deoxycholic acid; however, this was found to be less suitable for cell delivery matrices and is perhaps more beneficial for drug-delivery systems.
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Affiliation(s)
- Bozica Kovacevic
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School and Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (B.K.); (C.M.I.); (M.J.); (S.R.W.); (M.L.)
- Hearing Therapeutics Department, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia
| | - Corina Mihaela Ionescu
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School and Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (B.K.); (C.M.I.); (M.J.); (S.R.W.); (M.L.)
- Hearing Therapeutics Department, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia
| | - Melissa Jones
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School and Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (B.K.); (C.M.I.); (M.J.); (S.R.W.); (M.L.)
- Hearing Therapeutics Department, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia
| | - Susbin Raj Wagle
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School and Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (B.K.); (C.M.I.); (M.J.); (S.R.W.); (M.L.)
- Hearing Therapeutics Department, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia
| | - Michael Lewkowicz
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School and Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (B.K.); (C.M.I.); (M.J.); (S.R.W.); (M.L.)
- Hearing Therapeutics Department, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia
| | - Maja Đanić
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, 21101 Novi Sad, Serbia; (M.Đ.); (M.M.)
| | - Momir Mikov
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, 21101 Novi Sad, Serbia; (M.Đ.); (M.M.)
| | - Armin Mooranian
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School and Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (B.K.); (C.M.I.); (M.J.); (S.R.W.); (M.L.)
- Hearing Therapeutics Department, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia
- Correspondence: (A.M.); (H.A.-S.)
| | - Hani Al-Salami
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School and Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (B.K.); (C.M.I.); (M.J.); (S.R.W.); (M.L.)
- Hearing Therapeutics Department, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia
- Correspondence: (A.M.); (H.A.-S.)
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23
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Role of Bile Acids and Nuclear Receptors in Acupuncture in Improving Crohn's Disease. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:5814048. [PMID: 35600949 PMCID: PMC9122672 DOI: 10.1155/2022/5814048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 11/13/2021] [Accepted: 04/15/2022] [Indexed: 11/30/2022]
Abstract
Nuclear receptors (NRs) are ligand-dependent transcription factors that regulate the transcription of target genes. Bile acids (BAs) can be used as effector molecules to regulate physiological processes in the gut, and NRs are important receptors for bile acid signaling. Relevant studies have shown that NRs are closely related to the occurrence of Crohn's disease (CD). Although the mechanism of NRs in CD has not been clarified completely, growing evidence shows that NRs play an important role in regulating intestinal immunity, mucosal barrier, and intestinal flora. NRs can participate in the progress of CD by mediating inflammation, immunity, and autophagy. As the important parts of traditional Chinese medicine (TCM) therapy, acupuncture and moxibustion in the treatment of CD curative mechanism can get a lot of research support. At the same time, acupuncture and moxibustion can regulate the changes of related NRs. Therefore, to explore whether acupuncture can regulate BA circulation and NRs expression and then participate in the disease progression of CD, a new theoretical basis for acupuncture treatment of CD is provided.
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24
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Camilleri M. Bile acid detergency: permeability, inflammation, and effects of sulfation. Am J Physiol Gastrointest Liver Physiol 2022; 322:G480-G488. [PMID: 35258349 PMCID: PMC8993532 DOI: 10.1152/ajpgi.00011.2022] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/23/2022] [Accepted: 02/23/2022] [Indexed: 01/31/2023]
Abstract
Bile acids are amphipathic, detergent molecules. The detergent effects of di-α-hydroxy-bile acids are relevant to several colonic diseases. The aims were to review the concentrations of bile acids reaching the human colon in health and disease, the molecular structure of bile acids that determine detergent functions and the relationship to human diseases (neuroendocrine tumors, microscopic colitis, active celiac disease, and ulcerative colitis, Crohn's disease and ileal resection), the relationship to bacterial uptake into the mucosa, mucin depletion, and epithelial damage, the role of bile acids in mucosal inflammation and microscopic colitis, and the role of sulfation of bile salts in detoxification or prevention of the detergent effects of bile acids. The concentrations of bile acids reaching the human colon range from 2 to 10 mM; di-α-hydroxy bile acids are the only bile acids with detergent effects that include mucin depletion, mucosal damage, bacterial uptake, and microscopic inflammation that may be manifest in diseases associated with no overt inflammation of the mucosa, such as bile acid diarrhea, ileal diseases such as neuroendocrine tumors, ileal resection, and nonalcoholic steatohepatitis. Sulfation inactivates colonic secretion due to primary bile acids, but it may render secondary bile acids proinflammatory in the colon. Other evidence in preclinical models of inflammatory bowel disease (IBD) suggests reduced sulfation causes barrier dysfunction, inflammation, or carcinogenesis. These advances emphasize relevance and opportunities afforded by greater understanding of the chemistry and metabolism of bile acids, which stands to be further enhanced by research into the metabolic interactions of microbiota with bile acids.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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25
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Li M, Yang L, Mu C, Sun Y, Gu Y, Chen D, Liu T, Cao H. Gut microbial metabolome in inflammatory bowel disease: From association to therapeutic perspectives. Comput Struct Biotechnol J 2022; 20:2402-2414. [PMID: 35664229 PMCID: PMC9125655 DOI: 10.1016/j.csbj.2022.03.038] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 03/26/2022] [Accepted: 03/31/2022] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a set of clinically chronic, relapsing gastrointestinal inflammatory disease and lacks of an absolute cure. Although the precise etiology is unknown, developments in high-throughput microbial genomic sequencing significantly illuminate the changes in the intestinal microbial structure and functions in patients with IBD. The application of microbial metabolomics suggests that the microbiota can influence IBD pathogenesis by producing metabolites, which are implicated as crucial mediators of host-microbial crosstalk. This review aims to elaborate the current knowledge of perturbations of the microbiome-metabolome interface in IBD with description of altered composition and metabolite profiles of gut microbiota. We emphasized and elaborated recent findings of several potentially protective metabolite classes in IBD, including fatty acids, amino acids and derivatives and bile acids. This article will facilitate a deeper understanding of the new therapeutic approach for IBD by applying metabolome-based adjunctive treatment.
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Key Words
- AMPs, Antimicrobial peptides
- BAs, Bile acids
- BC, Bray Curtis
- CD, Crohn’s disease
- CDI, Clostridioides difficile infection
- DC, Diversion colitis
- DCA, Deoxycholic acid
- DSS, Dextran sulfate sodium
- FAs, Fatty acid
- FMT, Fecal microbiota transplantation
- FODMAP, Fermentable oligosaccharide, disaccharide, monosaccharide, and polyol
- GC–MS, Gas chromatography-mass spectrometry
- Gut microbiota
- HDAC, Histone deacetylase
- IBD, Inflammatory bowel disease
- Inflammatory bowel diseases
- LC-MS, Liquid chromatography-mass spectrometry
- LCA, Lithocholic acid
- LCFAs, Long-chain fatty acids
- MCFAs, Medium-chain fatty acids
- MD, Mediterranean diet
- MS, Mass spectrometry
- Metabolite
- Metabolomics
- Metagenomics
- Microbial therapeutics
- NMR, Nuclear magnetic resonance
- PBAs, Primary bile acids
- SBAs, Secondary bile acids
- SCD, Special carbohydrate diet
- SCFAs, Short-chain fatty acids
- TNBS, 2,4,6-trinitro-benzene sulfonic acid
- UC, Ulcerative colitis
- UDCA, Ursodeoxycholic acid
- UPLC-MS, ultraperformance liquid chromatography coupled to mass spectrometry
- UU, Unweighted UniFrac
- WMS, Whole-metagenome shotgun
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Affiliation(s)
| | | | | | - Yue Sun
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Yu Gu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Danfeng Chen
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Tianyu Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
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26
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Zhang Y, Wang Z, Dong Y, Cao J, Chen Y. Blue Light Alters the Composition of the Jejunal Microbiota and Promotes the Development of the Small Intestine by Reducing Oxidative Stress. Antioxidants (Basel) 2022; 11:274. [PMID: 35204158 PMCID: PMC8868333 DOI: 10.3390/antiox11020274] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/25/2022] [Accepted: 01/27/2022] [Indexed: 02/06/2023] Open
Abstract
Environmental light has an important impact on the growth, development and oxidative stress of chicks. Thus, we investigated the effects of colored lights on microbes and explored the molecular mechanism by which external color light information alters the gut microbiota and induces the cell response in vivo. We raised 96 chicks under 400-700 nm white (WL), 660 nm red (RL), 560 nm green (GL) or 480 nm blue light (BL) for 42 days. We used 16S rRNA high-throughput pyrosequencing and gas chromatography to explore the effect of different monochromatic lights on the jejunal microbiota. We used qRT-PCR, western blotting, immunohistochemistry and Elisa to determine the effect of different monochromatic lights on small intestine development and oxidative stress levels. With consistency in the upregulation of antioxidant enzyme ability and anti-inflammatory cytokine level, the 16S rRNA and gas chromatography results showed that BL significantly increased the diversity and richness of the jejunal microbiota and improved the relative abundances of Faecalibacterium, Ruminiclostridium_9 and metabolite butyrate content compared with WL, RL and GL (p < 0.05). In addition, we observed that BL increased the goblet cell numbers, PCNA cell numbers, villus-length-to-crypt-depth (V/C) ratios, ZO-1, Occludin, and Claudin-1 protein expression; decreased permeability; and enhanced the digestion and absorption capacity in the jejunum (p < 0.05). In the in vitro experiment, we found that butyrate promoted chick small intestinal epithelial cell (CIEC) proliferation and inhibited apoptosis (p < 0.05). These responses were abrogated by the Gi inhibitor, PI3K inhibitor or AKT inhibitor, but were mimicked by GPR43 agonists or the GSK-3β inhibitor (p < 0.05). Overall, these findings suggested that BL increased the relative abundance of Faecalibacterium, Ruminiclostridium_9 and butyrate production. Butyrate may act as one of the signals to mediate blue-light-induced small intestinal development and mucosal barrier integrity enhancement and promote cell proliferation via the GPR43/Gi/PI3K/AKT/p-GSK-3β/β-catenin pathway.
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Affiliation(s)
| | | | | | | | - Yaoxing Chen
- Laboratory of Anatomy of Domestic Animals, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; (Y.Z.); (Z.W.); (Y.D.); (J.C.)
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27
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Zhou A, Yuan Y, Yang M, Huang Y, Li X, Li S, Yang S, Tang B. Crosstalk Between the Gut Microbiota and Epithelial Cells Under Physiological and Infectious Conditions. Front Cell Infect Microbiol 2022; 12:832672. [PMID: 35155283 PMCID: PMC8829037 DOI: 10.3389/fcimb.2022.832672] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 01/10/2022] [Indexed: 12/15/2022] Open
Abstract
The gastrointestinal tract (GIT) is considered the largest immunological organ, with a diverse gut microbiota, that contributes to combatting pathogens and maintaining human health. Under physiological conditions, the crosstalk between gut microbiota and intestinal epithelial cells (IECs) plays a crucial role in GIT homeostasis. Gut microbiota and derived metabolites can compromise gut barrier integrity by activating some signaling pathways in IECs. Conversely, IECs can separate the gut microbiota from the host immune cells to avoid an excessive immune response and regulate the composition of the gut microbiota by providing an alternative energy source and releasing some molecules, such as hormones and mucus. Infections by various pathogens, such as bacteria, viruses, and parasites, can disturb the diversity of the gut microbiota and influence the structure and metabolism of IECs. However, the interaction between gut microbiota and IECs during infection is still not clear. In this review, we will focus on the existing evidence to elucidate the crosstalk between gut microbiota and IECs during infection and discuss some potential therapeutic methods, including probiotics, fecal microbiota transplantation (FMT), and dietary fiber. Understanding the role of crosstalk during infection may help us to establish novel strategies for prevention and treatment in patients with infectious diseases, such as C. difficile infection, HIV, and COVID-19.
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Affiliation(s)
- An Zhou
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yi Yuan
- Institution of Basic Medicine, Third Military Medical University, Chongqing, China
| | - Min Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yujiao Huang
- The First Clinical College, ChongQing Medical University, Chongqing, China
| | - Xin Li
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Shengpeng Li
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Shiming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
- *Correspondence: Shiming Yang, ; Bo Tang,
| | - Bo Tang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
- *Correspondence: Shiming Yang, ; Bo Tang,
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28
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Azuma Y, Uchiyama K, Sugaya T, Yasuda T, Hashimoto H, Kajiwara-Kubota M, Sugino S, Kitae H, Torii T, Mizushima K, Doi T, Inoue K, Dohi O, Yoshida N, Kamada K, Ishikawa T, Takagi T, Konishi H, Naito Y, Itoh Y. Deoxycholic acid delays the wound healing of colonic epithelial cells via transmembrane G-protein-coupled receptor 5. J Gastroenterol Hepatol 2022; 37:134-143. [PMID: 34477242 DOI: 10.1111/jgh.15676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 08/24/2021] [Accepted: 08/30/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Efficient intestinal wound healing is essential for good prognoses of ulcerative colitis (UC). Although bile acids and the transmembrane G-protein-coupled receptor (TGR) 5 have been reported to affect wound healing in intestinal epithelial cells, the detailed underlying mechanisms are unclear. Here, we investigated the role of TGR5 in wound healing in the context of colonic epithelial cells in the presence of bile acids. METHODS The expression of TGR5 in the colonic epithelium of both a dextran sulfate sodium (DSS)-induced colitis mouse model (recovery phase), and UC patients in clinical remission, was evaluated. Young adult mouse colonic epithelial (YAMC) cells were then used to evaluate wound healing after treatment with deoxycholic acid (DCA); TGR5 was silenced in YAMC cells via shRNA-transfection, and a wound-healing assay in the presence of DCA was performed. Furthermore, we investigated the role of the activation of AKT in the context of wound healing. RESULTS The expression of TGR5 was decreased in the colonic epithelium of both mice with DSS-induced colitis and UC patients. Additionally, DCA significantly delayed wound healing in YAMC cells but not in TGR5 silenced ones. Of note, the DCA-induced activation of AKT signaling in YAMC cells was inhibited by TGR5 silencing, and AKT inhibitors prevented the wound healing delay induced by DCA. CONCLUSIONS Overall, we show that DCA delays wound healing in the context of colonic epithelial cells through AKT activation. These results may support the development of new therapeutic approaches for epithelial regeneration in UC.
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Affiliation(s)
- Yuka Azuma
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kazuhiko Uchiyama
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takeshi Sugaya
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takeshi Yasuda
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hikaru Hashimoto
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Mariko Kajiwara-Kubota
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Satoshi Sugino
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hiroaki Kitae
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takashi Torii
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Katsura Mizushima
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Toshifumi Doi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Ken Inoue
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Osamu Dohi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Naohisa Yoshida
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kazuhiro Kamada
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takeshi Ishikawa
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tomohisa Takagi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hideyuki Konishi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yuji Naito
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshito Itoh
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
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29
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Xie AJ, Mai CT, Zhu YZ, Liu XC, Xie Y. Bile acids as regulatory molecules and potential targets in metabolic diseases. Life Sci 2021; 287:120152. [PMID: 34793769 DOI: 10.1016/j.lfs.2021.120152] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/06/2021] [Accepted: 11/11/2021] [Indexed: 02/07/2023]
Abstract
Bile acids are important hydroxylated steroids that are synthesized in the liver from cholesterol for intestinal absorption of lipids and other fatty-nutrient. They also display remarkable and immense functions such as regulating immune responses, managing the apoptosis of cells, participating in glucose metabolism, and so on. Some bile acids were used for the treatment or prevention of diseases such as gallstones, primary biliary cirrhosis, and colorectal cancer. Meanwhile, the accumulation of toxic bile acids leads to apoptosis, necrosis, and inflammation. Alteration of bile acids metabolism, as well as the gut microbiota that interacted with bile acids, contributes to the pathogenesis of metabolic diseases. Therefore, the purpose of this review is to summarize the current functions and pre-clinical or clinical applications of bile acids, and to further discuss the alteration of bile acids in metabolic disorders as well as the manipulation of bile acids metabolism as potential therapeutic targets.
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Affiliation(s)
- Ai-Jin Xie
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macau
| | - Chu-Tian Mai
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macau
| | - Yi-Zhun Zhu
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macau
| | - Xian-Cheng Liu
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, PR China.
| | - Ying Xie
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macau.
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30
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Anderson KM, Gayer CP. The Pathophysiology of Farnesoid X Receptor (FXR) in the GI Tract: Inflammation, Barrier Function and Innate Immunity. Cells 2021; 10:cells10113206. [PMID: 34831429 PMCID: PMC8624027 DOI: 10.3390/cells10113206] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 11/12/2021] [Indexed: 12/12/2022] Open
Abstract
The Farnesoid-X Receptor, FXR, is a nuclear bile acid receptor. Its originally described function is in bile acid synthesis and regulation within the liver. More recently, however, FXR has been increasingly appreciated for its breadth of function and expression across multiple organ systems, including the intestine. While FXR’s role within the liver continues to be investigated, increasing literature indicates that FXR has important roles in responding to inflammation, maintaining intestinal epithelial barrier function, and regulating immunity within the gastrointestinal (GI) tract. Given the complicated and multi-factorial nature of intestinal barrier dysfunction, it is not surprising that FXR’s role appears equally complicated and not without conflicting data in different model systems. Recent work has suggested translational applications of FXR modulation in GI pathology; however, a better understanding of FXR physiology is necessary for these treatments to gain widespread use in human disease. This review aims to discuss current scientific work on the role of FXR within the GI tract, specifically in its role in intestinal inflammation, barrier function, and immune response, while also exploring areas of controversy.
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Affiliation(s)
- Kemp M. Anderson
- Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA;
- Division of Pediatric Surgery, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Christopher P. Gayer
- Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA;
- Division of Pediatric Surgery, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA
- Correspondence: ; Tel.: +1-323-361-4974
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31
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Vidal JE, Wier MN, A. Angulo-Zamudio U, McDevitt E, Jop Vidal AG, Alibayov B, Scasny A, Wong SM, Akerley BJ, McDaniel LS. Prophylactic Inhibition of Colonization by Streptococcus pneumoniae with the Secondary Bile Acid Metabolite Deoxycholic Acid. Infect Immun 2021; 89:e0046321. [PMID: 34543118 PMCID: PMC8594607 DOI: 10.1128/iai.00463-21] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 09/07/2021] [Indexed: 12/26/2022] Open
Abstract
Streptococcus pneumoniae colonizes the nasopharynx of children and the elderly but also kills millions worldwide yearly. The secondary bile acid metabolite deoxycholic acid (DoC) affects the viability of human pathogens but also plays multiple roles in host physiology. We assessed in vitro the antimicrobial activity of DoC and investigated its potential to eradicate S. pneumoniae colonization using a model of human nasopharyngeal colonization and an in vivo mouse model of colonization. At a physiological concentration, DoC (0.5 mg/ml; 1.27 mM) killed all tested S. pneumoniae strains (n = 48) 2 h postinoculation. The model of nasopharyngeal colonization showed that DoC eradicated colonization by S. pneumoniae strains as soon as 10 min postexposure. The mechanism of action did not involve activation of autolysis, since the autolysis-defective double mutants ΔlytAΔlytC and ΔspxBΔlctO were as susceptible to DoC as was the wild type (WT). Oral streptococcal species (n = 20), however, were not susceptible to DoC (0.5 mg/ml). Unlike trimethoprim, whose spontaneous resistance frequency (srF) for TIGR4 or EF3030 was ≥1 × 10-9, no spontaneous resistance was observed with DoC (srF, ≥1 × 10-12). Finally, the efficacy of DoC to eradicate S. pneumoniae colonization was assessed in vivo using a topical route via intranasal (i.n.) administration and as a prophylactic treatment. Mice challenged with S. pneumoniae EF3030 carried a median of 4.05 × 105 CFU/ml 4 days postinoculation compared to 6.67 × 104 CFU/ml for mice treated with DoC. Mice in the prophylactic group had an ∼99% reduction of the pneumococcal density (median, 2.61 × 103 CFU/ml). Thus, DoC, an endogenous human bile salt, has therapeutic potential against S. pneumoniae.
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Affiliation(s)
- Jorge E. Vidal
- Department of Microbiology and Immunology, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Meagan N. Wier
- Department of Microbiology and Immunology, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | | | - Erin McDevitt
- Department of Microbiology and Immunology, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Ana G. Jop Vidal
- Department of Microbiology and Immunology, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Babek Alibayov
- Department of Microbiology and Immunology, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Anna Scasny
- Department of Microbiology and Immunology, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Sandy M. Wong
- Department of Microbiology and Immunology, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Brian J. Akerley
- Department of Microbiology and Immunology, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Larry S. McDaniel
- Department of Microbiology and Immunology, University of Mississippi Medical Center, Jackson, Mississippi, USA
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Su J, He Z, Yu Y, Lu M, Wu Z, Zhang D. Gualou Xiebai Decoction ameliorates increased Caco-2 monolayer permeability induced by bile acids via tight junction regulation, oxidative stress suppression and apoptosis reduction. J Bioenerg Biomembr 2021; 54:45-57. [PMID: 34718922 DOI: 10.1007/s10863-021-09927-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 10/22/2021] [Indexed: 12/11/2022]
Abstract
Gualou Xiebai Decoction (GXD), a classic prescription, is widely used to dealing with inflammatory diseases in China for thousands of years. Abnormal metabolic state of bile acids (BAs) is confirmed to cause intestinal epithelial barrier dysfunction. In preliminary work, we observed that GXD could decrease intestinal permeability in hyperlipidemia mice. The present study aimed to explore the protective effect of GXD on intestinal mucosa in vitro. Caco-2 cell monolayer permeability among different groups was determined by measuring the concentrations of FITC-dextran in the lower compartments and transepithelial electrical resistance (TEER). Meanwhile, mRNA and protein expressions of tight junctions (TJs) were investigated. Generation of intracellular reactive oxygen species (ROS) and the ratio of cell apoptosis induced by BAs were assessed by fluorescence probe and flow cytometry. GXD was shown to keep the cell monolayer in low permeable status, increase TEER and mRNA and protein expressions of occludin (Ocln) and zonula occluden 2 (ZO2) remarkably in cells challenged with cholic acid (CA), deoxycholic acid (DCA) and glycocholic acid (GCA). However, no significant effects were uncovered against the pathological effects of taurocholic acid (TCA). Meanwhile, generation of ROS and increased levels of apoptotic cells caused by CA, DCA and GCA were dramatically decreased by GXD, which were not observed on TCA. GXD could significantly attenuate intestinal barrier dysfunction induced by BAs via TJs regulation, oxidative stress suppression and cell apoptosis decrease, but such effects and behind mechanisms differed among different kinds of BAs.
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Affiliation(s)
- Jiyuan Su
- The Department of Geriatrics, 900TH Hospital of Joint Logistics Support Force (Clinical College of Fujian Medical University), Fuzhou, 350001, China
| | - Zhiqing He
- Department of Cardiology, Changzheng Hospital, Naval Military Medical University, Shanghai, 200003, China
| | - Yunhua Yu
- The Department of Geriatrics, 900TH Hospital of Joint Logistics Support Force (Clinical College of Fujian Medical University), Fuzhou, 350001, China
| | - Mingfang Lu
- The Department of Geriatrics, 900TH Hospital of Joint Logistics Support Force (Clinical College of Fujian Medical University), Fuzhou, 350001, China
| | - Zonggui Wu
- Department of Cardiology, Changzheng Hospital, Naval Military Medical University, Shanghai, 200003, China.
| | - Dongmei Zhang
- The Department of Geriatrics, 900TH Hospital of Joint Logistics Support Force (Clinical College of Fujian Medical University), Fuzhou, 350001, China.
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Burns GL, Hoedt EC, Walker MM, Talley NJ, Keely S. Physiological mechanisms of unexplained (functional) gastrointestinal disorders. J Physiol 2021; 599:5141-5161. [PMID: 34705270 DOI: 10.1113/jp281620] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 09/20/2021] [Indexed: 12/13/2022] Open
Abstract
Functional gastrointestinal disorders (FGIDs) encompass a range of complex conditions with similar clinical characteristics and no overt pathology. Recent recognition of sub-clinical pathologies in FGIDs, in conjunction with physiological and biochemical abnormalities including increased intestinal permeability, microbial profile alterations, differences in metabolites and extra-intestinal manifestations of disease, call into question the designation of these conditions as 'functional'. This is despite significant heterogeneity in both symptom profile and specifics of reported physiological abnormalities hampering efforts to determine defined mechanisms that drive onset and chronicity of symptoms. Instead, the literature demonstrates these conditions are disorders of homeostatic imbalance, with disruptions in both host and microbial function and metabolism. This imbalance is also associated with extraintestinal abnormalities including psychological comorbidities and fatigue that may be a consequence of gastrointestinal disruption. Given the exploitation of such abnormalities will be crucial for improved therapeutic selection, an enhanced understanding of the relationship between alterations in function of the gastrointestinal tract and the response of the immune system is of interest in identifying mechanisms that drive FGID onset and chronicity. Considerations for future research should include the role of sex hormones in regulating physiological functions and treatment responses in patients, as well as the importance of high-level phenotyping of clinical, immune, microbial and physiological parameters in study cohorts. There is opportunity to examine the functional contribution of the microbiota and associated metabolites as a source of mechanistic insight and targets for therapeutic modulation.
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Affiliation(s)
- Grace L Burns
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia.,NHMRC Centre for Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia.,New Lambton Heights, Hunter Medical Research Institute, Newcastle, NSW, Australia
| | - Emily C Hoedt
- NHMRC Centre for Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia.,New Lambton Heights, Hunter Medical Research Institute, Newcastle, NSW, Australia.,School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia
| | - Marjorie M Walker
- NHMRC Centre for Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia.,New Lambton Heights, Hunter Medical Research Institute, Newcastle, NSW, Australia.,School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia
| | - Nicholas J Talley
- NHMRC Centre for Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia.,New Lambton Heights, Hunter Medical Research Institute, Newcastle, NSW, Australia.,School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia
| | - Simon Keely
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia.,NHMRC Centre for Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia.,New Lambton Heights, Hunter Medical Research Institute, Newcastle, NSW, Australia
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Liang J, Shao W, Liu Q, Lu Q, Gu A, Jiang Z. Single Cell RNA-Sequencing Reveals a Murine Gallbladder Cell Transcriptome Atlas During the Process of Cholesterol Gallstone Formation. Front Cell Dev Biol 2021; 9:714271. [PMID: 34650971 PMCID: PMC8505819 DOI: 10.3389/fcell.2021.714271] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/19/2021] [Indexed: 12/20/2022] Open
Abstract
Gallstone disease is a worldwide common disease. However, the knowledge concerning the gallbladder in the pathogenesis of cholesterol gallstone formation remains limited. In this study, using single-cell RNA sequencing (scRNA-seq) to obtain the transcriptome of gallbladder cells, we showed cellular heterogeneity and transcriptomic dynamics in murine gallbladder cells during the process of lithogenesis. Our results indicated gallbladder walls were subjected to remodeling during the process of lithogenesis. The major molecular events that happened included proliferation of epithelial cells, infiltration of immune-cells, activation of angiogenesis, and extracellular matrix modulation. Furthermore, we observed partial reversal of gallbladder cell transcriptomes by ursodeoxycholic acid treatment. This work thus provides novel and integral knowledges on the cellular changes during lithogenesis, which is of great significance to the understanding of pathogenesis and treatment of cholesterol gallstone.
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Affiliation(s)
- Jingjia Liang
- Center of Gallbladder Disease, Shanghai East Hospital, Institution of Gallstone Disease, School of Medicine, Tongji University, Shanghai, China.,Key Laboratory of Modern Toxicology of Ministry of Education, State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Wentao Shao
- Center of Gallbladder Disease, Shanghai East Hospital, Institution of Gallstone Disease, School of Medicine, Tongji University, Shanghai, China.,Key Laboratory of Modern Toxicology of Ministry of Education, State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,School of Instrument Science and Engineering, Southeast University, Nanjing, China
| | - Qian Liu
- Key Laboratory of Modern Toxicology of Ministry of Education, State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Qifan Lu
- Center of Gallbladder Disease, Shanghai East Hospital, Institution of Gallstone Disease, School of Medicine, Tongji University, Shanghai, China
| | - Aihua Gu
- Key Laboratory of Modern Toxicology of Ministry of Education, State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Zhaoyan Jiang
- Center of Gallbladder Disease, Shanghai East Hospital, Institution of Gallstone Disease, School of Medicine, Tongji University, Shanghai, China
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35
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Integrated analysis of dysregulated microRNA and mRNA expression in intestinal epithelial cells following ethanol intoxication and burn injury. Sci Rep 2021; 11:20213. [PMID: 34642361 PMCID: PMC8510995 DOI: 10.1038/s41598-021-99281-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 09/14/2021] [Indexed: 02/06/2023] Open
Abstract
Gut barrier dysfunction is often implicated in pathology following alcohol intoxication and burn injury. MicroRNAs (miRNAs) are negative regulators of gene expression that play a central role in gut homeostasis, although their role after alcohol and burn injury is poorly understood. We performed an integrated analysis of miRNA and RNA sequencing data to identify a network of interactions within small intestinal epithelial cells (IECs) which could promote gut barrier disruption. Mice were gavaged with ~ 2.9 g/kg ethanol and four hours later given a ~ 12.5% TBSA full thickness scald injury. One day later, IECs were harvested and total RNA extracted for RNA-seq and miRNA-seq. RNA sequencing showed 712 differentially expressed genes (DEGs) (padj < 0.05) in IECs following alcohol and burn injury. Furthermore, miRNA sequencing revealed 17 differentially expressed miRNAs (DEMs) (padj < 0.1). Utilizing the miRNet, miRDB and TargetScan databases, we identified both validated and predicted miRNA gene targets. Integration of small RNA sequencing data with mRNA sequencing results identified correlated changes in miRNA and target expression. Upregulated miRNAs were associated with decreased proliferation (miR-98-3p and miR-381-3p) and cellular adhesion (miR-29a-3p, miR-429-3p and miR3535), while downregulated miRNAs were connected to upregulation of apoptosis (Let-7d-5p and miR-130b-5p) and metabolism (miR-674-3p and miR-185-5p). Overall, these findings suggest that alcohol and burn injury significantly alters the mRNA and miRNA expression profile of IECs and reveals numerous miRNA–mRNA interactions that regulate critical pathways for gut barrier function after alcohol and burn injury.
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36
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Zhang Y, Li JX, Zhang Y, Wang YL. Intestinal microbiota participates in nonalcoholic fatty liver disease progression by affecting intestinal homeostasis. World J Clin Cases 2021; 9:6654-6662. [PMID: 34447812 PMCID: PMC8362529 DOI: 10.12998/wjcc.v9.i23.6654] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/25/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease with a pathogenesis that has not been fully elucidated. With the development of the theory of the gut-liver axis and the deepening of related research, the role of the intestinal tract in the pathogenesis of NAFLD has been investigated more. Intestinal microbiota, intestinal metabolites, and intestinal epithelial and immune-based barriers constitute the intestinal environment, which uses crosstalk to maintain the homeostasis of the intestinal environment. This paper reviews the progress in the study of intestinal microbiota, intestinal environment, and NAFLD and suggests that repair of intestinal functional balance may be a new idea for early prevention and intervention of NAFLD.
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Affiliation(s)
- Yang Zhang
- Department of Gastroenterology, Dong Fang Hospital, Beijing University of Chinese Medicine, Beijing 100078, China
| | - Jun-Xiang Li
- Department of Gastroenterology, Dong Fang Hospital, Beijing University of Chinese Medicine, Beijing 100078, China
| | - Yan Zhang
- Department of Gastroenterology, Dong Fang Hospital, Beijing University of Chinese Medicine, Beijing 100078, China
| | - Yun-Liang Wang
- Department of Gastroenterology, Dong Fang Hospital, Beijing University of Chinese Medicine, Beijing 100078, China
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37
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Kayama H, Okumura R, Takeda K. Interaction Between the Microbiota, Epithelia, and Immune Cells in the Intestine. Annu Rev Immunol 2021; 38:23-48. [PMID: 32340570 DOI: 10.1146/annurev-immunol-070119-115104] [Citation(s) in RCA: 401] [Impact Index Per Article: 100.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The gastrointestinal tract harbors numerous commensal bacteria, referred to as the microbiota, that benefit host health by digesting dietary components and eliminating pathogens. The intestinal microbiota maintains epithelial barrier integrity and shapes the mucosal immune system, balancing host defense and oral tolerance with microbial metabolites, components, and attachment to host cells. To avoid aberrant immune responses, epithelial cells segregate the intestinal microbiota from immune cells by constructing chemical and physical barriers, leading to the establishment of host-commensal mutualism. Furthermore, intestinal immune cells participate in the maintenance of a healthy microbiota community and reinforce epithelial barrier functions. Perturbations of the microbiota composition are commonly observed in patients with autoimmune diseases and chronic inflammatory disorders. An understanding of the intimate interactions between the intestinal microbiota, epithelial cells, and immune cells that are crucial for the maintenance of intestinal homeostasis might promote advances in diagnostic and therapeutic approaches for various diseases.
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Affiliation(s)
- Hisako Kayama
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; , , .,WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.,Institute for Advanced Co-Creation Studies, Osaka University, Suita, Osaka 565-0871, Japan
| | - Ryu Okumura
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; , , .,WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan
| | - Kiyoshi Takeda
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; , , .,WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan
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38
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Li S, Zheng M, Zhang Z, Peng H, Dai W, Liu J. Galli gigeriae endothelium corneum: its intestinal barrier protective activity in vitro and chemical composition. Chin Med 2021; 16:22. [PMID: 33593395 PMCID: PMC7885590 DOI: 10.1186/s13020-021-00432-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 02/06/2021] [Indexed: 11/10/2022] Open
Abstract
Background Galli gigeriae endothelium corneum (GGEC) has been effectively used for centuries for the treatment of functional dyspepsia (FD) in clinical practice in Asian countries. However, its potential mechanism and chemical composition remains undertermined. Methods In this study, the chemical profile of GGEC ethyl acetate extract (EAE) was evaluated by HPLC-Q-TOF–MS/MS. The effects of EAE on intestinal barrier function and inflammation were investigated in IEC-6 cells and RAW264.7 cells. Results The results showed that 33 compounds were tentatively identified, including 12 soy isoflavones, 7 bile acids for the first time in EAE. EAE significantly reinforced intestinal barrier function via increasing the tight junction protein levels of ZO-1 and Occludin, reducing the mRNA expression levels of interleukin (IL)-1β and IL-6 in tumor necrosis factor alpha (TNF-α)-challenged IEC-6 cells. The scratch wound assay showed that EAE accelerated wound healing of IEC-6 cells. EAE evidently reduced the level of NO in a dose-dependent manner with an IC50 value of 18.12 μg/mL, and the mRNA expression of TNF-α, IL-1β, IL-6, iNOS and COX-2 in LPS-treated RAW264.7 cells. Conclusion This study revealed the intestinal barrier protective effects and chemical profile of GGEC, and the results indicated that GGEC strengthened the intestinal barrier by up-regulating protein expression of tight junctions and limiting inflammatory responses.
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Affiliation(s)
- Shanshan Li
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China
| | - Meng Zheng
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China
| | - Zhentang Zhang
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China
| | - Hengying Peng
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China
| | - Wenling Dai
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China
| | - Jihua Liu
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. .,State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
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39
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Loke YL, Chew MT, Ngeow YF, Lim WWD, Peh SC. Colon Carcinogenesis: The Interplay Between Diet and Gut Microbiota. Front Cell Infect Microbiol 2020; 10:603086. [PMID: 33364203 PMCID: PMC7753026 DOI: 10.3389/fcimb.2020.603086] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 10/28/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) incidence increases yearly, and is three to four times higher in developed countries compared to developing countries. The well-known risk factors have been attributed to low physical activity, overweight, obesity, dietary consumption including excessive consumption of red processed meats, alcohol, and low dietary fiber content. There is growing evidence of the interplay between diet and gut microbiota in CRC carcinogenesis. Although there appears to be a direct causal role for gut microbes in the development of CRC in some animal models, the link between diet, gut microbes, and colonic carcinogenesis has been established largely as an association rather than as a cause-and-effect relationship. This is especially true for human studies. As essential dietary factors influence CRC risk, the role of proteins, carbohydrates, fat, and their end products are considered as part of the interplay between diet and gut microbiota. The underlying molecular mechanisms of colon carcinogenesis mediated by gut microbiota are also discussed. Human biological responses such as inflammation, oxidative stress, deoxyribonucleic acid (DNA) damage can all influence dysbiosis and consequently CRC carcinogenesis. Dysbiosis could add to CRC risk by shifting the effect of dietary components toward promoting a colonic neoplasm together with interacting with gut microbiota. It follows that dietary intervention and gut microbiota modulation may play a vital role in reducing CRC risk.
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Affiliation(s)
- Yean Leng Loke
- Centre for Biomedical Physics, School of Healthcare and Medical Sciences, Sunway University, Petaling Jaya, Malaysia
| | - Ming Tsuey Chew
- Centre for Biomedical Physics, School of Healthcare and Medical Sciences, Sunway University, Petaling Jaya, Malaysia
| | - Yun Fong Ngeow
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Kajang, Malaysia.,Centre for Research on Communicable Diseases, Universiti Tunku Abdul Rahman, Kajang, Malaysia
| | - Wendy Wan Dee Lim
- Department of Gastroenterology, Sunway Medical Centre, Petaling Jaya, Malaysia
| | - Suat Cheng Peh
- Ageing Health and Well-Being Research Centre, Sunway University, Petaling Jaya, Malaysia.,Department of Medical Sciences, School of Healthcare and Medical Sciences, Sunway University, Petaling Jaya, Malaysia
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40
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Alhouayek M, Ameraoui H, Muccioli GG. Bioactive lipids in inflammatory bowel diseases - From pathophysiological alterations to therapeutic opportunities. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1866:158854. [PMID: 33157277 DOI: 10.1016/j.bbalip.2020.158854] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 10/16/2020] [Accepted: 10/27/2020] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel diseases (IBDs), such as Crohn's disease and ulcerative colitis, are lifelong diseases that remain challenging to treat. IBDs are characterized by alterations in intestinal barrier function and dysregulation of the innate and adaptive immunity. An increasing number of lipids are found to be important regulators of inflammation and immunity as well as gut physiology. Therefore, the study of lipid mediators in IBDs is expected to improve our understanding of disease pathogenesis and lead to novel therapeutic opportunities. Here, through selected examples - such as fatty acids, specialized proresolving mediators, lysophospholipids, endocannabinoids, and oxysterols - we discuss how lipid signaling is involved in IBD physiopathology and how modulating lipid signaling pathways could affect IBDs.
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Affiliation(s)
- Mireille Alhouayek
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Bruxelles, Belgium.
| | - Hafsa Ameraoui
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Bruxelles, Belgium
| | - Giulio G Muccioli
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Bruxelles, Belgium.
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41
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Li C, Zhang S, Li L, Hu Q, Ji S. Ursodeoxycholic Acid Protects Against Arsenic Induced Hepatotoxicity by the Nrf2 Signaling Pathway. Front Pharmacol 2020; 11:594496. [PMID: 33178028 PMCID: PMC7596389 DOI: 10.3389/fphar.2020.594496] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 09/16/2020] [Indexed: 12/13/2022] Open
Abstract
Arsenic is ubiquitous toxic metalloid responsible for many human diseases all over the world. Contrastingly, Ursodeoxycholic acid (UDCA) has been suggested as efficient antioxidant in various liver diseases. However, there are no reports of the effects of UDCA on arsenious acid [As(III)]-induced hepatotoxicity. The objective of this study is to elucidate the protective actions of UDCA on As(III)-induced hepatotoxicity and explore its controlling role in biomolecular mechanisms in vivo and in vitro. The remarkable liver damage induced by As(III) was ameliorated by treatment with UDCA, as reflected by reduced histopathological changes of liver and elevation of serum AST, ALT levels. UDCA play a critical role in stabilization of cellular membrane potential, inhibition of apoptosis and LDH leakage in LO2 cells. Meanwhile, the activities of SOD, CAT and GSH-Px and the level of TSH, GSH were enhanced with UDCA administration, while the accumulations of intracellular ROS, MDA and rate of GSSG/GSH were decreased in vivo and in vitro. Further study disclosed that UDCA significantly inhibited As(III)-induced apoptosis through increasing the expression of Bcl-2 and decreasing the expression of Bax, p53, Cyt C, Cleaved caspase-3 and 9. Moreover, UDCA promoted the expression of nuclear Nrf2, HO-1, and NQO1, although arsenic regulated nuclear translocation of Nrf2 positively. When Nrf2 was silenced, the protective effect of UDCA was abolished. Collectively, the results of this study showed that UDCA protects hepatocytes antagonize As(III)-induced cytotoxicity, and its mechanism may be related to activation of Nrf2 signaling.
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Affiliation(s)
- Chao Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine, Shanghai Institute for Food and Drug Control, Shanghai, China
| | - Sheng Zhang
- NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine, Shanghai Institute for Food and Drug Control, Shanghai, China.,School of Pharmacy, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Liming Li
- NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine, Shanghai Institute for Food and Drug Control, Shanghai, China
| | - Qing Hu
- NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine, Shanghai Institute for Food and Drug Control, Shanghai, China
| | - Shen Ji
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine, Shanghai Institute for Food and Drug Control, Shanghai, China
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42
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Keely S, Talley NJ. Duodenal bile acids as determinants of intestinal mucosal homeostasis and disease. Neurogastroenterol Motil 2020; 32:e13854. [PMID: 32323477 DOI: 10.1111/nmo.13854] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 03/18/2020] [Accepted: 03/18/2020] [Indexed: 12/14/2022]
Abstract
The duodenal epithelium plays a pivotal role in the uptake and transport of dietary nutrients while simultaneously acting as physical and biochemical barrier to protect against harmful bacteria and antigens. In the case of functional dyspepsia (FD), the duodenum is of particular interest, due to observed local immune involvement and the proximity to the stomach and exposure to acidopeptic secretions. Recent observations in FD pathophysiology, including those reported by Beeckmans et al in this issue of the journal, have identified a loss of barrier function in the duodenal epithelium, an altered duodenal microbiome and alterations in intestinal bile acid pools. Because FD symptoms coincide with food intake and, thus, secretion of bile acids, these findings may indicate loss or imbalance of bile-acid-microbiota-epithelial homeostasis as a process driving FD. Here, we review the evidence linking these observations to FD symptoms.
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Affiliation(s)
- Simon Keely
- Priority Research Centre for Digestive Health and Neurogastroenterology, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Nicholas J Talley
- Priority Research Centre for Digestive Health and Neurogastroenterology, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
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Thompson RS, Vargas F, Dorrestein PC, Chichlowski M, Berg BM, Fleshner M. Dietary prebiotics alter novel microbial dependent fecal metabolites that improve sleep. Sci Rep 2020; 10:3848. [PMID: 32123201 PMCID: PMC7051969 DOI: 10.1038/s41598-020-60679-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 02/13/2020] [Indexed: 01/01/2023] Open
Abstract
Dietary prebiotics produce favorable changes in the commensal gut microbiome and reduce host vulnerability to stress-induced disruptions in complex behaviors such as sleep. The mechanisms for how prebiotics modulate stress physiology remain unclear; however, emerging evidence suggests that gut microbes and their metabolites may play a role. This study tested if stress and/or dietary prebiotics (Test diet) alter the fecal metabolome; and explored if these changes were related to sleep and/or gut microbial alpha diversity. Male F344 rats on either Test or Control diet were instrumented for electroencephalography biotelemetry measures of sleep/wake. After 5 weeks on diet, rats were either stressed or remained in home cages. Based on untargeted mass spectrometry and 16S rRNA gene sequencing, both stress and Test diet altered the fecal metabolome/microbiome. In addition, Test diet prevented the stress-induced reduction in microbial alpha diversity based on PD_Whole_Tree, which has been previously published. Network propagation analysis revealed that stress increased members of the neuroactive steroidal pregnane molecular family; and that Test diet reduced this effect. We also discovered links between sleep, alpha diversity, and pyrimidine, secondary bile acid, and neuroactive glucocorticoid/pregnanolone-type steroidal metabolites. These results reveal novel microbial-dependent metabolites that may modulate stress physiology and sleep.
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Affiliation(s)
- Robert S Thompson
- Department of Integrative Physiology, University of Colorado at Boulder, Boulder, CO, 80309-0354, USA
- Center for Neuroscience, University of Colorado at Boulder, Boulder, CO, 80309-0354, USA
| | - Fernando Vargas
- Division of Biological Sciences, University of California, San Diego, CA, 92093, USA
- Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA, 92093, USA
| | - Pieter C Dorrestein
- Division of Biological Sciences, University of California, San Diego, CA, 92093, USA
- Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA, 92093, USA
| | | | - Brian M Berg
- Mead Johnson Pediatric Nutrition Institute, Evansville, IN, 47712, USA
| | - Monika Fleshner
- Department of Integrative Physiology, University of Colorado at Boulder, Boulder, CO, 80309-0354, USA.
- Center for Neuroscience, University of Colorado at Boulder, Boulder, CO, 80309-0354, USA.
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Keely SJ, Steer CJ, Lajczak-McGinley NK. Ursodeoxycholic acid: a promising therapeutic target for inflammatory bowel diseases? Am J Physiol Gastrointest Liver Physiol 2019; 317:G872-G881. [PMID: 31365646 DOI: 10.1152/ajpgi.00163.2019] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The secondary bile acid ursodeoxycholic acid (UDCA) has long been known to have medicinal properties. As the therapeutically active component of bear bile, it has been used for centuries in traditional Chinese medicine to treat a range of conditions, while manufactured UDCA has been used for decades in Western medicine to treat cholestatic liver diseases. The beneficial qualities of UDCA are thought to be due to its well-established cytoprotective and anti-inflammatory actions. In addition to its established role in treating liver diseases, UDCA is now under investigation for numerous conditions associated with inflammation and apoptosis, including neurological, ocular, metabolic, and cardiovascular diseases. Here, we review the growing evidence base from in vitro and in vivo models to suggest that UDCA may also have a role to play in the therapy of inflammatory bowel diseases.
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Affiliation(s)
- Stephen J Keely
- Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
| | - Clifford J Steer
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota Medical School, Minneapolis, Minnesota.,Department of Genetics, Cell Biology, and Development, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Natalia K Lajczak-McGinley
- Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
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Goossens JF, Bailly C. Ursodeoxycholic acid and cancer: From chemoprevention to chemotherapy. Pharmacol Ther 2019; 203:107396. [DOI: 10.1016/j.pharmthera.2019.107396] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 07/16/2019] [Indexed: 12/12/2022]
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Zheng JD, He Y, Yu HY, Liu YL, Ge YX, Li XT, Li X, Wang Y, Guo MR, Qu YL, Qin XF, Jiang MS, Wang XH. Unconjugated bilirubin alleviates experimental ulcerative colitis by regulating intestinal barrier function and immune inflammation. World J Gastroenterol 2019; 25:1865-1878. [PMID: 31057300 PMCID: PMC6478610 DOI: 10.3748/wjg.v25.i15.1865] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 03/05/2019] [Accepted: 03/15/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Unconjugated bilirubin (UCB) is generally considered toxic but has gained recent prominence for its anti-inflammatory properties. However, the effects of it on the interaction between intestinal flora and organisms and how it influences immune responses remain unresolved. AIM To investigate the role of UCB in intestinal barrier function and immune inflammation in mice with dextran-sulfate-sodium-induced colitis. METHODS Acute colitis was induced by 3% (w/v) dextran sulfate sodium salt in drinking water for 6 d followed by untreated water for 2 d. Concurrently, mice with colitis were administered 0.2 mL UCB (400 μmol/L) by intra-gastric gavage for 7 d. Disease activity index (DAI) was monitored daily. Mice were sacrificed at the end of the experiment. The length of the colon and weight of the spleen were recorded. Serum level of D-lactate, intestinal digestive proteases activity, and changes to the gut flora were analyzed. In addition, colonic specimens were analyzed by histology and for expression of inflammatory markers and proteins. RESULTS Mice treated with UCB had significantly relieved severity of colitis, including lower DAI, longer colon length, and lower spleen weight (colon length: 4.92 ± 0.09 cm vs 3.9 ± 0.15 cm; spleen weight: 0.33 ± 0.04 vs 0.74 ± 0.04, P < 0.001). UCB administration inactivated digestive proteases (chymotrypsin: 18.70 ± 0.69 U/g vs 44.81 ± 8.60 U/g; trypsin: 1.52 ± 0.23 U/g vs 9.05 ± 1.77 U/g, P < 0.01), increased expression of tight junction (0.99 ± 0.05 vs 0.57 ± 0.03, P < 0.001), decreased serum level of D-lactate (31.76 ± 3.37 μmol/L vs 54.25 ± 1.45 μmol/L, P < 0.001), and lowered histopathological score (4 ± 0.57 vs 7 ± 0.57, P < 0.001) and activity of myeloperoxidase (46.79 ± 2.57 U/g vs 110.32 ± 19.19 U/g, P < 0.001). UCB also regulated the intestinal microbiota, inhibited expression of tumor necrosis factor (TNF) α and interleukin 1β (TNF-α: 52.61 ± 7.81 pg/mg vs 105.04 ± 11.92 pg/mg, interleukin 1β: 13.43 ± 1.68 vs 32.41 ± 4.62 pg/mg, P < 0.001), decreased expression of Toll-like receptor 4 (0.61 ± 0.09 vs 1.07 ± 0.03, P < 0.001) and myeloid differentiation primary response gene 88 (0.73 ± 0.08 vs 1.01 ± 0.07, P < 0.05), and increased expression of TNF-receptor-associated factor 6 (0.79 ± 0.02 vs 0.43 ± 0.09 P < 0.05) and inhibitor of kappa B α (0.93 ± 0.07 vs 0.72 ± 0.07, P < 0.05) in the colon. CONCLUSION UCB can protect intestinal barrier function, regulate normal intestinal homeostasis, and suppress inflammation via the Toll-like receptor 4/ nuclear factor-κB signaling pathway.
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Affiliation(s)
- Jia-Dong Zheng
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Yan He
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Heng-Yuan Yu
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Yuan-Li Liu
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Yi-Xuan Ge
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Xue-Ting Li
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Xue Li
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Yan Wang
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Meng-Ru Guo
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Yi-Lin Qu
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Xiao-Fa Qin
- Founder, GI Biopharma Inc., Westfield, NJ 07090, United States
| | - Ming-Shan Jiang
- Department of General Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Xiu-Hong Wang
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
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Nuclear Receptors in the Pathogenesis and Management of Inflammatory Bowel Disease. Mediators Inflamm 2019; 2019:2624941. [PMID: 30804707 PMCID: PMC6360586 DOI: 10.1155/2019/2624941] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 12/01/2018] [Accepted: 12/23/2018] [Indexed: 12/12/2022] Open
Abstract
Nuclear receptors (NRs) are ligand-dependent transcription factors that regulate the transcription of target genes. Previous epidemiological and genetic studies have documented the association of NRs with the risk of inflammatory bowel disease (IBD). Although the mechanisms of action of NRs in IBD have not been fully established, accumulating evidence has demonstrated that NRs play complicated roles in regulating intestinal immunity, mucosal barriers, and intestinal flora. As one of the first-line medications for the treatment of IBD, 5-aminosalicylic acid (5-ASA) activates peroxisome proliferator-activated receptor gamma (PPARγ) to attenuate colitis. The protective roles of rifaximin and rifampicin partly depend on promoting pregnane X receptor (PXR) expression. The aims of this review are to discuss the roles of several important NRs, such as PPARγ, PXR, vitamin D receptor (VDR), farnesoid X receptor (FXR), and RAR-related orphan receptor gammat (RORγt), in the pathogenesis of IBD and management strategies based on targeting these receptors.
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Zhao YN, Xu CP. Etiology, pathogenesis, diagnosis and treatment of bile reflux gastritis. Shijie Huaren Xiaohua Zazhi 2018; 26:1886-1892. [DOI: 10.11569/wcjd.v26.i32.1886] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Bile reflux gastritis is a common disease of the digestive system, whose clinical characteristics are abdominal pain, abdominal distention and nausea and vomiting, affecting the quality of life of patients seriously. However, the etiology and pathogenesis of bile reflux gastritis are still unclear, which may be related to gastrointestinal surgery, gallbladder disease, Helicobacter pylori infection, psychological factors, etc. There are many diagnostic methods, but a consensus on diagnosis is still lacking. Most of the current treatments are symptomatic treatments, but the overall efficacy is poor. This article reviews the etiology, pathogenesis, diagnosis and treatment of bile reflux gastritis, with an aim to provide a reference for further research of this disease.
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Affiliation(s)
- Ya-Nan Zhao
- Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Cui-Ping Xu
- Department of Gastroenterology, The First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
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Kim SH, Chun HJ, Choi HS, Kim ES, Keum B, Seo YS, Jeen YT, Lee HS, Um SH, Kim CD. Ursodeoxycholic acid attenuates 5-fluorouracil-induced mucositis in a rat model. Oncol Lett 2018; 16:2585-2590. [PMID: 30008943 PMCID: PMC6036549 DOI: 10.3892/ol.2018.8893] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Accepted: 05/22/2018] [Indexed: 12/12/2022] Open
Abstract
Intestinal mucositis is a commonly encountered complication of chemotherapy. However, there are few effective treatments or preventive methods. Ursodeoxycholic acid (UDCA) stabilizes cell membranes, acts as an antioxidant and inhibits apoptosis, thereby exerting cytoprotective effects. The aim of the present study was to examine the ability of UDCA to protecting against chemotherapy-associated mucositis. Sprague-Dawley rats were randomly assigned to five groups: Control, vehicle + 5-fluorouracil (5-FU), 5-FU + UDCA (10 mg/kg/day), 5-FU + UDCA (100 mg/kg/day) and 5-FU + UDCA (500 mg/kg/day). Following randomization, a single dose of 5-FU was injected and varying amounts of UDCA was administered to each group. UDCA was administered orally to rats for 6 days, beginning 1 day prior to 5-FU administration. The rats were sacrificed 1 day following the last UDCA administration and intestinal tissue specimens were prepared for analysis. UDCA administration attenuated body weight loss, decreased inflammatory cytokine levels and curbed intestinal villus damage in the 10 and 100 mg/kg/day groups. When compared with the jejunal villi lengths in the vehicle+5-FU group (212.8±58.0 µm), those in the 5-FU + UDCA (10 mg/kg/day) and 5-FU + UDCA (100 mg/kg/day) groups were significantly greater [331.3±18.0 µm (P=0.001) and 310.0±112.6 µm (P=0.046), respectively]. Tumor necrosis factor-α and interleukin-6 levels were reduced in the 10 and 100 mg/kg/day UDCA groups (P<0.05). UDCA considerably attenuated the elevation in inflammatory cytokines and intestinal villus damage. The results of the study suggest that UDCA may be used as a protective agent against chemotherapy-associated intestinal mucositis.
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Affiliation(s)
- Seung Han Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Hoon Jai Chun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Hyuk Soon Choi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Eun Sun Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Bora Keum
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Yeon Seok Seo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Yoon Tae Jeen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Hong Sik Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Soon Ho Um
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Chang Duck Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Gastrointestinal Medical Instrument Research, Korea University College of Medicine, Seoul 02841, Republic of Korea
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