|
1
|
Czopik AK, McNamee EN, Vaughn V, Huang X, Bang IH, Clark T, Wang Y, Ruan W, Nguyen T, Masterson JC, Tak E, Frank S, Collins CB, Li H, Rodriguez-Aguayo C, Lopez-Berestein G, Gerich ME, Furuta GT, Yuan X, Sood AK, de Zoeten EF, Eltzschig HK. HIF-2α-dependent induction of miR-29a restrains T H1 activity during T cell dependent colitis. Nat Commun 2024; 15:8042. [PMID: 39271652 PMCID: PMC11399416 DOI: 10.1038/s41467-024-52113-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
Metabolic imbalance leading to inflammatory hypoxia and stabilization of hypoxia-inducible transcription factors (HIFs) is a hallmark of inflammatory bowel diseases. We hypothesize that HIF could be stabilized in CD4+ T cells during intestinal inflammation and alter the functional responses of T cells via regulation of microRNAs. Our assays reveal markedly increased T cell-intrinsic hypoxia and stabilization of HIF protein during experimental colitis. microRNA screen in primary CD4+ T cells points us towards miR-29a and our subsequent studies identify a selective role for HIF-2α in CD4-cell-intrinsic induction of miR-29a during hypoxia. Mice with T cell-intrinsic HIF-2α deletion display elevated T-bet (target of miR-29a) levels and exacerbated intestinal inflammation. Mice with miR-29a deficiency in T cells show enhanced intestinal inflammation. T cell-intrinsic overexpression of HIF-2α or delivery of miR-29a mimetic dampen TH1-driven colitis. In this work, we show a previously unrecognized function for hypoxia-dependent induction of miR-29a in attenuating TH1-mediated inflammation.
Collapse
Affiliation(s)
- Agnieszka K Czopik
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
| | - Eóin N McNamee
- Mucosal Inflammation Program, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
- Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, USA
| | - Victoria Vaughn
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Xiangsheng Huang
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - In Hyuk Bang
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Trent Clark
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Yanyu Wang
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Wei Ruan
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Tom Nguyen
- Mucosal Inflammation Program, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
- Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, USA
| | - Joanne C Masterson
- Mucosal Inflammation Program, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
- Gastrointestinal Eosinophilic Disease Program University of Colorado Anschutz School of Medicine, Aurora, CO, USA
- Department of Pediatrics, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
| | - Eunyoung Tak
- Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, USA
- Department of Convergence Medicine, Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sandra Frank
- Organ Protection Program, Department of Anesthesiology, University of Colorado - Anschutz Medical Campus, Aurora, CO, USA
- Department of Anaesthesiology, LMU University Hospital, LMU Munich, Munich, Germany
| | - Colm B Collins
- Mucosal Inflammation Program, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
- Department of Pediatrics, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
| | - Howard Li
- Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado - Anschutz Medical Campus, Aurora, CO, USA
| | - Cristian Rodriguez-Aguayo
- Departmental of Experimental Therapeutics and Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Gabriel Lopez-Berestein
- Departmental of Experimental Therapeutics and Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mark E Gerich
- Mucosal Inflammation Program, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
- Division of Gastroenterology & Hepatology, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
| | - Glenn T Furuta
- Mucosal Inflammation Program, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
- Gastrointestinal Eosinophilic Disease Program University of Colorado Anschutz School of Medicine, Aurora, CO, USA
- Department of Pediatrics, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
| | - Xiaoyi Yuan
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Anil K Sood
- Departmental of Experimental Therapeutics and Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Edwin F de Zoeten
- Mucosal Inflammation Program, University of Colorado Anschutz School of Medicine, Aurora, CO, USA.
- Department of Pediatrics, University of Colorado Anschutz School of Medicine, Aurora, CO, USA.
| | - Holger K Eltzschig
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- Center for Outcomes Research, Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center, Houston, TX, USA
| |
Collapse
|
|
2
|
Abdulazeez I, Ismail IS, Mohd Faudzi SM, Christianus A, Chong SG. Study on the acute toxicity of sodium taurocholate via zebrafish mortality, behavioral response, and NMR-metabolomics analysis. Drug Chem Toxicol 2024; 47:115-130. [PMID: 37548163 DOI: 10.1080/01480545.2023.2242005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 07/20/2023] [Indexed: 08/08/2023]
Abstract
Sodium taurocholate (NaT) is a hydrophobic bile salt that exhibits varying toxicity and antimicrobial activity. The accumulation of BSs during their entero-hepatic cycle causes cytotoxicity in the liver and intestine and could also alter the intestinal microbiome leading to various diseases. In this research, the acute toxicity of sodium taurocholate in different concentrations (3000 mg/L, 1500 mg/L, 750 mg/L, 375 mg/L, and 0 mg/L) was investigated on four months old zebrafish by immersion in water for 96 h. The results were determined based on the fish mortality, behavioral response, and NMR metabolomics analysis which revealed LC50 of 1760.32 mg/L and 1050.42 mg/L after 72 and 96 h treatment, respectively. However, the non-lethal NaT concentrations of 750 mg/L and 375 mg/L at 96 h exposure significantly (p ≤ 0.05) decreased the total distance traveled and the activity duration, also caused surface respiration on the zebrafish. Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) revealed that the metabolome of the fish treated with 750 mg/L was discriminated from that of the control by PC1. Major significantly downregulated metabolites by NaT-induction include valine, isoleucine, 2-hydroxyvalerate, glycine, glycerol, choline, glucose, pyruvate, anserine, threonine, carnitine and homoserine. On the contrary, taurine, creatine, lactate, acetate and 3-hydroxybutyrate were upregulated suggesting cellular consumption of lipids, glucose and amino acids for adenosine triphosphate (ATP) generation during immune and inflammatory response. whereby these metabolites were released in the process. In conclusion, the research revealed the toxic effect of NaT and its potential to trigger changes in zebrafish metabolism.
Collapse
Affiliation(s)
- Isah Abdulazeez
- Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, UPM Serdang Selangor, Malaysia
| | - Intan Safinar Ismail
- Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, UPM Serdang Selangor, Malaysia
- Natural Medicines and Product Research Laboratory (NaturMeds), Institute of Bioscience (IBS), Universiti Putra Malaysia, UPM Serdang Selangor, Malaysia
| | - Siti Munirah Mohd Faudzi
- Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, UPM Serdang Selangor, Malaysia
| | - Annie Christianus
- Department of Aquaculture, Faculty of Agricultural Sciences, Universiti Putra Malaysia, UPM Serdang Selangor, Malaysia
| | - Seok-Giok Chong
- Natural Medicines and Product Research Laboratory (NaturMeds), Institute of Bioscience (IBS), Universiti Putra Malaysia, UPM Serdang Selangor, Malaysia
| |
Collapse
|
|
3
|
Jiang L, Li J, Ji K, Lei L, Li H. MAT2A inhibition suppresses inflammation in Porphyromonas gingivalis-infected human gingival fibroblasts. J Oral Microbiol 2023; 16:2292375. [PMID: 38130504 PMCID: PMC10732205 DOI: 10.1080/20002297.2023.2292375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 12/03/2023] [Indexed: 12/23/2023] Open
Abstract
Background Methionine adenosyl transferase II alpha (MAT2A) is the key enzyme to transform methionine into S-adenosylmethionine (SAM), the main methylgroup donor involved in the methylation. The purpose of our study wasto explore whether MAT2A-mediated methionine metabolism affected theexpression of inflammatory cytokines in human gingival fibroblasts(hGFs). Methods Both healthy and inflamed human gingiva were collected. HGFs werecultured and treated with P. gingivalis, with or without MAT2Ainhibitor (PF9366), small interference RNA (siRNA), or extrinsic SAMpretreatment. The levels of inflammatory cytokines were detected byreal-time PCR, western blotting, and ELISA. SAM levels were detectedby ELISA. The nuclear factor-kappa B (NF-κB) and mitogen-activatedprotein kinase (MAPK) pathway was explored by western blotting. Results The expression of MAT2A was increased in the inflamed tissues. P.gingivalis infection promoted the expression of MAT2A and SAM inhGFs. Meanwhile, PF9366 and MAT2A-knockdown significantly decreasedexpression of inflammatory cytokines and SAM production. PF9366inhibited activation of NF-κB/MAPK pathway in P. gingivalis-treatedhGFs. Conclusions MAT2A-mediated methionine metabolism promoted P. gingivalis-inducedinflammation in hGFs. Targeting MAT2A may provide a novel therapeuticmethod for modulating periodontitis.
Collapse
Affiliation(s)
- Lishan Jiang
- Nanjing Stomatological Hospital, Affiliated Hospital of medical School, Nanjing University, Nanjing, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of medical School, Nanjing University, Nanjing, China
| | - Jingwen Li
- Nanjing Stomatological Hospital, Affiliated Hospital of medical School, Nanjing University, Nanjing, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of medical School, Nanjing University, Nanjing, China
| | - Kun Ji
- Nanjing Stomatological Hospital, Affiliated Hospital of medical School, Nanjing University, Nanjing, China
| | - Lang Lei
- Nanjing Stomatological Hospital, Affiliated Hospital of medical School, Nanjing University, Nanjing, China
| | - Houxuan Li
- Nanjing Stomatological Hospital, Affiliated Hospital of medical School, Nanjing University, Nanjing, China
| |
Collapse
|
|
4
|
Fardous AM, Heydari AR. Uncovering the Hidden Dangers and Molecular Mechanisms of Excess Folate: A Narrative Review. Nutrients 2023; 15:4699. [PMID: 37960352 PMCID: PMC10648405 DOI: 10.3390/nu15214699] [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: 09/29/2023] [Revised: 10/26/2023] [Accepted: 11/03/2023] [Indexed: 11/15/2023] Open
Abstract
This review delves into the intricate relationship between excess folate (vitamin B9) intake, especially its synthetic form, namely, folic acid, and its implications on health and disease. While folate plays a pivotal role in the one-carbon cycle, which is essential for DNA synthesis, repair, and methylation, concerns arise about its excessive intake. The literature underscores potential deleterious effects, such as an increased risk of carcinogenesis; disruption in DNA methylation; and impacts on embryogenesis, pregnancy outcomes, neurodevelopment, and disease risk. Notably, these consequences stretch beyond the immediate effects, potentially influencing future generations through epigenetic reprogramming. The molecular mechanisms underlying these effects were examined, including altered one-carbon metabolism, the accumulation of unmetabolized folic acid, vitamin-B12-dependent mechanisms, altered methylation patterns, and interactions with critical receptors and signaling pathways. Furthermore, differences in the effects and mechanisms mediated by folic acid compared with natural folate are highlighted. Given the widespread folic acid supplementation, it is imperative to further research its optimal intake levels and the molecular pathways impacted by its excessive intake, ensuring the health and well-being of the global population.
Collapse
Affiliation(s)
- Ali M. Fardous
- Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA;
| | - Ahmad R. Heydari
- Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA;
- Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48202, USA
| |
Collapse
|
|
5
|
Abstract
The intestinal tract is the entry gate for nutrients and symbiotic organisms, being in constant contact with external environment. DNA methylation is one of the keys to how environmental conditions, diet and nutritional status included, shape functionality in the gut and systemically. This review aims to summarise findings on the importance of methylation to gut development, differentiation and function. Evidence to date on how external factors such as diet, dietary supplements, nutritional status and microbiota modifications modulate intestinal function through DNA methylation is also presented.
Collapse
|
|
6
|
Montenegro-Burke JR, Kok BP, Guijas C, Domingo-Almenara X, Moon C, Galmozzi A, Kitamura S, Eckmann L, Saez E, Siuzdak GE, Wolan DW. Metabolomics activity screening of T cell-induced colitis reveals anti-inflammatory metabolites. Sci Signal 2021; 14:eabf6584. [PMID: 34582249 DOI: 10.1126/scisignal.abf6584] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
[Figure: see text].
Collapse
Affiliation(s)
- J Rafael Montenegro-Burke
- Scripps Center for Metabolomics and Mass Spectrometry, Scripps Research Institute; La Jolla, California 92037, USA
| | - Bernard P Kok
- Scripps Center for Metabolomics and Mass Spectrometry, Scripps Research Institute; La Jolla, California 92037, USA
| | - Carlos Guijas
- Scripps Center for Metabolomics and Mass Spectrometry, Scripps Research Institute; La Jolla, California 92037, USA
| | - Xavier Domingo-Almenara
- Scripps Center for Metabolomics and Mass Spectrometry, Scripps Research Institute; La Jolla, California 92037, USA
| | - Clara Moon
- Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA 92037, USA
| | - Andrea Galmozzi
- Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA 92037, USA
| | - Seiya Kitamura
- Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA 92037, USA
| | - Lars Eckmann
- Department of Medicine, University of California, La Jolla CA 92093, USA
| | - Enrique Saez
- Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA 92037, USA
| | - Gary E Siuzdak
- Scripps Center for Metabolomics and Mass Spectrometry, Scripps Research Institute; La Jolla, California 92037, USA.,Department of Structural and Computational Biology, Scripps Research Institute, La Jolla, CA 92037, USA
| | - Dennis W Wolan
- Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA 92037, USA.,Department of Structural and Computational Biology, Scripps Research Institute, La Jolla, CA 92037, USA
| |
Collapse
|
|
7
|
Singh I, Kim J, Saxena N, Choi S, Islam SMT, Singh AK, Khan M, Won J. Vascular and immunopathological role of Asymmetric Dimethylarginine (ADMA) in Experimental Autoimmune Encephalomyelitis. Immunology 2021; 164:602-616. [PMID: 34310708 DOI: 10.1111/imm.13396] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 07/01/2021] [Accepted: 07/12/2021] [Indexed: 12/11/2022] Open
Abstract
Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor/uncoupler inducing vascular pathology. Vascular pathology is an important factor for the development and progression of CNS pathology of MS, yet the role of ADMA in MS remains elusive. Patients with multiple sclerosis (MS) are reported to have elevated blood levels of ADMA, and mice with experimental autoimmune encephalomyelitis (EAE, an animal model of MS) generated by auto-immunization of myelin oligodendrocyte glycoprotein (MOG) and blood-brain barrier (BBB) disruption by pertussis toxin also had increased blood ADMA levels in parallel with induction of clinical disease. To explore the role of ADMA in EAE pathogenesis, EAE mice were treated with a daily dose of ADMA. It is of special interest that ADMA treatment enhanced the BBB disruption in EAE mice and exacerbated the clinical and CNS disease of EAE. ADMA treatment also induced the BBB disruption and EAE disease in MOG-immunized mice even without pertussis toxin treatment, suggesting the role of ADMA in BBB dysfunction in EAE. T-cell polarization studies also documented that ADMA treatment promotes TH 1- and TH 17-mediated immune responses but without affecting Treg-mediated immune response in EAE mice as well as in in vitro T-cell culture. Taken together, these data, for the first time, document the vascular and immunopathogenic roles of ADMA in EAE, thus pointing to the potential of ADMA-mediated mechanism as a new target of potential therapy for MS.
Collapse
Affiliation(s)
- Inderjit Singh
- Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA.,Research Service, Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina, USA
| | - Judong Kim
- Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Nishant Saxena
- Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Seungho Choi
- Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA
| | - S M Touhidul Islam
- Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Avtar K Singh
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.,Pathology and Laboratory Medicine Service, Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina, USA
| | - Mushfiquddin Khan
- Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Jeseong Won
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| |
Collapse
|
|
8
|
Berg NK, Li J, Kim B, Mills T, Pei G, Zhao Z, Li X, Zhang X, Ruan W, Eltzschig HK, Yuan X. Hypoxia-inducible factor-dependent induction of myeloid-derived netrin-1 attenuates natural killer cell infiltration during endotoxin-induced lung injury. FASEB J 2021; 35:e21334. [PMID: 33715200 PMCID: PMC8251729 DOI: 10.1096/fj.202002407r] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 12/21/2022]
Abstract
Sepsis and sepsis‐associated lung inflammation significantly contribute to the morbidity and mortality of critical illness. Here, we examined the hypothesis that neuronal guidance proteins could orchestrate inflammatory events during endotoxin‐induced lung injury. Through a targeted array, we identified netrin‐1 as the top upregulated neuronal guidance protein in macrophages treated with lipopolysaccharide (LPS). Furthermore, we found that netrin‐1 is highly enriched in infiltrating myeloid cells, particularly in macrophages during LPS‐induced lung injury. Transcriptional studies implicate hypoxia‐inducible factor HIF‐1α in the transcriptional induction of netrin‐1 during LPS treatment. Subsequently, the deletion of netrin‐1 in the myeloid compartment (Ntn1loxp/loxp LysM Cre) resulted in exaggerated mortality and lung inflammation. Surprisingly, further studies revealed enhanced natural killer cells (NK cells) infiltration in Ntn1loxp/loxp LysM Cre mice, and neutralization of NK cell chemoattractant chemokine (C‐C motif) ligand 2 (CCL2) reversed the exaggerated lung inflammation. Together, these studies provide functional insight into myeloid cell‐derived netrin‐1 in controlling lung inflammation through the modulation of CCL2‐dependent infiltration of NK cells.
Collapse
Affiliation(s)
- Nathaniel K Berg
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Jiwen Li
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.,Department of Cardiac Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Boyun Kim
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Tingting Mills
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Guangsheng Pei
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center, Houston, TX, USA
| | - Zhongming Zhao
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center, Houston, TX, USA.,Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, TX, USA
| | - Xiangyun Li
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.,Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China
| | - Xu Zhang
- Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA.,Center for Clinical and Translational Sciences, The University of Texas Health Science Center, Houston, TX, USA
| | - Wei Ruan
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.,Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Holger K Eltzschig
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Xiaoyi Yuan
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| |
Collapse
|
|
9
|
Qu X, Neuhoff C, Cinar MU, Pröll M, Tholen E, Tesfaye D, Hölker M, Schellander K, Uddin MJ. Epigenetic Modulation of TLR4 Expression by Sulforaphane Increases Anti-Inflammatory Capacity in Porcine Monocyte-Derived Dendritic Cells. BIOLOGY 2021; 10:biology10060490. [PMID: 34072812 PMCID: PMC8227201 DOI: 10.3390/biology10060490] [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: 04/19/2021] [Revised: 05/21/2021] [Accepted: 05/28/2021] [Indexed: 11/16/2022]
Abstract
Simple Summary Epigenetic modifications of the genes regulate the inflammation process that includes the DNA methylation and histone acetylation. Sulforaphane is well known for its immunomodulatory properties. Notably, the mechanism of its anti-inflammatory functions involving epigenetic modifications is unclear. This study highlighted the regulatory mechanism of sulforaphane in the innate immunity responses in an acute inflammatory state employ in vivo cell culture model. Porcine monocyte-derived dendritic cells were exposed to LPS with or without sulforaphane pre-treatment for these purposes. Epigenetics modulations of the important genes and regulatory factors were studies as well as the immune responses of the cells were vigorously studied over the period of time. This study deciphers the mechanism of SFN in restricting the excessive inflammatory reactions, thereby, exerting its protective and anti-inflammatory function though epigenetic mechanism. Abstract Inflammation is regulated by epigenetic modifications, including DNA methylation and histone acetylation. Sulforaphane (SFN), a histone deacetylase (HDAC) inhibitor, is also a potent immunomodulatory agent, but its anti-inflammatory functions through epigenetic modifications remain unclear. Therefore, this study aimed to investigate the epigenetic effects of SFN in maintaining the immunomodulatory homeostasis of innate immunity during acute inflammation. For this purpose, SFN-induced epigenetic changes and expression levels of immune-related genes in response to lipopolysaccharide (LPS) stimulation of monocyte-derived dendritic cells (moDCs) were analyzed. These results demonstrated that SFN inhibited HDAC activity and caused histone H3 and H4 acetylation. SFN treatment also induced DNA demethylation in the promoter region of the MHC-SLA1 gene, resulting in the upregulation of Toll-like receptor 4 (TLR4), MHC-SLA1, and inflammatory cytokines’ expression at 6 h of LPS stimulation. Moreover, the protein levels of cytokines in the cell culture supernatants were significantly inhibited by SFN pre-treatment followed by LPS stimulation in a time-dependent manner, suggesting that inhibition of HDAC activity and DNA methylation by SFN may restrict the excessive inflammatory cytokine availability in the extracellular environment. We postulate that SFN may exert a protective and anti-inflammatory function by epigenetically influencing signaling pathways in experimental conditions employing porcine moDCs.
Collapse
Affiliation(s)
- Xueqi Qu
- The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen 518055, China
- Institute of Animal Science, Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115 Bonn, Germany; (M.P.); (E.T.); (D.T.); (M.H.); (K.S.); (M.J.U.)
- Correspondence: (X.Q.); (C.N.)
| | - Christiane Neuhoff
- Institute of Animal Science, Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115 Bonn, Germany; (M.P.); (E.T.); (D.T.); (M.H.); (K.S.); (M.J.U.)
- Correspondence: (X.Q.); (C.N.)
| | - Mehmet Ulas Cinar
- Department of Animal Science, Faculty of Agriculture, Erciyes University, 38039 Kayseri, Turkey;
| | - Maren Pröll
- Institute of Animal Science, Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115 Bonn, Germany; (M.P.); (E.T.); (D.T.); (M.H.); (K.S.); (M.J.U.)
| | - Ernst Tholen
- Institute of Animal Science, Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115 Bonn, Germany; (M.P.); (E.T.); (D.T.); (M.H.); (K.S.); (M.J.U.)
| | - Dawit Tesfaye
- Institute of Animal Science, Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115 Bonn, Germany; (M.P.); (E.T.); (D.T.); (M.H.); (K.S.); (M.J.U.)
| | - Michael Hölker
- Institute of Animal Science, Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115 Bonn, Germany; (M.P.); (E.T.); (D.T.); (M.H.); (K.S.); (M.J.U.)
| | - Karl Schellander
- Institute of Animal Science, Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115 Bonn, Germany; (M.P.); (E.T.); (D.T.); (M.H.); (K.S.); (M.J.U.)
| | - Muhammad Jasim Uddin
- Institute of Animal Science, Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115 Bonn, Germany; (M.P.); (E.T.); (D.T.); (M.H.); (K.S.); (M.J.U.)
- School of Veterinary Medicine, Murdoch University, Murdoch, WA 6150, Australia
- Department of Medicine, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh
- School of Veterinary Science, University of Queensland, Gatton, QLD 4343, Australia
| |
Collapse
|
|
10
|
Ellrichmann M, Bethge J, Boesenkoetter J, Conrad C, Noth R, Bahmer T, Nikolaus S, Aden K, Zeissig S, Schreiber S. Subclinical Pulmonary Involvement in Active IBD Responds to Biologic Therapy. J Crohns Colitis 2021; 15:1339-1345. [PMID: 33544122 PMCID: PMC8521732 DOI: 10.1093/ecco-jcc/jjab024] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Increased mortality from respiratory diseases was observed in epidemiological studies of patients with ulcerative colitis [UC] as a potentially underestimated extraintestinal manifestation. We therefore investigated the presence of pulmonary manifestations of inflammatory bowel disease [IBD] and the potential effect of tumour necrosis factor alpha [TNF-α] inhibitors on pulmonary function tests [PFT] in a prospective, longitudinal study. METHODS In all, 92 consecutive patients with IBD (49 Crohn´s disease [CD], 43 UC) and 20 healthy controls were recruited. Fifty patients with IBD were in remission, and 42 had active disease with 22 of these being examined before and 6 weeks after initiating anti-TNF therapy. Pulmonary function tests [PFT] were evaluated using the Medical Research Council [MRC] dyspnoea index and a standardized body plethysmography. IBD activity was assessed using Harvey-Bradshaw index for CD and partial Mayo score for UC. Data are presented as mean ± standard error of the mean [SEM]. RESULTS Patients with active IBD showed significant reduction of PFT. Forced expiration [Tiffeneau index] values [FEV1%] were significantly reduced in IBD patients with active disease [78.8 ± 1.1] compared with remission [86.1 ± 0.9; p = 0.0002] and with controls [87.3 ± 1.3; p = 0.001]. Treatment with anti-TNF induced a significant relief in obstruction [p = 0.003 for FEV1% in comparison with baseline levels]. The level of pulmonary obstruction significantly correlated with clinical inflammation scores [HBI or Mayo]. CONCLUSIONS: PATIENTS with active IBD present with significant obstructive abnormalities in their PFTs. Obstruction is related to inflammatory activity, with anti-TNF improving PFTs. Pulmonary obstruction and possibly chronic bronchopulmonary inflammation is an overlooked problem in active IBD that is probably obscured by intestinal symptoms.
Collapse
Affiliation(s)
- M Ellrichmann
- Medical Department I, University Medical Center Schleswig Holstein, Kiel, Germany,Corresponding author: Mark Ellrichmann, MD, PhD, , Medical Department I, Arnold-Heller-Str. 3, Haus C, 24105 Kiel, Germany. Tel.: +49-431-500-22220; fax: +49-431-500-22378;
| | - J Bethge
- Medical Department I, University Medical Center Schleswig Holstein, Kiel, Germany
| | - J Boesenkoetter
- Medical Department I, University Medical Center Schleswig Holstein, Kiel, Germany
| | - C Conrad
- Medical Department I, University Medical Center Schleswig Holstein, Kiel, Germany
| | - R Noth
- Medical Department I, University Medical Center Schleswig Holstein, Kiel, Germany
| | - T Bahmer
- Medical Department I, University Medical Center Schleswig Holstein, Kiel, Germany
| | - S Nikolaus
- Medical Department I, University Medical Center Schleswig Holstein, Kiel, Germany
| | - K Aden
- Medical Department I, University Medical Center Schleswig Holstein, Kiel, Germany
| | - S Zeissig
- Department of Medicine I, University Medical Center Dresden, and Center for Regenerative Therapies Dresden [CRTD], Dresden, Germany
| | - S Schreiber
- Medical Department I, University Medical Center Schleswig Holstein, Kiel, Germany
| |
Collapse
|
|
11
|
Yue R, Wei X, Zhao J, Zhou Z, Zhong W. Essential Role of IFN-γ in Regulating Gut Antimicrobial Peptides and Microbiota to Protect Against Alcohol-Induced Bacterial Translocation and Hepatic Inflammation in Mice. Front Physiol 2021; 11:629141. [PMID: 33536944 PMCID: PMC7848155 DOI: 10.3389/fphys.2020.629141] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 12/23/2020] [Indexed: 12/12/2022] Open
Abstract
The mechanisms by which alcohol provokes bacterial translocation in the development of alcoholic liver disease (ALD) remain incompletely defined. Our previous study demonstrates that impaired gut epithelial antimicrobial defense is critically involved in the pathogenesis of ALD. The study was set to determine the mechanisms of how alcohol inhibits the antimicrobial ability of intestinal epithelial cells (IECs) and to explore possible solutions to this issue. C57BL/6J mice were fed either alcohol or isocaloric dextrin liquid diet for 8 weeks, and intestinal IFN-γ-signal transducer and activator of transcription (STAT) signaling was analyzed. We found that chronic alcohol exposure led to a significant reduction in intestinal IFN-γ levels compared to a control; the protein levels of phosphorylated STAT1 (p-STAT1) and p-STAT3 were both declined by alcohol. We then tested the effects of IFN-γ-STAT signaling on regulating antimicrobial peptides (AMPs), gut microbiota, and disease progression of ALD in a mouse model of chronic alcohol feeding, time-course acute IFN-γ treatment, and in vivo and in vitro IEC-specific STAT1 or STAT3 knockout mouse models, respectively. Administration of IFN-γ activated intestinal STAT1 and STAT3, upregulated the expression of Reg3 and α-defensins, orchestrated gut microbiota, and reversed alcohol-induced intestinal ZO-1 disruption and systemic endotoxin elevation as well as hepatic inflammation. Meanwhile, acute IFN-γ treatment time-dependently induced AMP expression and α-defensin activation. We then dissected the roles of STAT1 and STAT3 in this progress. Lack of IEC-specific STAT3 inhibited IFN-γ-induced expression of Reg3 and α-defensins and hindered activation of α-defensins via inactivating matrix metallopeptidase 7 (MMP7), whereas lack of IEC-specific STAT1 impaired IFN-γ-stimulated expression of α-defensins and the IEC marker, sodium-hydrogen exchanger 3. Lastly, we found that interleukin (IL)-18, a known IFN-γ inducer, was also reduced by alcohol in mice. IL-18 treatment to alcohol-fed mice normalized gut IFN-γ levels and ameliorated organ damages in both the intestine and liver. Taken together, the study reveals that IFN-γ is critically involved in the regulation of AMPs through regulation of STAT1 and STAT3; impaired IFN-γ-STAT signaling provides an explanation for alcohol-induced gut antimicrobial dysfunction and microbial dysbiosis. Therefore, IFN-γ remains a promising host defense-enhancing cytokine with unexplored clinical potential in ALD therapy.
Collapse
Affiliation(s)
- Ruichao Yue
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, United States
| | - Xiaoyuan Wei
- Division of Agriculture, Department of Animal Science, University of Arkansas, Fayetteville, AR, United States
| | - Jiangchao Zhao
- Division of Agriculture, Department of Animal Science, University of Arkansas, Fayetteville, AR, United States
| | - Zhanxiang Zhou
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, United States.,Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, United States
| | - Wei Zhong
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, United States.,Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, United States
| |
Collapse
|
|
12
|
Moein S, Vaghari-Tabari M, Qujeq D, Kashifard M, Shokri-Shirvani J, Hajian-Tilaki K. Association between serum folate with inflammatory markers, disease clinical activity and serum homocysteine in patients with inflammatory bowel disease. Does folate level have an effect on maintaining clinical remission? ACTA BIO-MEDICA : ATENEI PARMENSIS 2020; 91:e2020106. [PMID: 33525287 PMCID: PMC7927538 DOI: 10.23750/abm.v91i4.8467] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Accepted: 11/24/2019] [Indexed: 12/18/2022]
Abstract
Background: Folate is an important vitamin with protective effect against some human diseases. The aim of this study was to evaluate the relationship between serum folate levels, inflammatory markers and disease clinical activity in patients with inflammatory bowel disease (IBD). Methods: The participants were classified into two groups in which 38 IBD patients and 38 healthy controls were studied. Disease clinical activities were evaluated by means of established score systems. Serum folate, homocysteine and C-reactive protein and ESR were measured. Obtained data were analyzed with proper statistical methods and P- value less than 0.05 was considered as statistical significant. Results: The level of serum folate was significantly reduced in IBD patients with active disease compared to patients with clinical remission (p=0.043) and also healthy controls (p=0.008). Moreover, there was a significant inverse correlation between serum folate levels and C-reactive protein in IBD patients (r=-0.563 p=0.001). Conclusion: Serum folate levels is associated with inflammatory markers and disease clinical activity in IBD patients, therefore there is a possibility that disease clinical activity is reduced with adequate folate level. (www.actabiomedica.it)
Collapse
Affiliation(s)
| | - Mostafa Vaghari-Tabari
- Department of Clinical Biochemistry and Laboratory medicine, faculty of medicine, Tabriz university of medical sciences.
| | | | | | | | | |
Collapse
|
|
13
|
Yang L, Zhang J, Yang G, Xu H, Lin J, Shao L, Li J, Guo C, Du Y, Guo L, Li X, Han-Zhang H, Wang C, Chuai S, Ye J, Kang Q, Liu H, Ying J, Wang Y. The prognostic value of a Methylome-based Malignancy Density Scoring System to predict recurrence risk in early-stage Lung Adenocarcinoma. Theranostics 2020; 10:7635-7644. [PMID: 32685009 PMCID: PMC7359091 DOI: 10.7150/thno.44229] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 06/01/2020] [Indexed: 12/11/2022] Open
Abstract
Current NCCN guidelines do not recommend the use of adjuvant chemotherapy for stage IA lung adenocarcinoma patients with R0 surgery. However, 25% to 40% of patients with stage IA disease experience recurrence. Stratifying patients according to the recurrence risk may tailor adjuvant therapy and surveillance imaging for those with a higher risk. However, prognostic markers are often identified by comparing high-risk and low-risk cases which might introduce bias due to the widespread interpatient heterogeneity. Here, we developed a scoring system quantifying the degree of field cancerization in adjacent normal tissues and revealed its association with disease-free survival (DFS). Methods: We recruited a cohort of 44 patients with resected stage IA lung adenocarcinoma who did not receive adjuvant therapy. Both tumor and adjacent normal tissues were obtained from each patient and subjected to capture-based targeted genomic and epigenomic profiling. A novel methylome-based scoring system namely malignancy density ratio (MD ratio) was developed based on 39 patients by comparing tumor and corresponding adjacent normal tissues of each patient. A MD score was then obtained by Wald statistics. The correlations of MD ratio, MD score, and genomic features with clinical outcome were investigated. Results: Patients with a high-risk MD ratio showed a significantly shorter postsurgical DFS compared with those with a low-risk MD ratio (HR=4.47, P=0.01). The MD ratio was not associated with T stage (P=1), tumor cell fraction (P=0.748) nor inflammatory status (p=0.548). Patients with a high-risk MD score also demonstrated an inferior DFS (HR=4.69, P=0.039). In addition, multivariate analysis revealed EGFR 19 del (HR=5.39, P=0.012) and MD score (HR= 7.90, P=0.01) were independent prognostic markers. Conclusion: The novel methylome-based scoring system, developed by comparing the signatures between tumor and corresponding adjacent normal tissues of individual patients, largely minimizes the bias of interpatient heterogeneity and reveals a robust prognostic value in patients with resected lung adenocarcinoma.
Collapse
|
|
14
|
Translational Potential of Metabolomics on Animal Models of Inflammatory Bowel Disease-A Systematic Critical Review. Int J Mol Sci 2020; 21:ijms21113856. [PMID: 32485793 PMCID: PMC7312423 DOI: 10.3390/ijms21113856] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 05/24/2020] [Accepted: 05/26/2020] [Indexed: 12/16/2022] Open
Abstract
In the development of inflammatory bowel disease (IBD), the gut microbiota has been established as a key factor. Recently, metabolomics has become important for understanding the functional relevance of gut microbial changes in disease. Animal models for IBD enable the study of factors involved in disease development. However, results from animal studies may not represent the human situation. The aim of this study was to investigate whether results from metabolomics studies on animal models for IBD were similar to those from studies on IBD patients. Medline and Embase were searched for relevant studies up to May 2017. The Covidence systematic review software was used for study screening, and quality assessment was conducted for all included studies. Data showed a convergence of ~17% for metabolites differentiated between IBD and controls in human and animal studies with amino acids being the most differentiated metabolite subclass. The acute dextran sodium sulfate model appeared as a good model for analysis of systemic metabolites in IBD, but analytical platform, age, and biological sample type did not show clear correlations with any significant metabolites. In conclusion, this systematic review highlights the variation in metabolomics results, and emphasizes the importance of expanding the applied detection methods to ensure greater coverage and convergence between the various different patient phenotypes and animal models of inflammatory bowel disease.
Collapse
|
|
15
|
Liu G, Baird AW, Parsons MJ, Fan K, Skerrett-Byrne DA, Nair PM, Makanyengo S, Chen J, Neal R, Goggins BJ, Tay H, Mathe A, Soh WS, Minahan K, Hansbro PM, Nixon B, McCaughan GW, Holtmann G, Colgan SP, Keely S. Platelet activating factor receptor acts to limit colitis-induced liver inflammation. FASEB J 2020; 34:7718-7732. [PMID: 32293760 DOI: 10.1096/fj.201901779r] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 03/25/2020] [Accepted: 03/25/2020] [Indexed: 12/31/2022]
Abstract
Liver inflammation is a common extraintestinal manifestation in inflammatory bowel disease (IBD), yet, the mechanisms driving gut-liver axis inflammation remain poorly understood. IBD leads to a breakdown in the integrity of the intestinal barrier causing an increase in portal and systemic gut-derived antigens, which challenge the liver. Here, we examined the role of platelet activating factor receptor (PAFR) in colitis-associated liver damage using dextran sulfate sodium (DSS) and anti-CD40-induced colitis models. Both DSS and anti-CD40 models exhibited liver inflammation associated with colitis. Colitis reduced global PAFR protein expression in mouse livers causing an exclusive re-localization of PAFR to the portal triad. The global decrease in liver PAFR was associated with increased sirtuin 1 while relocalized PAFR expression was limited to Kupffer cells (KCs) and co-localized with toll-like receptor 4. DSS activated the NLRP3-inflammasome and increased interleukin (IL)-1β in the liver. Antagonism of PAFR amplified the inflammasome response by increasing NLRP3, caspase-1, and IL-1β protein levels in the liver. LPS also increased NLRP3 response in human hepatocytes, however, overexpression of PAFR restored the levels of NLPR3 and caspase-1 proteins. Interestingly, KCs depletion also increased IL-1β protein in mouse liver after DSS challenge. These data suggest a protective role for PAFR-expressing KCs during colitis and that regulation of PAFR is important for gut-liver axis homeostasis.
Collapse
Affiliation(s)
- Gang Liu
- Priority Research Centre for Digestive Health and Neurogastroenterology, The University of Newcastle, Newcastle, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW, Australia.,School of Life Science, Faculty of Science, University of Technology Sydney, Ultimo, NSW, Australia.,Centre for Inflammation, Centenary Institute, Camperdown, NSW, Australia
| | - Alan W Baird
- UCD School of Veterinary Medicine, University College Dublin, Dublin, Ireland
| | - Marie J Parsons
- Priority Research Centre for Digestive Health and Neurogastroenterology, The University of Newcastle, Newcastle, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW, Australia
| | - Kening Fan
- Priority Research Centre for Digestive Health and Neurogastroenterology, The University of Newcastle, Newcastle, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW, Australia
| | - David A Skerrett-Byrne
- Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,School of Environmental and Life Sciences, Priority Research Centre for Reproductive Science, The University of Newcastle, Callaghan, NSW, Australia
| | - Prema M Nair
- Priority Research Centre for Digestive Health and Neurogastroenterology, The University of Newcastle, Newcastle, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW, Australia
| | - Samwel Makanyengo
- Priority Research Centre for Digestive Health and Neurogastroenterology, The University of Newcastle, Newcastle, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW, Australia
| | - Jinbiao Chen
- Liver Injury and Cancer Program, Centenary Research Institute, Camperdown, NSW, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Rachel Neal
- Priority Research Centre for Digestive Health and Neurogastroenterology, The University of Newcastle, Newcastle, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW, Australia
| | - Bridie J Goggins
- Priority Research Centre for Digestive Health and Neurogastroenterology, The University of Newcastle, Newcastle, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW, Australia
| | - Hock Tay
- Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW, Australia.,Priority Research Centre for Healthy Lungs, The University of Newcastle, Newcastle, NSW, Australia
| | - Andrea Mathe
- Priority Research Centre for Digestive Health and Neurogastroenterology, The University of Newcastle, Newcastle, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW, Australia
| | - Wai S Soh
- Priority Research Centre for Digestive Health and Neurogastroenterology, The University of Newcastle, Newcastle, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW, Australia
| | - Kyra Minahan
- Priority Research Centre for Digestive Health and Neurogastroenterology, The University of Newcastle, Newcastle, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW, Australia
| | - Phil M Hansbro
- School of Life Science, Faculty of Science, University of Technology Sydney, Ultimo, NSW, Australia.,Centre for Inflammation, Centenary Institute, Camperdown, NSW, Australia
| | - Brett Nixon
- Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,School of Environmental and Life Sciences, Priority Research Centre for Reproductive Science, The University of Newcastle, Callaghan, NSW, Australia
| | - Geoffrey W McCaughan
- Liver Injury and Cancer Program, Centenary Research Institute, Camperdown, NSW, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Gerald Holtmann
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Woolloongabba, QLD, Australia.,Faculty of Medicine, The University of Queensland, Woolloongabba, QLD, Australia
| | - Sean P Colgan
- University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Simon Keely
- Priority Research Centre for Digestive Health and Neurogastroenterology, The University of Newcastle, Newcastle, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW, Australia
| |
Collapse
|
|
16
|
Jones P, Lucock M, Scarlett CJ, Veysey M, Beckett EL. Folate and Inflammation – links between folate and features of inflammatory conditions. JOURNAL OF NUTRITION & INTERMEDIARY METABOLISM 2019. [DOI: 10.1016/j.jnim.2019.100104] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
|
|
17
|
Liu G, Mateer SW, Hsu A, Goggins BJ, Tay H, Mathe A, Fan K, Neal R, Bruce J, Burns G, Minahan K, Maltby S, Fricker M, Foster PS, Wark PAB, Hansbro PM, Keely S. Platelet activating factor receptor regulates colitis-induced pulmonary inflammation through the NLRP3 inflammasome. Mucosal Immunol 2019; 12:862-873. [PMID: 30976089 DOI: 10.1038/s41385-019-0163-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 03/07/2019] [Accepted: 03/24/2019] [Indexed: 02/04/2023]
Abstract
Extra-intestinal manifestations (EIM) are common in inflammatory bowel disease (IBD). One such EIM is sub-clinical pulmonary inflammation, which occurs in up to 50% of IBD patients. In animal models of colitis, pulmonary inflammation is driven by neutrophilic infiltrations, primarily in response to the systemic bacteraemia and increased bacterial load in the lungs. Platelet activating factor receptor (PAFR) plays a critical role in regulating pulmonary responses to infection in conditions, such as chronic obstructive pulmonary disease and asthma. We investigated the role of PAFR in pulmonary EIMs of IBD, using dextran sulfate sodium (DSS) and anti-CD40 murine models of colitis. Both models induced neutrophilic inflammation, with increased TNF and IL-1β levels, bacterial load and PAFR protein expression in mouse lungs. Antagonism of PAFR decreased lung neutrophilia, TNF, and IL-1β in an NLRP3 inflammasome-dependent manner. Lipopolysaccharide from phosphorylcholine (ChoP)-positive bacteria induced NLRP3 and caspase-1 proteins in human alveolar epithelial cells, however antagonism of PAFR prevented NLRP3 activation by ChoP. Amoxicillin reduced bacterial populations in the lungs and reduced NLRP3 inflammasome protein levels, but did not reduce PAFR. These data suggest a role for PAFR in microbial pattern recognition and NLRP3 inflammasome signaling in the lung.
Collapse
Affiliation(s)
- Gang Liu
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Callaghan, NSW, Australia
| | - Sean W Mateer
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Callaghan, NSW, Australia
| | - Alan Hsu
- Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia
| | - Bridie J Goggins
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Callaghan, NSW, Australia
| | - Hock Tay
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Andrea Mathe
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Callaghan, NSW, Australia
| | - Kening Fan
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Callaghan, NSW, Australia
| | - Rachel Neal
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Callaghan, NSW, Australia
| | - Jessica Bruce
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Callaghan, NSW, Australia
| | - Grace Burns
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Callaghan, NSW, Australia
| | - Kyra Minahan
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Callaghan, NSW, Australia
| | - Steven Maltby
- Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,School of Nursing and Midwifery, University of Newcastle, Callaghan, NSW, Australia
| | - Michael Fricker
- Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia
| | - Paul S Foster
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Peter A B Wark
- Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.,School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia
| | - Philip M Hansbro
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Simon Keely
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia. .,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia. .,Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Callaghan, NSW, Australia.
| |
Collapse
|
|
18
|
Food Supplements to Mitigate Detrimental Effects of Pelvic Radiotherapy. Microorganisms 2019; 7:microorganisms7040097. [PMID: 30987157 PMCID: PMC6518429 DOI: 10.3390/microorganisms7040097] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 03/21/2019] [Accepted: 03/28/2019] [Indexed: 12/12/2022] Open
Abstract
Pelvic radiotherapy has been frequently reported to cause acute and late onset gastrointestinal (GI) toxicities associated with significant morbidity and mortality. Although the underlying mechanisms of pelvic radiation-induced GI toxicity are poorly understood, they are known to involve a complex interplay between all cell types comprising the intestinal wall. Furthermore, increasing evidence states that the human gut microbiome plays a role in the development of radiation-induced health damaging effects. Gut microbial dysbiosis leads to diarrhea and fatigue in half of the patients. As a result, reinforcement of the microbiome has become a hot topic in various medical disciplines. To counteract GI radiotoxicities, apart from traditional pharmacological compounds, adjuvant therapies are being developed including food supplements like vitamins, prebiotics, and probiotics. Despite the easy, cheap, safe, and feasible approach to protect patients against acute radiation-induced toxicity, clinical trials have yielded contradictory results. In this review, a detailed overview is given of the various clinical, intestinal manifestations after pelvic irradiation as well as the role of the gut microbiome herein. Furthermore, whilst discussing possible strategies to prevent these symptoms, food supplements are presented as auspicious, prophylactic, and therapeutic options to mitigate acute pelvic radiation-induced GI injury by exploring their molecular mechanisms of action.
Collapse
|
|
19
|
Alexeev EE, Lanis JM, Kao DJ, Campbell EL, Kelly CJ, Battista KD, Gerich ME, Jenkins BR, Walk ST, Kominsky DJ, Colgan SP. Microbiota-Derived Indole Metabolites Promote Human and Murine Intestinal Homeostasis through Regulation of Interleukin-10 Receptor. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:1183-1194. [PMID: 29454749 DOI: 10.1016/j.ajpath.2018.01.011] [Citation(s) in RCA: 341] [Impact Index Per Article: 48.7] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 12/22/2017] [Accepted: 01/08/2018] [Indexed: 12/29/2022]
Abstract
Interactions between the gut microbiota and the host are important for health, where dysbiosis has emerged as a likely component of mucosal disease. The specific constituents of the microbiota that contribute to mucosal disease are not well defined. The authors sought to define microbial components that regulate homeostasis within the intestinal mucosa. Using an unbiased, metabolomic profiling approach, a selective depletion of indole and indole-derived metabolites was identified in murine and human colitis. Indole-3-propionic acid (IPA) was selectively diminished in circulating serum from human subjects with active colitis, and IPA served as a biomarker of disease remission. Administration of indole metabolites showed prominent induction of IL-10R1 on cultured intestinal epithelia that was explained by activation of the aryl hydrocarbon receptor. Colonization of germ-free mice with wild-type Escherichia coli, but not E. coli mutants unable to generate indole, induced colonic epithelial IL-10R1. Moreover, oral administration of IPA significantly ameliorated disease in a chemically induced murine colitis model. This work defines a novel role of indole metabolites in anti-inflammatory pathways mediated by epithelial IL-10 signaling and identifies possible avenues for utilizing indoles as novel therapeutics in mucosal disease.
Collapse
Affiliation(s)
- Erica E Alexeev
- Mucosal Inflammation Program and Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Jordi M Lanis
- Mucosal Inflammation Program and Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Daniel J Kao
- Mucosal Inflammation Program and Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Eric L Campbell
- Centre for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom
| | - Caleb J Kelly
- Mucosal Inflammation Program and Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Kayla D Battista
- Mucosal Inflammation Program and Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Mark E Gerich
- Mucosal Inflammation Program and Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Brittany R Jenkins
- Department of Microbiology and Immunology, Montana State University, Bozeman, Montana
| | - Seth T Walk
- Department of Microbiology and Immunology, Montana State University, Bozeman, Montana
| | - Douglas J Kominsky
- Department of Microbiology and Immunology, Montana State University, Bozeman, Montana.
| | - Sean P Colgan
- Mucosal Inflammation Program and Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
| |
Collapse
|
|
20
|
Tsai KD, Lee WX, Chen W, Chen BY, Chen KL, Hsiao TC, Wang SH, Lee YJ, Liang SY, Shieh JC, Lin TH. Upregulation of PRMT6 by LPS suppresses Klotho expression through interaction with NF-κB in glomerular mesangial cells. J Cell Biochem 2018; 119:3404-3416. [PMID: 29131380 DOI: 10.1002/jcb.26511] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2017] [Accepted: 11/09/2017] [Indexed: 01/13/2023]
Abstract
Lipopolysaccharide (LPS) released from gram-negative bacteria stimulates immune responses in infected cells. Epigenetic modifications such as DNA methylation and protein methylation modulate LPS-induced innate immune gene expressions. Expression of the Klotho protein decreased with LPS treatment in rats. In a cellular model, information regarding the effect of LPS on Klotho expression was meager. In the present study, we demonstrated that LPS triggered global DNA and protein methylation in glomerular mesangial MES-13 cells. LPS upregulated protein expressions of enzymes central to cellular methylation reactions, especially protein arginine methyltransferase 6 (PRMT6) in MES-13 cells. Expression of the Klotho protein was diminished by LPS and was restored by 5-Aza-2'-deoxycytidine (5-Aza-2'-dc), AMI-1, and ammonium pyrrolidinedithiocarbamate (PDTC), but not adenosine aldehyde (AdOx). NF-κB was identified as a substrate for arginine methylation and interacted with PRMT6 in MES-13 cells. Inhibition of PRMT activity by AMI-1 blocked LPS-induced NF-κB nuclear translocation in MES-13 cells. Our data indicate that NF-κB negatively regulated Klotho expression with an interaction with PRMT6, which was upregulated by LPS in MES-13 cells.
Collapse
Affiliation(s)
- Kuen-Daw Tsai
- Department of Internal Medicine, China Medical University Beigang Hospital, Beigang Township, Yunlin County, Taiwan, Republic of China.,Institute of Molecular Biology, National Chung Cheng University, Minhsiung Township, Chiayi County, Taiwan, Republic of China.,School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan, Republic of China
| | - Wen-Xi Lee
- School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan, Republic of China.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China
| | - Wei Chen
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chia-Yi Christian Hospital, Chiayi, Taiwan, Republic of China
| | - Bo-Yu Chen
- School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan, Republic of China.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China
| | - Kuan-Lin Chen
- School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan, Republic of China.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China
| | - Tzu-Chia Hsiao
- School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan, Republic of China.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China
| | - Sue-Hong Wang
- School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan, Republic of China.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China
| | - Yi-Ju Lee
- Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan, Republic of China
| | - Shan-Yuan Liang
- School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan, Republic of China.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China
| | - Jia-Ching Shieh
- School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan, Republic of China.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China
| | - Ting-Hui Lin
- School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan, Republic of China.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China
| |
Collapse
|
|
21
|
Cronje PB. Essential role of methyl donors in animal productivity. ANIMAL PRODUCTION SCIENCE 2018. [DOI: 10.1071/an15729] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Dietary requirements for the methyl donors, choline, betaine and folate, in livestock species are poorly defined and have not been included in diet formulation software or simulation models for animals. A deficiency of methyl donors may promote an inflammatory state, which is significant for the livestock industry because chronic low-grade inflammation is widespread among livestock under commercial conditions. Furthermore, recent evidence showing that methyl donors activate adenosine monophosphate-activated protein kinase, an anti-inflammatory master switch, indicates that dietary methyl-donor supplementation could be used to prevent or ameliorate chronic inflammation and its sequelae in livestock, which include fatty liver disease in dairy cows, fatty liver and kidney syndrome in broilers, fatty liver haemorrhagic syndrome in layers, gut ulcers in pigs, liver abscesses in feedlot cattle, enteritis in poultry and susceptibility to heat stress in all species. Because of the complexity of interactions among methyl donors, a modelling approach inclusive of a supporting research effort will be required to harness the potential of methyl-donor supplementation in livestock production.
Collapse
|
|
22
|
Dietary l-arginine inhibits intestinal Clostridium perfringens colonisation and attenuates intestinal mucosal injury in broiler chickens. Br J Nutr 2017; 118:321-332. [PMID: 28901890 DOI: 10.1017/s0007114517002094] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
We investigated the effects of dietary l-arginine level and feeding duration on the intestinal damage of broilers induced by Clostridium perfringens (CP) in vivo, and the antimicrobial effect of its metabolite nitric oxide (NO) in vitro. The in vivo experiment was designed as a factorial arrangement of three dietary treatments×two challenge statuses. Broilers were fed a basal diet (CON) or a high-arginine diet (ARG) containing 1·87 % l-arginine, or CON for the first 8 d and ARG from days 9 to 28 (CON/ARG). Birds were co-infected with or without Eimeria and CP (EM/CP). EM/CP challenge led to intestinal injury, as evidenced by lower plasma d-xylose concentration (P<0·01), higher paracellular permeability in the ileum (P<0·05) and higher numbers of Escherichia coli (P<0·05) and CP (P<0·001) in caecal digesta; however, this situation could be alleviated by l-arginine supplementation (P<0·05). The intestinal claudin-1 and occludin mRNA expression levels were decreased (P<0·05) following EM/CP challenge; this was reversed by l-arginine supplementation (P<0·05). Moreover, EM/CP challenge up-regulated (P<0·05) claudin-2, interferon-γ (IFN-γ), toll-like receptor 2 and nucleotide-binding oligomerisation domain 1 (NOD1) mRNA expression, and l-arginine supplementation elevated (P<0·05) IFN-γ, IL-10 and NOD1 mRNA expression. In vitro study showed that NO had bacteriostatic activity against CP (P<0·001). In conclusion, l-arginine supplementation could inhibit CP overgrowth and alleviate intestinal mucosal injury by modulating innate immune responses, enhancing barrier function and producing NO.
Collapse
|
|
23
|
Lanis JM, Alexeev EE, Curtis VF, Kitzenberg DA, Kao DJ, Battista KD, Gerich ME, Glover LE, Kominsky DJ, Colgan SP. Tryptophan metabolite activation of the aryl hydrocarbon receptor regulates IL-10 receptor expression on intestinal epithelia. Mucosal Immunol 2017; 10:1133-1144. [PMID: 28098246 PMCID: PMC5515702 DOI: 10.1038/mi.2016.133] [Citation(s) in RCA: 144] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 11/15/2016] [Indexed: 02/04/2023]
Abstract
IL-10 is a potent anti-inflammatory cytokine that inhibits the production of proinflammatory mediators. Signaling by IL-10 occurs through the IL-10 receptor (IL-10R), which is expressed in numerous cell types, including intestinal epithelial cells (IECs), where it is associated with development and maintenance of barrier function. Guided by an unbiased metabolomics screen, we identified tryptophan (Trp) metabolism as a major modifying pathway in interferon-γ (IFNγ)-dominant murine colitis. In parallel, we demonstrated that IFNγ induction of indoleamine 2,3-dioxygenase 1, an enzyme that catalyzes the conversion of Trp to kynurenine (Kyn), induces IL-10R1 expression. Based on these findings, we hypothesized that IL-10R1 expression on IEC is regulated by Trp metabolites. Analysis of the promoter region of IL-10R1 revealed a functional aryl hydrocarbon response element, which is induced by Kyn in luciferase-based IL-10R1 promoter assays. Additionally, this analysis confirmed that IL-10R1 protein levels were increased in response to Kyn in IEC in vitro. Studies using in vitro wounding assays revealed that Kyn accelerates IL-10-dependent wound closure. Finally, reduction of murine dextran sodium sulfate colitis through Kyn administration correlates with colonic IL-10R1 expression. Taken together, these results provide evidence on the importance of IL-10 signaling in intestinal epithelia and implicate AHR in the regulation of IL-10R1 expression in the colon.
Collapse
Affiliation(s)
- J M Lanis
- Mucosal Inflammation Program, Aurora, Colarado, USA
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colarado, USA
| | - E E Alexeev
- Mucosal Inflammation Program, Aurora, Colarado, USA
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colarado, USA
| | - V F Curtis
- Mucosal Inflammation Program, Aurora, Colarado, USA
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colarado, USA
| | - D A Kitzenberg
- Mucosal Inflammation Program, Aurora, Colarado, USA
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colarado, USA
| | - D J Kao
- Mucosal Inflammation Program, Aurora, Colarado, USA
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colarado, USA
| | - K D Battista
- Mucosal Inflammation Program, Aurora, Colarado, USA
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colarado, USA
| | - M E Gerich
- Mucosal Inflammation Program, Aurora, Colarado, USA
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colarado, USA
| | - L E Glover
- Mucosal Inflammation Program, Aurora, Colarado, USA
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colarado, USA
| | - D J Kominsky
- Mucosal Inflammation Program, Aurora, Colarado, USA
- Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, USA
| | - S P Colgan
- Mucosal Inflammation Program, Aurora, Colarado, USA
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colarado, USA
| |
Collapse
|
|
24
|
Li H, Lu H, Tang W, Zuo J. Targeting methionine cycle as a potential therapeutic strategy for immune disorders. Expert Opin Ther Targets 2017; 21:1-17. [PMID: 28829212 DOI: 10.1080/14728222.2017.1370454] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Methionine cycle plays an essential role in regulating many cellular events, especially transmethylation reactions, incorporating the methyl donor S-adenosylmethionine (SAM). The transmethylations and substances involved in the cycle have shown complicated effects and mechanisms on immunocytes developments and activations, and exert crucial impacts on the pathological processes in immune disorders. Areas covered: Methionine cycle has been considered as an effective means of drug developments. This review discussed the role of methionine cycle in immune responses and summarized the potential therapeutic strategies based on the cycle, including SAM analogs, methyltransferase inhibitors, S-adenosylhomocysteine hydrolase (SAHH) inhibitors, adenosine receptors specific agonists or antagonists and homocysteine (Hcy)-lowering reagents, in treating human immunodeficiency virus (HIV) infections, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), systemic sclerosis (SSc) and other immune disorders. Expert opinion: New targets and biomarkers grown out of methionine cycle have developed rapidly in the past decades. However, impacts of epigenetic regulations on immune disorders are unclear and whether the substances in methionine cycle can be clarified as biomarkers remains controversial. Therefore, further elucidation on the role of epigenetic regulations and substances in methionine cycle may contribute to exploring the cycle-derived biomarkers and drugs in immune disorders.
Collapse
Affiliation(s)
- Heng Li
- a Laboratory of Immunopharmacology, State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , China
- b College of Pharmacy , University of Chinese Academy of Sciences , Beijing , China
| | - Huimin Lu
- a Laboratory of Immunopharmacology, State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , China
- b College of Pharmacy , University of Chinese Academy of Sciences , Beijing , China
| | - Wei Tang
- a Laboratory of Immunopharmacology, State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , China
- b College of Pharmacy , University of Chinese Academy of Sciences , Beijing , China
| | - Jianping Zuo
- a Laboratory of Immunopharmacology, State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , China
- b College of Pharmacy , University of Chinese Academy of Sciences , Beijing , China
| |
Collapse
|
|
25
|
Epigenetic Changes in Chronic Inflammatory Diseases. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2017; 106:139-189. [DOI: 10.1016/bs.apcsb.2016.09.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
26
|
Abstract
The incidence and prevalence of inflammatory bowel disease (IBD) continues to rise with time, signifying its emergence as a global disease. Clinical onset of IBD, comprising Crohn's disease and ulcerative colitis, typically occurs before or at peak reproductive age. Although active disease in female patients is associated with reduced fertility and adverse obstetric outcomes in pregnancy, the molecular mechanisms underlying this altered reproductive course, and its impact on IBD transmission to offspring, remain poorly understood. Clinical and experimental studies have now begun to elucidate the hormonal, environmental, and microbial factors that modulate immune-reproductive cross talk in IBD and define their impact on maternal health, fetal development, and heritability of disease risk. Evolving insight into maternal-fetal imprinting in IBD has important implications for patient counseling and disease management during pregnancy and may help predict clinical outcomes for both mother and child.
Collapse
|
|
27
|
Genetics, Mucosal Inflammation and the Environment in Post-Infectious Chronic Gut Syndromes. ACTA ACUST UNITED AC 2016. [DOI: 10.1038/ajgsup.2016.14] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
|
|
28
|
Frasch SC, McNamee EN, Kominsky D, Jedlicka P, Jakubzick C, Zemski Berry K, Mack M, Furuta GT, Lee JJ, Henson PM, Colgan SP, Bratton DL. G2A Signaling Dampens Colitic Inflammation via Production of IFN-γ. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2016; 197:1425-34. [PMID: 27402702 PMCID: PMC4975950 DOI: 10.4049/jimmunol.1600264] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 06/06/2016] [Indexed: 12/19/2022]
Abstract
Proinflammatory consequences have been described for lysophosphatidylcholine, a lipid product of cellular injury, signaling via the G protein-coupled receptor G2A on myeloid and lymphoid inflammatory cells. This prompted the hypothesis that genetic deletion of G2A would limit intestinal inflammation in a mouse model of colitis induced by dextran sodium sulfate. Surprisingly, G2A(-/-) mice exhibited significantly worsened colitis compared with wild-type mice, as demonstrated by disease activity, colon shortening, histology, and elevated IL-6 and IL-5 in colon tissues. Investigation of inflammatory cells recruited to inflamed G2A(-/-) colons showed significantly more TNF-α(+) and Ly6C(hi)MHCII(-) proinflammatory monocytes and eosinophils than in wild-type colons. Both monocytes and eosinophils were pathogenic as their depletion abolished the excess inflammation in G2A(-/-) mice. G2A(-/-) mice also had less IFN-γ in inflamed colon tissues than wild-type mice. Fewer CD4(+) lymphocytes were recruited to inflamed G2A(-/-) colons, and fewer colonic lymphocytes produced IFN-γ upon ex vivo stimulation. Administration of IFN-γ to G2A(-/-) mice during dextran sodium sulfate exposure abolished the excess colitic inflammation and reduced colonic IL-5 and eosinophil numbers to levels seen in wild-type mice. Furthermore, IFN-γ reduced the numbers of TNF-α(+) monocyte and enhanced their maturation from Ly6C(hi)MHCII(-) to Ly6C(int)MHCII(+) Taken together, the data suggest that G2A signaling serves to dampen intestinal inflammation via the production of IFN-γ, which, in turn, enhances monocyte maturation to a less inflammatory program and ultimately reduces eosinophil-induced injury of colonic tissues.
Collapse
Affiliation(s)
| | - Eóin N McNamee
- Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045
| | - Douglas Kominsky
- Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045
| | - Paul Jedlicka
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045
| | - Claudia Jakubzick
- Department of Pediatrics, National Jewish Health, Denver, CO 80206; Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80206
| | - Karin Zemski Berry
- Department of Pharmacology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045
| | - Matthias Mack
- Department of Internal Medicine, University of Regensburg, 93042 Regensburg, Germany
| | - Glenn T Furuta
- Digestive Health Institute, Children's Hospital Colorado, Aurora, CO 80045; Gastrointestinal Eosinophilic Diseases Program, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045; and
| | - James J Lee
- Division of Pulmonary Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona, Scottsdale, AZ 85259
| | - Peter M Henson
- Department of Pediatrics, National Jewish Health, Denver, CO 80206
| | - Sean P Colgan
- Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045
| | - Donna L Bratton
- Department of Pediatrics, National Jewish Health, Denver, CO 80206
| |
Collapse
|
|
29
|
Walker C, Crookenden M, Henty K, Handley R, Kuhn-Sherlock B, White H, Donkin S, Snell R, Meier S, Heiser A, Loor J, Mitchell M, Roche J. Epigenetic regulation of pyruvate carboxylase gene expression in the postpartum liver. J Dairy Sci 2016; 99:5820-5827. [DOI: 10.3168/jds.2015-10331] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2015] [Accepted: 02/29/2016] [Indexed: 12/15/2022]
|
|
30
|
Elliott EN, Sheaffer KL, Kaestner KH. The 'de novo' DNA methyltransferase Dnmt3b compensates the Dnmt1-deficient intestinal epithelium. eLife 2016; 5:e12975. [PMID: 26808831 PMCID: PMC4786433 DOI: 10.7554/elife.12975] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 01/25/2016] [Indexed: 12/11/2022] Open
Abstract
Dnmt1 is critical for immediate postnatal intestinal development, but is not required for the survival of the adult intestinal epithelium, the only rapidly dividing somatic tissue for which this has been shown. Acute Dnmt1 deletion elicits dramatic hypomethylation and genomic instability. Recovery of DNA methylation state and intestinal health is dependent on the de novo methyltransferase Dnmt3b. Ablation of both Dnmt1 and Dnmt3b in the intestinal epithelium is lethal, while deletion of either Dnmt1 or Dnmt3b has no effect on survival. These results demonstrate that Dnmt1 and Dnmt3b cooperate to maintain DNA methylation and genomic integrity in the intestinal epithelium.
Collapse
Affiliation(s)
- Ellen N Elliott
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
- Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
| | - Karyn L Sheaffer
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
- Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
| | - Klaus H Kaestner
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
- Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
| |
Collapse
|
|
31
|
Abstract
Crohn's disease and ulcerative colitis, the two major forms of idiopathic inflammatory bowel disease (IBD), are thought to occur through a loss of intestinal barrier leading to an inappropriate immune response toward intestinal microbiota. While genome-wide association studies (GWAS) have provided much information about susceptibility loci associated with these diseases, the etiology of IBD is still unknown. Metabolomic analysis allows for the comprehensive measurement of multiple small molecule metabolites in biological samples. During the past decade, metabolomic techniques have yielded novel and potentially important findings, revealing insight into metabolic perturbations associated with these diseases. This chapter provides metabolomic methodologies describing a nuclear magnetic resonance (NMR)-based non-targeted approach that has been utilized to make important contributions toward a better understanding of IBD.
Collapse
Affiliation(s)
- Daniel J Kao
- Department of Medicine, The University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Mucosal Inflammation Program, The University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Jordi M Lanis
- Department of Medicine, The University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Mucosal Inflammation Program, The University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Erica Alexeev
- Department of Medicine, The University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Mucosal Inflammation Program, The University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Douglas J Kominsky
- Department of Microbiology and Immunology, Montana State University, 109 Lewis Hall, Bozeman, MT, 59717, USA.
| |
Collapse
|
|
32
|
Rokavec M, Öner MG, Hermeking H. lnflammation-induced epigenetic switches in cancer. Cell Mol Life Sci 2016; 73:23-39. [PMID: 26394635 PMCID: PMC11108555 DOI: 10.1007/s00018-015-2045-5] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 08/22/2015] [Accepted: 09/10/2015] [Indexed: 02/07/2023]
Abstract
The link between inflammation and cancer is well established. Chronic inflammation promotes cancer initiation and progression. Various studies showed that the underlying mechanisms involve epigenetic alterations. These epigenetic alterations might culminate into an epigenetic switch that transforms premalignant cells into tumor cells or non-invasive into invasive tumor cells, thereby promoting metastasis. Epigenetic switches require an initiating event, which can be inflammation, whereas the resulting phenotype is inherited without the initiating signal. Epigenetic switches are induced and maintained by DNA methylation, histone modifications, polycomb group (PcG)/trithorax group (TrxG) proteins, and feedback loops consisting of transcription factors and microRNAs. Since epigenetic switches are reversible, they might represent an important basis for the design of novel anticancer therapeutics. This review summarizes published evidence of epigenetic switches in cancer development that are induced by inflammation.
Collapse
Affiliation(s)
- Matjaz Rokavec
- Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Thalkirchner Strasse 36, 80337, Munich, Germany
| | - Meryem Gülfem Öner
- Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Thalkirchner Strasse 36, 80337, Munich, Germany
| | - Heiko Hermeking
- Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Thalkirchner Strasse 36, 80337, Munich, Germany.
- German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
- German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
| |
Collapse
|
|
33
|
Gerecke C, Scholtka B, Löwenstein Y, Fait I, Gottschalk U, Rogoll D, Melcher R, Kleuser B. Hypermethylation of ITGA4, TFPI2 and VIMENTIN promoters is increased in inflamed colon tissue: putative risk markers for colitis-associated cancer. J Cancer Res Clin Oncol 2015; 141:2097-107. [PMID: 25902909 DOI: 10.1007/s00432-015-1972-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 04/13/2015] [Indexed: 12/18/2022]
Abstract
PURPOSE Epigenetic silencing of tumor suppressor genes is involved in early transforming events and has a high impact on colorectal carcinogenesis. Likewise, colon cancers that derive from chronically inflamed bowel diseases frequently exhibit epigenetic changes. But there is little data about epigenetic aberrations causing colorectal cancer in chronically inflamed tissue. The aim of the present study was to evaluate the aberrant gain of methylation in the gene promoters of VIM, TFPI2 and ITGA4 as putative early markers in the development from inflamed tissue via precancerous lesions toward colorectal cancer. METHODS Initial screening of different cancer cell lines by using methylation-specific PCR revealed a putative colon cancer-specific methylation pattern. Additionally, a demethylation assay was performed to investigate the methylation-dependent gene silencing of ITGA4. The candidate markers were analyzed in colonic tissue specimens from patients with colorectal cancer (n = 15), adenomas (n = 76), serrated lesions (n = 13), chronic inflammation (n = 10) and normal mucosal samples (n = 9). RESULTS A high methylation frequency of VIM (55.6 %) was observed in normal colon tissue, whereas ITGA4 and TFPI2 were completely unmethylated in controls. A significant gain of methylation frequency with progression of disease as well as an age-dependent effect was detectable for TFPI2. ITGA4 methylation frequency was high in precancerous and cancerous tissues as well as in inflammatory bowel diseases (IBD). CONCLUSION The already established methylation marker VIM does not permit a specific and sensitive discrimination of healthy and neoplastic tissue. The methylation markers ITGA4 and TFPI2 seem to be suitable risk markers for inflammation-associated colon cancer.
Collapse
Affiliation(s)
- Christian Gerecke
- Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
| | - Bettina Scholtka
- Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
| | - Yvonne Löwenstein
- Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
| | - Isabel Fait
- Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
| | - Uwe Gottschalk
- Department of Internal Medicine, Gastroenterology and Interventional Endoscopy, Vivantes-Klinikum im Friedrichshain, Berlin, Germany
| | - Dorothee Rogoll
- Division of Gastroenterology, Department of Medicine II, University of Würzburg, Würzburg, Germany
| | - Ralph Melcher
- Division of Gastroenterology, Department of Medicine II, University of Würzburg, Würzburg, Germany
| | - Burkhard Kleuser
- Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
| |
Collapse
|
|
34
|
Multi-faceted integrated omics analysis revealed parsley (Petroselinum crispum) as a novel dietary intervention in dextran sodium sulphate induced colitic mice. J Funct Foods 2014. [DOI: 10.1016/j.jff.2014.09.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
|
|
35
|
Abstract
Most of what is known about the pathogenesis of inflammatory bowel disease (IBD) pertains to complex interplay between host genetics, immunity, and environmental factors. Epigenetic modifications play pivotal roles in intestinal immunity and mucosal homeostasis as well as mediating gene-environment interactions. In this article, we provide a historical account of epigenetic research either directly related or pertinent to the pathogenesis and management of IBD. We further collate emerging evidence supporting roles for epigenetic mechanisms in relevant aspects of IBD biology, including deregulated immunity, host-pathogen recognition and mucosal integrity. Finally, we highlight key epigenetic mechanisms that link chronic inflammation to specific IBD comorbidities, including colitis-associated cancer and discuss their potential utility as novel biomarkers or pharmacologic targets in IBD therapy.
Collapse
|
|
36
|
Harris RA, Nagy-Szakal D, Mir SAV, Frank E, Szigeti R, Kaplan JL, Bronsky J, Opekun A, Ferry GD, Winter H, Kellermayer R. DNA methylation-associated colonic mucosal immune and defense responses in treatment-naïve pediatric ulcerative colitis. Epigenetics 2014; 9:1131-7. [PMID: 24937444 PMCID: PMC4164498 DOI: 10.4161/epi.29446] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) are emerging globally, indicating that environmental factors may be important in their pathogenesis. Colonic mucosal epigenetic changes, such as DNA methylation, can occur in response to the environment and have been implicated in IBD pathology. However, mucosal DNA methylation has not been examined in treatment-naïve patients. We studied DNA methylation in untreated, left sided colonic biopsy specimens using the Infinium HumanMethylation450 BeadChip array. We analyzed 22 control (C) patients, 15 untreated Crohn’s disease (CD) patients, and 9 untreated ulcerative colitis (UC) patients from two cohorts. Samples obtained at the time of clinical remission from two of the treatment-naïve UC patients were also included into the analysis. UC-specific gene expression was interrogated in a subset of adjacent samples (5 C and 5 UC) using the Affymetrix GeneChip PrimeView Human Gene Expression Arrays. Only treatment-naïve UC separated from control. One-hundred-and-twenty genes with significant expression change in UC (> 2-fold, P < 0.05) were associated with differentially methylated regions (DMRs). Epigenetically associated gene expression changes (including gene expression changes in the IFITM1, ITGB2, S100A9, SLPI, SAA1, and STAT3 genes) were linked to colonic mucosal immune and defense responses. These findings underscore the relationship between epigenetic changes and inflammation in pediatric treatment-naïve UC and may have potential etiologic, diagnostic, and therapeutic relevance for IBD.
Collapse
Affiliation(s)
- R Alan Harris
- Department of Molecular and Human Genetics; Baylor College of Medicine; Houston, TX USA
| | - Dorottya Nagy-Szakal
- Department of Pediatrics; Baylor College of Medicine; USDA/ARS Children's Nutrition Research Center; Texas Children's Hospital; Houston, TX USA
| | - Sabina A V Mir
- Department of Pediatrics; Baylor College of Medicine; USDA/ARS Children's Nutrition Research Center; Texas Children's Hospital; Houston, TX USA
| | - Eibe Frank
- Department of Computer Science; University of Waikato; Hamilton, New Zealand
| | - Reka Szigeti
- Department of Pathology; Baylor College of Medicine; Houston, TX USA
| | - Jess L Kaplan
- Department of Pediatrics; MassGeneral Hospital for Children; Boston, MA USA
| | - Jiri Bronsky
- Department of Pediatrics; Charles University and University Hospital Motol; Prague, Czech Republic
| | - Antone Opekun
- Department of Gastroenterology; Baylor College of Medicine; Houston, TX USA
| | - George D Ferry
- Department of Pediatrics; Baylor College of Medicine; USDA/ARS Children's Nutrition Research Center; Texas Children's Hospital; Houston, TX USA
| | - Harland Winter
- Department of Pediatrics; MassGeneral Hospital for Children; Boston, MA USA
| | - Richard Kellermayer
- Department of Pediatrics; Baylor College of Medicine; USDA/ARS Children's Nutrition Research Center; Texas Children's Hospital; Houston, TX USA
| |
Collapse
|
|
37
|
Maeda S, Ohno K, Fujiwara-Igarashi A, Tomiyasu H, Fujino Y, Tsujimoto H. Methylation of TNFRSF13B and TNFRSF13C in duodenal mucosa in canine inflammatory bowel disease and its association with decreased mucosal IgA expression. Vet Immunol Immunopathol 2014; 160:97-106. [PMID: 24814046 DOI: 10.1016/j.vetimm.2014.04.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2014] [Revised: 04/10/2014] [Accepted: 04/12/2014] [Indexed: 01/28/2023]
Abstract
Although decreased intestinal IgA expression has been reported in dogs with inflammatory bowel disease (IBD), the mechanism underlying this decrease is unknown. Transmembrane activator and calcium-modulating cyclophilin-ligand interactor (TACI) and B cell-activating factor of the TNF family (BAFF) receptor (BAFF-R) are key receptors for T cell-independent IgA class switching by the binding of IgA-inducing cytokine a proliferation-inducing ligand (APRIL) and BAFF. Here we show decreased TACI and BAFF-R mRNA expression and hypermethylation of their corresponding genes TNFRSF13B and TNFRSF13C, respectively in the duodenal mucosa of dogs with IBD. To examine whether DNA methylation of the TNFRSF13B and TNFRSF13C influences the mRNA expression of TACI and BAFF-R, respectively, we first analyzed methylation and mRNA expression levels in vitro using 2 canine B lymphoid cell lines, GL-1 and CLBL-1. Methylation profiles in the cells were examined by bisulfite sequencing and methylation-specific PCR (MSP) with primer pairs specific to methylated or unmethylated sequences. These methylation analyses revealed hypermethylation of the CpG islands of both TNFRSF13B and TNFRSF13C in GL-1, but not in CLBL-1 cells. The mRNA expression levels of TACI and BAFF-R were significantly lower in GL-1 than in CLBL-1 cells. Treatment with 5-aza-2'-deoxycytidine significantly increased TACI and BAFF-R mRNA expression in GL-1 cells through demethylation of TNFRSF13B and TNFRSF13C, respectively. These results suggest that the mRNA expression of TACI and BAFF-R is regulated through methylation of their genes in canine B cells. Quantitative real-time MSP showed significant hypermethylation of the CpG islands of TNFRSF13B and TNFRSF13C in the duodenal mucosa of dogs with IBD. Furthermore, duodenal mRNA expression levels of TACI and BAFF-R were significantly lower in dogs with IBD than in healthy controls. The mRNA expression levels of TACI positively correlated with intestinal IgA expression, whereas the methylation level of its gene (TNFRSF13B) negatively correlated with IgA expression. The present results suggest the role of TACI in the regulation of mucosal IgA expression through epigenetic modifications.
Collapse
Affiliation(s)
- Shingo Maeda
- Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Koichi Ohno
- Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
| | - Aki Fujiwara-Igarashi
- Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Hirotaka Tomiyasu
- Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Yasuhito Fujino
- Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Hajime Tsujimoto
- Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| |
Collapse
|
|
38
|
Kominsky DJ, Campbell EL, Ehrentraut SF, Wilson KE, Kelly CJ, Glover LE, Collins CB, Bayless AJ, Saeedi B, Dobrinskikh E, Bowers BE, MacManus CF, Müller W, Colgan SP, Bruder D. IFN-γ-mediated induction of an apical IL-10 receptor on polarized intestinal epithelia. THE JOURNAL OF IMMUNOLOGY 2013; 192:1267-76. [PMID: 24367025 DOI: 10.4049/jimmunol.1301757] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Cytokines secreted at sites of inflammation impact the onset, progression, and resolution of inflammation. In this article, we investigated potential proresolving mechanisms of IFN-γ in models of inflammatory bowel disease. Guided by initial microarray analysis, in vitro studies revealed that IFN-γ selectively induced the expression of IL-10R1 on intestinal epithelia. Further analysis revealed that IL-10R1 was expressed predominantly on the apical membrane of polarized epithelial cells. Receptor activation functionally induced canonical IL-10 target gene expression in epithelia, concomitant with enhanced barrier restitution. Furthermore, knockdown of IL-10R1 in intestinal epithelial cells results in impaired barrier function in vitro. Colonic tissue isolated from murine colitis revealed that levels of IL-10R1 and suppressor of cytokine signaling 3 were increased in the epithelium and coincided with increased tissue IFN-γ and IL-10 cytokines. In parallel, studies showed that treatment of mice with rIFN-γ was sufficient to drive expression of IL-10R1 in the colonic epithelium. Studies of dextran sodium sulfate colitis in intestinal epithelial-specific IL-10R1-null mice revealed a remarkable increase in disease susceptibility associated with increased intestinal permeability. Together, these results provide novel insight into the crucial and underappreciated role of epithelial IL-10 signaling in the maintenance and restitution of epithelial barrier and of the temporal regulation of these pathways by IFN-γ.
Collapse
Affiliation(s)
- Douglas J Kominsky
- Department of Anesthesiology and Perioperative Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Leddin D, Tamim H, Levy AR. Is folate involved in the pathogenesis of inflammatory bowel disease? Med Hypotheses 2013; 81:940-1. [PMID: 24045091 DOI: 10.1016/j.mehy.2013.08.025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Revised: 08/16/2013] [Accepted: 08/23/2013] [Indexed: 02/08/2023]
Abstract
The inflammatory bowel diseases, Crohn's and ulcerative colitis, are common and a significant cause of morbidity. They were rare before the 1930's but the incidence has been increasing in both developed and developing countries. We have recently reported that the incidence in Nova Scotia, the area with one of the highest reported burden globally, is decreasing since 1997. We postulate that this decrease may be due to the addition of folate to cereals. This was mandated in 1998 but the process of fortification began in 1997. There is circumstantial evidence from epidemiology studies that a diet deficient in folate may have contributed to the global rise in these diseases. This hypothesis, if proven to be correct, has important implications for the prevention and treatment of these diseases.
Collapse
Affiliation(s)
- Desmond Leddin
- Department of Medicine, Dalhousie University, Halifax, Canada.
| | | | | |
Collapse
|
|
40
|
Low D, Mizoguchi A, Mizoguchi E. DNA methylation in inflammatory bowel disease and beyond. World J Gastroenterol 2013; 19:5238-5249. [PMID: 23983426 PMCID: PMC3752557 DOI: 10.3748/wjg.v19.i32.5238] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Revised: 05/13/2013] [Accepted: 07/19/2013] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a consequence of the complex, dysregulated interplay between genetic predisposition, environmental factors, and microbial composition in the intestine. Despite a great advancement in identifying host-susceptibility genes using genome-wide association studies (GWAS), the majority of IBD cases are still underrepresented. The immediate challenge in post-GWAS era is to identify other causative genetic factors of IBD. DNA methylation has received increasing attention for its mechanistical role in IBD pathogenesis. This stable, yet dynamic DNA modification, can directly affect gene expression that have important implications in IBD development. The alterations in DNA methylation associated with IBD are likely to outset as early as embryogenesis all the way until old-age. In this review, we will discuss the recent advancement in understanding how DNA methylation alterations can contribute to the development of IBD.
Collapse
|
|
41
|
Schönig S, Recke A, Hirose M, Ludwig RJ, Seeger K. Metabolite analysis distinguishes between mice with epidermolysis bullosa acquisita and healthy mice. Orphanet J Rare Dis 2013; 8:93. [PMID: 23800341 PMCID: PMC3703300 DOI: 10.1186/1750-1172-8-93] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Accepted: 06/23/2013] [Indexed: 01/09/2023] Open
Abstract
Background Epidermolysis bullosa acquisita (EBA) is a rare skin blistering disease with a prevalence of 0.2/ million people. EBA is characterized by autoantibodies against type VII collagen. Type VII collagen builds anchoring fibrils that are essential for the dermal-epidermal junction. The pathogenic relevance of antibodies against type VII collagen subdomains has been demonstrated both in vitro and in vivo. Despite the multitude of clinical and immunological data, no information on metabolic changes exists. Methods We used an animal model of EBA to obtain insights into metabolomic changes during EBA. Sera from mice with immunization-induced EBA and control mice were obtained and metabolites were isolated by filtration. Proton nuclear magnetic resonance (NMR) spectra were recorded and analyzed by principal component analysis (PCA), partial least squares discrimination analysis (PLS-DA) and random forest. Results The metabolic pattern of immunized mice and control mice could be clearly distinguished with PCA and PLS-DA. Metabolites that contribute to the discrimination could be identified via random forest. The observed changes in the metabolic pattern of EBA sera, i.e. increased levels of amino acid, point toward an increased energy demand in EBA. Conclusions Knowledge about metabolic changes due to EBA could help in future to assess the disease status during treatment. Confirming the metabolic changes in patients needs probably large cohorts.
Collapse
Affiliation(s)
- Sarah Schönig
- Excellence Cluster Inflammation at Interfaces, Schleswig-Holstein, Germany
| | | | | | | | | |
Collapse
|
|
42
|
Hypermethylation and low transcription of TLR2 gene in chronic periodontitis. Hum Immunol 2013; 74:1231-6. [PMID: 23747679 DOI: 10.1016/j.humimm.2013.04.037] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Revised: 02/06/2013] [Accepted: 04/23/2013] [Indexed: 11/20/2022]
Abstract
Periodontitis is an inflammatory disorder characterized by interactions between periodontal pathogens and host's immune response. Epigenetic may contribute to disease development and outcome by influencing the expression of genes involved in the immune response. It has been shown that Toll-like receptors (TLR) play an important role in the response to periodontopathic bacteria. The aim of study was to evaluate the methylation status and the expression of TLR2 gene in gingival samples from individuals with and without periodontitis. DNA was analyzed using the Methyl Profiler DNA Methylation qPCR assay. DNA methylation and transcript levels were evaluated by real-time polymerase chain reaction. The periodontitis group showed a hypermethylated profile and a low expression of gene. Positive correlation between the TLR2 methylation frequency and probing depth was observed. This study gives the first evidence of methylation frequency in inflamed periodontal tissues and of the possible participation of methylation in the development of periodontitis.
Collapse
|
|
43
|
Tardif V, Manenkova Y, Berger M, Hoebe K, Zuo JP, Yuan C, Kono DH, Theofilopoulos AN, Lawson BR. Critical role of transmethylation in TLR signaling and systemic lupus erythematosus. Clin Immunol 2013; 147:133-43. [PMID: 23583916 DOI: 10.1016/j.clim.2013.02.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2013] [Accepted: 02/19/2013] [Indexed: 10/27/2022]
Abstract
Post-translational protein modifications can play a significant role in immune cell signaling. Recently, we showed that inhibition of transmethylation curtails experimental autoimmune encephalomyelitis, notably by reducing T cell receptor (TCR)-induced activation of CD4(+) T cells. Here, we demonstrate that transmethylation inhibition by a reversible S-adenosyl-l-homocysteine hydrolase inhibitor (DZ2002) led to immunosuppression by reducing TLR-, B cell receptor (BCR)- and TCR-induced activation of immune cells, most likely by blocking NF-κB activity. Moreover, prophylactic treatment with DZ2002 prevented lupus-like disease from developing in both BXSB and MRL-Fas(lpr) mouse models. DZ2002 treatment initiated during active disease significantly improved outcomes in both in vivo models, suggesting methylation inhibition as a novel approach for the treatment of autoimmune/inflammatory diseases.
Collapse
Affiliation(s)
- Virginie Tardif
- Department of Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Epigenetics and the developmental origins of inflammatory bowel diseases. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2013; 26:909-15. [PMID: 23248794 DOI: 10.1155/2012/526408] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The gut microbiota, the intestinal mucosa and the host immune system are among the large biological networks involved in the development of inflammatory bowel disease (IBD), which includes Crohn disease (CD) and ulcerative colitis (UC). Host genetics and environmental factors can significantly modulate the interactive relationships among these biological systems and influence predilection toward IBD. High monozygotic twin discordance rates and the rapid rise in the prevalence of IBD indicate that environmental influences may be as important or even more important in their pathogenesis than genetic susceptibility. However, the nature and timing of environmental factors critical for inducing IBD remain largely unknown. The molecular mechanisms and the key biological component(s) that may be affected by such factors are also in question. Epigenetic changes, such as DNA methylation (the methylation of cytosines followed by a guanine in CpG dinucleotides) can be modified by environmental influences during finite developmental periods and have been implicated in the pathogenesis of IBD. Mucosal DNA methylation can also react to changes in the commensal microbiota, underscoring the intercalating relationships among the large biological systems involved in gastrointestinal disorders. Therefore, transient environmental influences during specific periods of development may induce critical change(s) in an isolated or concomitant fashion within the intestinal biomic networks and lead to increased susceptibility to IBD. The present review focuses on the emerging paradigm shift considering IBD to originate from critical environmental effects during pre- and postnatal development.
Collapse
|
|
45
|
Lightfoot YL, Yang T, Sahay B, Mohamadzadeh M. Targeting aberrant colon cancer-specific DNA methylation with lipoteichoic acid-deficient Lactobacillus acidophilus. Gut Microbes 2013; 4:84-8. [PMID: 23137966 PMCID: PMC3555892 DOI: 10.4161/gmic.22822] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pathogenic autoinflammatory responses triggered by dysregulated microbial interactions may lead to intestinal disorders and malignancies. Previously, we demonstrated that a lipoteichoic acid (LTA)-deficient Lactobacillus acidophilus strain, NCK2025, ameliorated inflammation-induced colitis, significantly reduced the number of polyps in a colonic polyposis cancer model and restored physiological homeostasis in both cases. Nonetheless, the regulatory signals delivered by NCK2025 to reprogram the gastrointestinal microenvironment, and thus resist colonic cancer progression, remain unknown. Accumulating evidence suggest that epigenetic changes, in the presence and absence of pathogenic inflammation, can result in colorectal cancer (CRC). To test possible epigenetic modifications induced by NCK2025, the expression of epigenetically regulated, CRC-associated genes was measured with and without bacterial treatment. In vivo and in vitro, NCK2025 enhanced the expression of tumor suppressor genes that may regulate CRC development. Therefore, differential epigenetic regulation of CRC-related genes by NCK2025 represents a potential therapy against colitis-associated and sporadic CRC.
Collapse
|
|
46
|
Chronic inflammation as a promotor of mutagenesis in essential thrombocythemia, polycythemia vera and myelofibrosis. A human inflammation model for cancer development? Leuk Res 2012; 37:214-20. [PMID: 23174192 DOI: 10.1016/j.leukres.2012.10.020] [Citation(s) in RCA: 184] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2012] [Revised: 08/11/2012] [Accepted: 10/24/2012] [Indexed: 12/27/2022]
Abstract
The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are acquired stem cell neoplasms, in which a stem cell lesion induces an autonomous proliferative advantage. In addition to the JAK2V617 mutation several other mutations have been described. Recently chronic inflammation has been proposed as a trigger and driver of clonal evolution in MPNs. Herein, it is hypothesized that sustained inflammation may elicit the stem cell insult by inducing a state of chronic oxidative stress with elevated levels of reactive oxygen species (ROS) in the bone marrow, thereby creating a high-risk microenvironment for induction of mutations due to the persistent inflammation-induced oxidative damage to DNA in hematopoietic cells. Alterations in the epigenome induced by the chronic inflammatory drive may likely elicit a "epigenetic switch" promoting persistent inflammation. The perspectives of chronic inflammation as the driver of mutagenesis in MPNs are discussed, including early intervention with interferon-alpha2 and potent anti-inflammatory agents (e.g. JAK1-2 inhibitors, histone deacetylase inhibitors, DNA-hypomethylators and statins) to disrupt the self-perpetuating chronic inflammation state and accordingly eliminating a potential trigger of clonal evolution and disease progression with myelofibrotic and leukemic transformation.
Collapse
|
|
47
|
Gonda TA, Kim YI, Salas MC, Gamble MV, Shibata W, Muthupalani S, Sohn KJ, Abrams JA, Fox JG, Wang TC, Tycko B. Folic acid increases global DNA methylation and reduces inflammation to prevent Helicobacter-associated gastric cancer in mice. Gastroenterology 2012; 142:824-833.e7. [PMID: 22248660 DOI: 10.1053/j.gastro.2011.12.058] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2011] [Revised: 12/22/2011] [Accepted: 12/31/2011] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Previous studies have suggested that dietary folic acid (FA) can protect against certain types of cancers. However, the findings have varied, and the mechanisms by which FA exerts chemopreventive effects remain to be clarified. We examined the effects of FA supplementation on DNA methylation, gene expression, and gastric dysplasia in a transgenic mouse model that is etiologically and histologically well matched with human gastric cancers. METHODS Hypergastrinemic mice infected with Helicobacter felis were studied at multiple stages of gastric dysplasia and early cancer with FA supplementation initiated both at weaning and later in life. Global DNA methylation was assessed by a methylation sensitive cytosine incorporation assay, bisulfite pyrosequencing of B1 repetitive elements, and immunohistochemistry with anti-5-methylcytosine. We also profiled gene expression in the same tissues. RESULTS We found a decrease in global DNA methylation and tissue folate and an increase in serum homocysteine with progression of gastric dysplasia. FA supplementation prevented this loss of global DNA methylation and markedly reduced gastric dysplasia and mucosal inflammation. FA protected against the loss of global DNA methylation both in the dysplastic gastric epithelial cells and in gastric stromal myofibroblasts. In addition, FA supplementation had an anti-inflammatory effect, as indicated by expression profiling and immunohistochemistry for lymphocyte markers. CONCLUSIONS We conclude that FA supplementation is chemopreventive in this model of Helicobacter-associated gastric cancer. The beneficial effect of FA is likely due to its ability to prevent global loss of methylation and suppress inflammation.
Collapse
Affiliation(s)
- Tamas A Gonda
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York 10032, USA.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Abstract
Crohn's disease is a chronic relapsing condition that has no certain cure. Both genetic susceptibility and nutrition have key roles, but their level of involvement varies between patients. Interacting gene pathways influence the probability of disease development, but these are affected by stress and various environmental factors, including diet. In addition, the role of the gut microbiome must not be underestimated, as it is substantially altered in patients with Crohn's disease. Although an elemental diet might lead to disease remission, reintroducing real foods and sustainable diets in patients with Crohn's disease is currently difficult, and would benefit from the sensitivity and rapid feedback provided by the field of nutrigenomics. Nutrigenomics utilizes high-throughput genomics technologies to reveal changes in gene and protein expression that are modulated by the patient's nutrition. The most widely used technique thus far is transcriptomics, which permits measurement of changes in the expression of thousands of genes simultaneously in one sample. Given the volume of numbers generated in such studies, data-basing and bioinformatics are essential to ensure the correct application of nutrigenomics at the population level. These methods have been successfully applied to animal models of Crohn's disease, and the time is right to move them to human studies.
Collapse
Affiliation(s)
- Lynnette R Ferguson
- Discipline of Nutrition, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
| |
Collapse
|
|
49
|
Abstract
Inflammation can result from a range of sources including microbial infections, exposure to allergens and toxic chemicals, autoimmune disease and obesity. A well-balanced immune response can be anti-tumorigenic; however, a sustained or chronic inflammatory response is generally harmful as the immune response becomes distorted. A causal link between chronic inflammation and cancer is now well accepted and many chronically inflamed organs of the gastrointestinal tract show this association. For example, patients with inflammatory bowel disease (IBD), including both ulcerative colitis and Crohn's disease, have a 2- to 3-fold greater lifetime risk of developing colorectal cancer compared with the general population. The development of colitis-associated cancer (CAC) is thought to be multifaceted and is probably due to a combination of genetic factors, epigenetic factors and the duration, extent and severity of disease. Recently, epigenetic alterations, in particular alterations in DNA methylation, have been observed during inflammation and inflammation-associated carcinogenesis. The mediators of this, the significance of these changes in DNA methylation and the effect this has on gene expression and the malignant transformation of the epithelial cells during IBD and CAC are discussed in this review. The recent advances in technologies to study genome-wide DNA methylation and the therapeutic potential of understanding these molecular mechanisms are also highlighted.
Collapse
Affiliation(s)
- Lori Hartnett
- Department of Pharmacology and Therapeutics, National University of Ireland, Galway, Ireland
| | | |
Collapse
|
|
50
|
Abstract
Chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (IBDs) are chronic inflammatory diseases of mucosal tissues that affect the respiratory and gastrointestinal tracts, respectively. They share many similarities in epidemiological and clinical characteristics, as well as in inflammatory pathologies. Importantly, both conditions are accompanied by systemic comorbidities that are largely overlooked in both basic and clinical research. Therefore, consideration of these complications may maximize the efficacy of prevention and treatment approaches. Here, we examine both the intestinal involvement in COPD and the pulmonary manifestations of IBD. We also review the evidence for inflammatory organ cross-talk that may drive these associations, and discuss the current frontiers of research into these issues.
Collapse
|