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1.
Nature ; 579(7797): 123-129, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32103176

RESUMO

A mosaic of cross-phylum chemical interactions occurs between all metazoans and their microbiomes. A number of molecular families that are known to be produced by the microbiome have a marked effect on the balance between health and disease1-9. Considering the diversity of the human microbiome (which numbers over 40,000 operational taxonomic units10), the effect of the microbiome on the chemistry of an entire animal remains underexplored. Here we use mass spectrometry informatics and data visualization approaches11-13 to provide an assessment of the effects of the microbiome on the chemistry of an entire mammal by comparing metabolomics data from germ-free and specific-pathogen-free mice. We found that the microbiota affects the chemistry of all organs. This included the amino acid conjugations of host bile acids that were used to produce phenylalanocholic acid, tyrosocholic acid and leucocholic acid, which have not previously been characterized despite extensive research on bile-acid chemistry14. These bile-acid conjugates were also found in humans, and were enriched in patients with inflammatory bowel disease or cystic fibrosis. These compounds agonized the farnesoid X receptor in vitro, and mice gavaged with the compounds showed reduced expression of bile-acid synthesis genes in vivo. Further studies are required to confirm whether these compounds have a physiological role in the host, and whether they contribute to gut diseases that are associated with microbiome dysbiosis.


Assuntos
Ácidos e Sais Biliares/biossíntese , Ácidos e Sais Biliares/química , Metabolômica , Microbiota/fisiologia , Animais , Ácidos e Sais Biliares/metabolismo , Ácido Cólico/biossíntese , Ácido Cólico/química , Ácido Cólico/metabolismo , Fibrose Cística/genética , Fibrose Cística/metabolismo , Fibrose Cística/microbiologia , Vida Livre de Germes , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/microbiologia , Camundongos , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo
2.
Yakugaku Zasshi ; 139(12): 1523-1530, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31787639

RESUMO

Oxidative stress, including reactive oxygen species (ROS) generation and resulting glutathione oxidation, have been implicated in numerous aspects of cell physiology and human pathology such as cell senescence, cell differentiation, and inflammation. Significant effort has been made to establish methods of analyzing ROS levels and glutathione oxidation within a living cell. The recent development of redox-sensitive green fluorescent protein (GFP) variants enables a robust and accurate estimation of ROS level and glutathione oxidation at subcellular resolution. We created membrane-targeted versions of glutathione and hydrogen peroxide sensors by attaching palmitoylation signals to existing sensors (Grx1-roGFP2 and roGFP2-Orp1, respectively), and demonstrated the nonuniform distribution of these oxidative elements within cytosol. In living cells, cytosolic glutathione is highly reduced, and hydrogen peroxide is barely detected. Nevertheless, near the cytoplasmic side of intracellular vesicular membranes, significant glutathione oxidation and hydrogen peroxide were successfully probed by our sensors, clearly showing the difference between various areas within cytosol. Currently, these sensors are being applied to an intestinal inflammation model which is constituted by co-culturing intestinal epithelial cells and macrophage-like inflammatory cells derived from THP-1. This review covers the current status of studies regarding the association of oxidative stress and intestinal inflammation, with a focus on the redox regulation of intracellular glutathione.


Assuntos
Glutationa/metabolismo , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/metabolismo , Estresse Oxidativo , Citoplasma/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Células THP-1
3.
Med J Aust ; 211(10): 461-467, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31680263

RESUMO

OBJECTIVES: To assess the clinical effectiveness of faecal calprotectin (FC) testing for distinguishing between organic gastrointestinal diseases (organic GID), such as inflammatory bowel disease (IBD), and functional gastrointestinal disorders (functional GIDs). STUDY DESIGN: Studies that assessed the accuracy of FC testing for differentiating between IBD or organic GID and functional GIDs were reviewed. Articles published in English during January 1998 - June 2018 that compared diagnostic FC testing in primary care and outpatient hospital settings with a reference test and employed the standard enzyme-linked immunosorbent FC assay method with a cut-off of 50 or 100 µg/g faeces were included. Study quality was assessed with QUADAS-2, an evidence-based quality assessment tool for diagnostic accuracy studies. DATA SOURCES: MEDLINE and EMBASE; reference lists of screened articles. DATA SYNTHESIS: Eighteen relevant studies were identified. For distinguishing patients with organic GID (including IBD) from those with functional GIDs (16 studies), the estimated sensitivity of FC testing was 81% (95% CI, 74-86%), the specificity 81% (95% CI, 71-88%); area under the curve (AUC) was 0.87. For distinguishing IBD from functional GIDs (ten studies), sensitivity was 88% (95% CI, 80-93%), specificity 72% (95% CI, 59-82%), and AUC 0.89. Assuming a population prevalence of organic GID of 1%, the positive predictive value was 4.2%, the negative predictive value 100%. The difference in sensitivity and specificity between FC testing cut-offs of 50 µg/g and 100 µg/g faeces was not statistically significant (P = 0.77). CONCLUSIONS: FC testing is clinically useful for distinguishing organic GID (including IBD) from functional GIDs, and its incorporation into clinical practice for evaluating patients with lower gastrointestinal symptoms could lead to fewer patients with functional GIDs undergoing colonoscopy, reducing costs for both patients and the health system. PROSPERO REGISTRATION: CRD4201810507.


Assuntos
Fezes/química , Doenças Inflamatórias Intestinais/diagnóstico , Complexo Antígeno L1 Leucocitário/análise , Adulto , Criança , Pré-Escolar , Humanos , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/metabolismo , Pessoa de Meia-Idade
5.
Acta Biochim Biophys Sin (Shanghai) ; 51(11): 1087-1095, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31609412

RESUMO

Autophagy, a metabolic pathway that plays an important role in maintaining the dynamic balance of cells, has two types, i.e. non-selective autophagy and selective autophagy. The role of non-selective autophagy is primarily to allow cells to circulate nutrients in an energy-limited environment, while selective autophagy primarily cleans up the organelles inside the cells to maintain the cell structure. The NLRP3 inflammasome is an innate immune response produced by the organism that can promote the secretion of interleukin-1ß and interleukin-18 through caspase-1 activation and resist the damage of some pathogens. However, when the NLRP3 inflammasome is overactivated, it can cause various inflammatory diseases, such as inflammatory liver disease and inflammatory bowel disease. Many previous studies have shown that autophagy can inhibit the NLRP3 inflammasome, while in recent years, new studies have found that autophagy can also promote the NLRP3 inflammasome in some cases, and the NLRP3 inflammasome can, in turn, affect autophagy. In this review, the interaction between autophagy and the NLRP3 inflammasome is explored, and then the application of this interaction in disease treatment is discussed.


Assuntos
Autofagia/fisiologia , Hepatite/metabolismo , Inflamassomos/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Humanos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Camundongos , Ratos
6.
Int J Mol Sci ; 20(19)2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31574900

RESUMO

Inflammatory bowel diseases (IBD) are chronic, inflammatory processes that affect the gastrointestinal tract and are mainly represented by ulcerative colitis (UC) and Crohn's disease (CD). Omega 3 (ω3) fatty acids (eicosapentanoic acid and docosahexaenoic acid) show an indispensable role in the inflammatory processes and, for these reasons, we aimed to review the effects of these acids on UC and CD. Databases such as PUMED and EMBASE were searched, and the final selection included fifteen studies that fulfilled the inclusion criteria. The results showed that ω3 fatty acids reduce intestinal inflammation, induce and maintain clinical remission in UC patients, and are related with the reduction of proinflammatory cytokines, decrease disease activity and increase the quality of life of CD patients. Furthermore, the consumption of these fatty acids may be related to a reduced risk of developing IBD. Many studies have shown the beneficial effects of ω3 as adjunctive in the treatment or prevention of UC or CD. Nevertheless, most were performed with a small number of patients and there are many variations in the mode of consumption, the type of food or the type of formulation used. All these factors substantially interfere with the results and do not allow reliable comparisons.


Assuntos
Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos/metabolismo , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/metabolismo , Animais , Suscetibilidade a Doenças , Humanos , Doenças Inflamatórias Intestinais/patologia , Pesquisa
7.
Arch Oral Biol ; 107: 104528, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31442931

RESUMO

OBJECTIVES: To assess the concentration of calprotectin, a heterodimer of S100A8 and S100A9 implicated in inflammatory bowel disease (IBD), in saliva of IBD patients compared to controls. METHODS: Unstimulated and stimulated saliva, and serum was collected from 23 IBD patients with active intestinal inflammation, verified by endoscopy. Fifteen patients were re-sampled after treatment. Saliva was collected from 15 controls for protocol validation and group comparisons. Calprotectin concentrations were measured by enzyme-linked immunosorbent assay, correlated to clinical data/indexes and routine laboratory parameters. RESULTS: Calprotectin was 4.0-fold (median) elevated in stimulated saliva of IBD patients compared to controls and tended to be elevated in unstimulated saliva (P = 0.001, P = 0.090). Crohn's (CD) patients had significantly elevated calprotectin in both unstimulated and stimulated saliva compared to controls (P = 0.011, P = 0.002). Newly diagnosed, treatment naïve CD patients had 8.2-fold (median) higher calprotectin concentrations in unstimulated saliva and 1.5-fold in stimulated saliva, compared to CD patients with established disease (P = 0.059, P = 0.019). Calprotectin decreased in serum of IBD patients after treatment (P = 0.011), and in unstimulated saliva of newly diagnosed, treatment naïve CD patients (P = 0.046, P = 0.028). CONCLUSION: Salivary calprotectin is elevated in IBD, which suggests subclinical inflammatory responses in the oral cavity as a manifestation of IBD.


Assuntos
Doença de Crohn/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Complexo Antígeno L1 Leucocitário/análise , Saliva/química , Biomarcadores/análise , Ensaio de Imunoadsorção Enzimática , Humanos
8.
J Physiol Pharmacol ; 70(2)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31443089

RESUMO

Crohn's Disease (CD), one of the types of inflammatory bowel disease, poses a significant challenge to modern healthcare. This condition severely impacts patients' quality of life, and its incidence is continuously rising. Despite constant research, current treatment options are limited and largely unsuccessful and result in serious side effects, therefore new therapy alternatives are needed. Liposomal formulation provides a new hope for disease management. In our study, we characterized the anti-inflammatory activity of mesalazine (5-ASA) and chlorogenic acid (CGA) encapsulated in liposomal formulation in the animal model of CD. Liposomes were obtained by thin film hydration method and characterized in terms of suspension stability and particle size and distribution. Colitis was induced in mice by intracolonic (i.c.) administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS). The effect of treatment with liposomal suspensions of 5-ASA and CGA was evaluated macroscopically and by measuring myeloperoxidase (MPO) activity. We observed that liposome-encapsulated 5-ASA (5 mg/kg), but not CGA (20 mg/kg) attenuated colitis as evidenced by a decreased macroscopic and microscopic scores. It may be hypothesized that the composition of liposomal lipid bilayer as well as the switch in macrophage populations leading to unfavorable accumulation of anti-inflammatory agents in the cells may underly the efficiency of obtained liposomes and need to be taken into consideration in further studies on drug delivery.


Assuntos
Ácido Clorogênico/química , Ácido Clorogênico/farmacologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Lipossomos/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Colite/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Modelos Animais de Doenças , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Masculino , Mesalamina/química , Mesalamina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Peroxidase/metabolismo , Qualidade de Vida , Ácido Trinitrobenzenossulfônico
9.
Int J Mol Sci ; 20(16)2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31434263

RESUMO

One of the main mechanisms carried out by the cells to counteract several forms of stress is the activation of the nuclear factor erythroid 2-related factor (Nrf2) signaling. Nrf2 signaling controls the expression of many genes through the binding of a specific cis-acting element known as the antioxidant response element (ARE). Activation of Nrf2/ARE signaling can mitigate several pathologic mechanisms associated with an autoimmune response, digestive and metabolic disorders, as well as respiratory, cardiovascular, and neurodegenerative diseases. Indeed, several studies have demonstrated that Nrf2 pathway plays a key role in inflammation and in cancer development in many organs, including the intestine. Nrf2 appears to be involved in inflammatory bowel disease (IBD), an immune-mediated chronic and disabling disease, with a high risk of developing intestinal fibrotic strictures and cancer. Currently, drugs able to increase cytoprotective Nrf2 function are in clinical trials or already being used in clinical practice to reduce the progression of some degenerative conditions. The role of Nrf2 in cancer development and progression is controversial, and drugs able to inhibit abnormal levels of Nrf2 are also under investigation. The goal of this review is to analyze and discuss Nrf2-dependent signals in the initiation and progression of intestinal fibrosis and cancers occurring in IBD.


Assuntos
Neoplasias Colorretais/metabolismo , Inflamação/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Fibrose/metabolismo , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologia
10.
J Immunol Res ; 2019: 8630871, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31276001

RESUMO

Inflammatory bowel disease-associated spondyloarthritis is a systemic disease characterized by the chronic inflammation of both the gastrointestinal tract and the musculoskeletal system. Since inflammatory bowel disease-associated spondyloarthritis has been associated with a significant diagnostic delay, which may lead to poor quality of life and progression of joint damage, efforts to discover new reliable and noninvasive diagnostic biomarkers have been made. We reviewed the state of the art of biomarker research in inflammatory bowel disease-associated spondyloarthritis, showing that to date it has been largely unsatisfactory. Only a few of the biomarkers that have been investigated are likely to enter the clinical practice upon further validation in independent cohorts. The research of new and innovative biomarkers for inflammatory bowel disease-associated spondyloarthritis is warranted.


Assuntos
Biomarcadores , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/metabolismo , Espondilartrite/etiologia , Espondilartrite/metabolismo , Animais , Suscetibilidade a Doenças , Predisposição Genética para Doença , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Prognóstico , Espondilartrite/diagnóstico
11.
EBioMedicine ; 46: 522-531, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31327693

RESUMO

The gastrointestinal mucosa is critical for maintaining the integrity and functions of the gut. Disruption of this barrier is a hallmark and a risk factor for many intestinal and chronic inflammatory diseases. Inflammatory bowel disease (IBD) and HIV infection are characterized by microbial translocation and systemic inflammation. Despite the clinical overlaps between HIV and IBD, significant differences exist such as the severity of gut damage and mechanisms of immune cell homeostasis. Studies have supported the role of metabolic activation of immune cells in promoting chronic inflammation in HIV and IBD. This inflammatory response persists in HIV+ persons even after long-term virologic suppression by antiretroviral therapy (ART). Here, we review gut dysfunction and microbiota changes during HIV infection and IBD, and discuss how this may induce metabolic reprogramming of monocytes, macrophages and T cells to impact disease outcomes. Drawing from parallels with IBD, we highlight how factors such as lipopolysaccharides, residual viral replication, and extracellular vesicles activate biochemical pathways that regulate immunometabolic processes essential for HIV persistence and non-AIDS metabolic comorbidities. This review highlights new mechanisms and support for the use of immunometabolic-based therapeutics towards HIV remission/cure, and treatment of metabolic diseases.


Assuntos
Gastroenteropatias/etiologia , Gastroenteropatias/fisiopatologia , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , HIV/imunologia , Animais , Permeabilidade da Membrana Celular , Comorbidade , Disbiose , Metabolismo Energético , Ácidos Graxos/metabolismo , Microbioma Gastrointestinal/imunologia , Infecções por HIV/complicações , Infecções por HIV/virologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Macrófagos/imunologia , Macrófagos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo
12.
Clin Lab ; 65(7)2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31307176

RESUMO

BACKGROUND: Fecal calprotectin is widely used as a marker for inflammatory bowel diseases (IBD). IBD often affects women during their reproductive years, but there are no established reference intervals during pregnancy. The aim of the present study was to define reference values during pregnancy and in the postpartum period to allow comparisons between patient results and reference values. METHODS: Fecal samples were collected from 84 healthy females during pregnancy week 26 to 28 and a second sample was collected six months after delivery. The samples were weighed, extracted, and centrifugated to remove debris. The extracted samples were then analyzed on a chemistry analyzer using a particle enhanced turbidimetric immunoassay reagent. RESULTS: The calculated reference interval during pregnancy was < 127 µg/g (90% confidence interval, 90 - 164 µg/g) and the corresponding reference interval during the postpartum period was < 143 µg/g (60 - 226 µg/g). There were no significant statistical differences between F-calprotectin values analyzed at the two sampling times. CONCLUSIONS: The reference values are slightly higher than the cutoff values of 50 - 100 µg/g often used as General cutoff for fecal calprotectin.


Assuntos
Biomarcadores/análise , Ensaio de Imunoadsorção Enzimática/métodos , Fezes/química , Complexo Antígeno L1 Leucocitário/análise , Nefelometria e Turbidimetria/métodos , Adulto , Feminino , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/metabolismo , Gravidez , Valores de Referência , Adulto Jovem
13.
Nat Commun ; 10(1): 3371, 2019 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358760

RESUMO

TNF-like ligand 1 A (TL1A) and death receptor 3 (DR3) are a ligand-receptor pair involved in the pathogenesis of inflammatory bowel disease. Group 3 innate lymphoid cells (ILC3s) regulate intestinal immunity and highly express DR3. Here, we report that activation of DR3 signaling by an agonistic anti-DR3 antibody increases GM-CSF production from ILC3s through the p38 MAPK pathway. GM-CSF causes accumulation of eosinophils, neutrophils and CD11b+CD11c+ myeloid cells, resulting in loss of ILC3s from the intestine in an IL-23-dependent manner and exacerbating colitis. Blockade of GM-CSF or IL-23 reverses anti-DR3 antibody-driven ILC3 loss, whereas overexpression of IL-23 induces loss of ILC3s in the absence of GM-CSF. Neutralization of TL1A by soluble DR3 ameliorates both DSS and anti-CD40 antibody-induced colitis. Moreover, ILC3s are required for the deleterious effect of anti-DR3 antibodies on innate colitis. These findings clarify the process and consequences of DR3 signaling-induced intestinal inflammation through regulation of ILC3s.


Assuntos
Colite/imunologia , Doenças Inflamatórias Intestinais/imunologia , Linfócitos/imunologia , Membro 25 de Receptores de Fatores de Necrose Tumoral/imunologia , Transdução de Sinais/imunologia , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Células Cultivadas , Colite/genética , Colite/metabolismo , Eosinófilos/citologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Interleucina-23/farmacologia , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células Mieloides/citologia , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Membro 25 de Receptores de Fatores de Necrose Tumoral/genética , Membro 25 de Receptores de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais/genética
14.
J Agric Food Chem ; 67(33): 9277-9285, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31353906

RESUMO

3,3'-Diindolylmethane (DIM), a digestive metabolite originating from cruciferous vegetables, has dietary potential for the treatment of various human intestinal diseases. Although intestinal permeability dysfunction is closely related to the initiation and progression of human intestinal inflammatory diseases (IBDs), the effect of DIM on intestinal permeability is unclear. We evaluated the effect of DIM on the intestinal permeability of human intestinal cell monolayers and the animal model Caenorhabditis elegans, which were treated with IL-1ß and Pseudomonas aeruginosa, respectively, to mimic IBD conditions. DIM substantially restored the intestinal permeability of differentiated Caco-2 cells by enhancing the expression of tight junction proteins (including occludin and ZO-1). Compared to the IL-1ß single treatment (551.0 ± 49.0 Ω·cm2), DIM (10 µM) significantly increased the transepithelial electrical resistance (TEER) of Caco-2 cell monolayers (919.0 ± 66.4 Ω·cm2, p < 0.001). DIM also ameliorated the impaired intestinal permeability and extended the lifespan of C. elegans fed P. aeruginosa. The mean lifespan of DIM-treated worms (10.8 ± 1.3 days) was higher than that of control-treated worms (9.7 ± 1.1 days, p < 0.01). Thus, DIM is a potential nutraceutical candidate for the treatment of leaky gut syndrome by improving intestinal permeability.


Assuntos
Indóis/administração & dosagem , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Animais , Células CACO-2 , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Mucosa Intestinal/metabolismo , Intestinos , Masculino , Ocludina/genética , Ocludina/metabolismo , Permeabilidade/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismo
15.
Int J Mol Sci ; 20(15)2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31357438

RESUMO

Cell-free nucleic acids (cfNAs) are defined as any nucleic acids that are present outside the cell. They represent valuable biomarkers in various diagnostic protocols such as prenatal diagnostics, the detection of cancer, and cardiovascular or autoimmune diseases. However, in the current literature, little is known about their implication in inflammatory bowel disease (IBD). IBD is a group of multifactorial, autoimmune, and debilitating diseases with increasing incidence worldwide. Despite extensive research, their etiology and exact pathogenesis is still unclear. Since cfNAs were observed in other autoimmune diseases and appear to be relevant in inflammatory processes, their role in the pathogenesis of IBD has also been suggested. This review provides a summary of knowledge from the available literature about cfDNA and cfRNA and the structures involving them such as exosomes and neutrophil extracellular traps and their association with IBD. Current studies showed the promise of cfNAs in the management of IBD not only as biomarkers distinguishing patients from healthy people and differentiating active from inactive disease state, but also as a potential therapeutic target. However, the detailed biological characteristics of cfNAs need to be fully elucidated in future experimental and clinical studies.


Assuntos
Ácidos Nucleicos Livres , Suscetibilidade a Doenças , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/metabolismo , Animais , Biomarcadores , DNA Mitocondrial , Gerenciamento Clínico , Exossomos , Armadilhas Extracelulares , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/terapia , Terapia de Alvo Molecular , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia , RNA Longo não Codificante/genética
16.
J Vet Med Sci ; 81(9): 1249-1258, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31341112

RESUMO

Inflammatory bowel disease (IBD) is a common gastrointestinal disease in dogs. Decreased production of intestinal immunoglobulin A (IgA) has been suggested as a possible pathogenesis in a subset of canine IBD; however, the underlying cause remains unclear. Sphingosine-1-phosphate (S1P) is a lipid mediator that regulates intestinal IgA production by controlling lymphocyte trafficking in mice. The objectives of this study were to clarify the role of S1P in IgA production in dogs and to evaluate the expression of S1P-related molecules in dogs with IBD. First, an S1P receptor antagonist was administrated to five healthy dogs. The S1P receptor antagonist significantly decreased the IgA concentration in sera and feces but did not affect the IgG concentration. Moreover, the immunoreactivity of intestinal IgA was significantly decreased by S1P signal blockade. These results indicate that S1P signaling specifically regulates the intestinal IgA production in dogs. Subsequently, the intestinal S1P concentration and the expression of S1P-related molecules were measured in dogs with IBD and healthy dogs. The intestinal concentration of S1P was significantly lower in dogs with IBD than in healthy dogs. In addition, the gene expression levels of S1P receptor (S1P1) and S1P synthase (SK1) were significantly lower in dogs with IBD than in healthy dogs. Taken together, these observations suggest that decreased S1P production, likely caused by a lower expression of S1P synthetase, leads to attenuation of S1P/S1P1 signaling pathway and the production of intestinal IgA in dogs with IBD.


Assuntos
Doenças do Cão/metabolismo , Imunoglobulina A/metabolismo , Doenças Inflamatórias Intestinais/veterinária , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Animais , Doenças do Cão/patologia , Cães , Fezes/química , Cloridrato de Fingolimode/administração & dosagem , Expressão Gênica , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Intestinos/química , Masculino , Esfingosina/metabolismo , /genética
17.
Mediators Inflamm ; 2019: 6953963, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275059

RESUMO

Mesenchymal stem cells (MSCs) exert powerful immunosuppression in inflammatory bowel disease (IBD). Macrophages are the dominant inflammatory cells in enteritis regulated via MSCs. However, the roles of macrophages in the process of MSCs attenuating IBD and the mechanisms of MSCs regulating macrophages are largely unknown. In this study, DSS- (dextran sulfate sodium salt-) induced IBD in macrophage-depleted models of CD11b-DTR mice was used to study the relationship between hucMSCs (human umbilical cord mesenchymal stromal cells) and macrophage. Body weights, disease activities, and pathological changes were documented to assess the therapeutic effects of hucMSCs. Furthermore, hucMSCs transfected with miR148b-5p mimics and miR148b-5p inhibitors were cocultured with LPS-induced RAW264.7 cells to investigate the role of miR148b-5p in hucMSC-regulated colitis. The outcome indicated that hucMSCs attenuated the IBD by downregulating 15-lox-1 expression in macrophages. Further findings pointed out that hucMSCs transfected with miR148b-5p mimics could be elevated to promote the tissue repair and inhibit the expression of 15-lox-1 but failed to perform the function of easing enteritis when treated with miR148b-5p inhibitors. In conclusions, we propose that hucMSCs attenuate IBD by releasing miR148b-5p to inhibit the expression of 15-lox-1 in macrophages.


Assuntos
Araquidonato 15-Lipoxigenase/metabolismo , Sulfato de Dextrana/toxicidade , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/terapia , Animais , Araquidonato 15-Lipoxigenase/genética , Western Blotting , Imunofluorescência , Humanos , Inibidores de Lipoxigenase/uso terapêutico , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Células RAW 264.7 , Reação em Cadeia da Polimerase em Tempo Real
18.
Gastroenterology ; 157(4): 1032-1043.e1, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31228441

RESUMO

BACKGROUND & AIMS: There is no consensus on the best way to integrate biomarkers into inflammatory bowel disease (IBD) research and clinical practice. The International Organization for the Study of Inflammatory Bowel Disease aimed to outline biomarker definitions, categories, and operating properties required for their use in registration trials and clinical practice. Using fecal calprotectin as an example, we provide a framework for biomarker development and validation in patients with IBD. METHODS: We reviewed international society guidelines, regulatory agency guidance documents, and standardized reporting guidelines for biomarkers, in combination with publications on fecal calprotectin levels in patients with IBD. We assessed the validity of fecal calprotectin to serve as a surrogate biomarker of IBD activity and outlined a framework for further validation and development of biomarkers. RESULTS: No endpoints have been fully validated as surrogates of risk of disease complications; mucosal healing is the most valid endpoint used to determine risk of disease complications. Fecal level of calprotectin has not been validated as a biomarker for IBD activity because of lack of technical and clinical reliability, assessment of performance when used as a replacement for endoscopy, and assessment of responsiveness to changes in disease states. The level of fecal calprotectin can be used only as a prognostic factor for disease recurrence in patients in remission after medical or surgical treatment. CONCLUSIONS: We reviewed guidelines, regulatory documents, and publications to identify properties required for the development of biomarkers of IBD activity and areas in need of clarification from regulatory agencies and societies. We propose a path forward for research of biomarkers for IBD.


Assuntos
Ensaios Clínicos como Assunto/métodos , Procedimentos Clínicos , Fezes/química , Doenças Inflamatórias Intestinais/terapia , Complexo Antígeno L1 Leucocitário/metabolismo , Biomarcadores/metabolismo , Consenso , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/metabolismo , Valor Preditivo dos Testes , Recidiva , Indução de Remissão , Reprodutibilidade dos Testes , Projetos de Pesquisa , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
19.
BMC Genomics ; 20(1): 517, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31234773

RESUMO

BACKGROUND: In the biochemical milieu of human colon, bile acids act as signaling mediators between the host and its gut microbiota. Biotransformation of primary to secondary bile acids have been known to be involved in the immune regulation of human physiology. Several 16S amplicon-based studies with inflammatory bowel disease (IBD) subjects were found to have an association with the level of fecal bile acids. However, a detailed investigation of all the bile salt biotransformation genes in the gut microbiome of healthy and IBD subjects has not been performed. RESULTS: Here, we report a comprehensive analysis of the bile salt biotransformation genes and their distribution at the phyla level. Based on the analysis of shotgun metagenomes, we found that the IBD subjects harbored a significantly lower abundance of these genes compared to the healthy controls. Majority of these genes originated from Firmicutes in comparison to other phyla. From metabolomics data, we found that the IBD subjects were measured with a significantly low level of secondary bile acids and high levels of primary bile acids compared to that of the healthy controls. CONCLUSIONS: Our bioinformatics-driven approach of identifying bile salt biotransformation genes predicts the bile salt biotransformation potential in the gut microbiota of IBD subjects. The functional level of dysbiosis likely contributes to the variation in the bile acid pool. This study sets the stage to envisage potential solutions to modulate the gut microbiome with the objective to restore the bile acid pool in the gut.


Assuntos
Bactérias/metabolismo , Ácidos e Sais Biliares/metabolismo , Microbioma Gastrointestinal/genética , Bactérias/classificação , Bactérias/genética , Proteínas de Bactérias/genética , Biotransformação/genética , Disbiose/metabolismo , Disbiose/microbiologia , Firmicutes/genética , Firmicutes/metabolismo , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/microbiologia , Metagenômica
20.
Nat Commun ; 10(1): 2892, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253778

RESUMO

Clinical manifestations and response to therapies in ulcerative colitis (UC) are heterogeneous, yet patient classification criteria for tailored therapies are currently lacking. Here, we present an unsupervised molecular classification of UC patients, concordant with response to therapy in independent retrospective cohorts. We show that classical clustering of UC patient tissue transcriptomic data sets does not identify clinically relevant profiles, likely due to associated covariates. To overcome this, we compare cross-sectional human data sets with a newly generated longitudinal transcriptome profile of murine DSS-induced colitis. We show that the majority of colitis risk-associated gene expression peaks during the inflammatory rather than the recovery phase. Moreover, we achieve UC patient clustering into two distinct transcriptomic profiles, differing in neutrophil-related gene activation. Notably, 87% of patients in UC1 cluster are unresponsive to two most widely used biological therapies. These results demonstrate that cross-species comparison enables stratification of patients undistinguishable by other molecular approaches.


Assuntos
Mapeamento Cromossômico , Colite/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Transcriptoma , Animais , Colite/induzido quimicamente , Colite/genética , Citometria de Fluxo , Regulação da Expressão Gênica , Humanos , Camundongos , Membrana Mucosa/citologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
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