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1.
Nihon Yakurigaku Zasshi ; 154(3): 92-96, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31527366

RESUMO

Transient receptor potential vanilloid 4 (TRPV4) is a non-selective cation channel that responds to mechanical, thermal, and chemical stimuli in addition to various endogenous ligands, such as arachidonic acid metabolites. The present study aimed to elucidate the expression of TRPV4 in the gastrointestinal tract and the pathogenic roles of TRPV4 in dextran sulphate sodium (DSS)-induced colitis. TRPV4-immunoreactivity was detected in epithelial-like cells of the mouse tongue, esophagus, stomach, ileum, and colon; TRPV4 expression in the tongue was higher than other gastrointestinal tracts. TRPV4 colocalized with a type IV cell marker sonic hedgehog in circumvallate papillae. These findings suggest that TRPV4 contributes to sour taste sensing by regulating type III taste cell differentiation in mice. DSS-induced colitis was significantly attenuated in TRPV4-knockout (TRPV4KO) mice when compared to wild-type mice. DSS treatment upregulated TRPV4 expression in vascular endothelia of colonic mucosa and submucosa. DSS treatment increased vascular permeability, which was abolished in TRPV4KO mice. The activation of TRPV4 decreased VE-cadherin expression in mouse aortic endothelial cells exposed to TNF-α. These findings indicate that the upregulation of TRPV4 in vascular endothelial cells contributes to the progression of colonic inflammation via the activation of vascular permeability. Thus, TRPV4 is an attractive target for the treatment of inflammatory bowel diseases.


Assuntos
Colite/fisiopatologia , Células Endoteliais/fisiologia , Trato Gastrointestinal/fisiologia , Trato Gastrointestinal/fisiopatologia , Canais de Cátion TRPV/fisiologia , Animais , Colite/induzido quimicamente , Sulfato de Dextrana , Camundongos , Camundongos Knockout , Língua/fisiologia
2.
Toxicol Lett ; 315: 23-30, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31442584

RESUMO

Ulcerative colitis2 (UC) is an inflammatory bowel disease3 (IBD) that causes long-lasting inflammation and ulcers in the human digestive tract. The repair function of TLR4 in the intestinal epithelium is still unknown. Here, wild-type4 (WT) mice, TLR4-knockout mice5 (KO; TLR4-/-) and commensal-depleted mice were used as dextran sulfate sodium6 (DSS)-induced or radiation-induced colitis and injury models to explore the role of TLR4 signaling in intestinal injury. Exogenous lipopolysaccharide7 (LPS) promoted DSS-induced inflammatory cytokines and aggravated intestinal damage. TLR4 deficiency and commensal bacterial depletion inhibited the toxic effects of LPS, but these mice were more susceptible to DSS-induced and radiation-induced intestinal damage. Compared with WT mice, neither DSS nor radiation promoted production of more inflammatory cytokines in the guts of TLR4-KO and commensal-depleted mice. Introducing the cytokine repair factors, PGE2 and GM-CSF, increased the cytokine levels in the guts of DSS-induced colitis mice. We hypothesized that TLR4 and its ligands repaired the epithelium after DSS-induced and radiation-induced intestinal damage by upregulating PGE2 and GM-CSF. Transwell migration assays suggested that LPS, IL6, TNF, PGE2 and GM-CSF promoted intestinal cell migration, and cell viability analysis suggested that these factors protected against radiation-induced intestinal damage. Our data underscore the importance of the balancing role of TLR4 in intestinal injury and repair.


Assuntos
Linhagem Celular/efeitos da radiação , Colite/induzido quimicamente , Colite/fisiopatologia , Sulfato de Dextrana/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos da radiação , Receptor 4 Toll-Like/efeitos da radiação , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação
3.
BMC Gastroenterol ; 19(1): 96, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221091

RESUMO

BACKGROUND: Children in poor areas show significant growth retardation that does not improve with an adequate supply of energy and nutrients, which may be related to asymptomatic intestinal infection caused by poor sanitation. Our objective was to explore the mechanism of intestinal inflammation inhibiting growth in the setting of asymptomatic colitis. METHODS: Forty-eight 3-week-old Wistar rats were randomly divided into three groups: the control group, colitis group (with asymptomatic colitis induced by 2.5% trinitrobenzenesulphonic acid) and pair-fed group (daily food intake matched to the pair in the colitis group). The linear growth was assessed, and the plasma levels of hormone and systemic cytokines were detected and compared by independent two-sample t-test or one-way ANOVA among groups. RESULTS: At d5, the increases in the body length of the control, colitis and pair-fed groups were 1.65 ± 0.34 cm, 1.10 ± 0.30 cm and 1.38 ± 0.26 cm, respectively, and the increase in the body length in the colitis group was significantly less than that in the control group (P < 0.05). There were significant differences in the levels of hormone and cytokines among three groups (P < 0.05). Compared with the control group, rats in the colitis group exhibited linear growth failure, as well as higher expression of calprotectin, tumour necrosis factor-α, interleukin-6 and insulin-like growth factor binding protein 2, lower insulin-like growth factor-1 and insulin-like growth factor binding protein 3, and lower expression of nuclear factor kappa B in hepatocytes. CONCLUSIONS: In addition to undernutrition, the systemic inflammatory response caused by asymptomatic colitis may inhibit the linear growth of rats by its influence on the insulin-like growth factor/insulin-like growth factor binding protein axis.


Assuntos
Colite/fisiopatologia , Crescimento/fisiologia , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Análise de Variância , Animais , Colite/induzido quimicamente , Hepatócitos/metabolismo , Inflamação , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Interleucina-6/metabolismo , Complexo Antígeno L1 Leucocitário/metabolismo , Fígado/metabolismo , Desnutrição/fisiopatologia , NF-kappa B/metabolismo , Ratos , Ratos Wistar , Ácido Trinitrobenzenossulfônico , Fator de Necrose Tumoral alfa/metabolismo
4.
J Biomed Sci ; 26(1): 46, 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31189465

RESUMO

BACKGROUND: Triggering receptor expressed on myeloid cells-1 (TREM-1) is highly expressed on macrophages in inflamed intestines and reportedly promotes inflammatory bowel disease (IBD) by augmenting pro-inflammatory responses. To study the mechanism mediated by TREM-1 on macrophages, we generated an independent TREM-1 deficient mouse. METHODS: Acute colitis was induced in C57BL/6 and TREM-1-deficient mice by the administration of dextran sodium sulfate (DSS). Colonic lamina propria immune cell composition and cytokines were analyzed. An innate lymphoid cell (ILC) co-culture experiment with macrophages was used to analyze IL-22 levels. Exogenous IL-22 and TREM-1-expressing macrophages were supplied to TREM-1-deficient mice for examining their effects on intestinal barrier integrity. RESULTS: In inflamed colons, TREM-1 loss compromised the activation of ILC3 and their production of IL-22, which is required for intestinal barrier integrity. ILC3-mediated IL-22 production depends on IL-1ß secreted by M1-polarized macrophages, and we found that TREM-1 deficiency results in a decreased number of IL-1ß producing-M1 macrophages in colons exposed to DSS. Accordingly, DSS-mediated damage was ameliorated by supplying exogenous IL-22 and TREM-1-expressing macrophages to TREM-1-deficient mice. CONCLUSIONS: TREM-1 plays a crucial role in regulating IL-22 production by ILC3 through modulating M1-macrophage polarization during DSS-induced acute colitis.


Assuntos
Colite/patologia , Interleucinas/metabolismo , Mucosa Intestinal/fisiologia , Linfócitos/imunologia , Macrófagos/fisiologia , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Animais , Colite/induzido quimicamente , Colite/fisiopatologia , Sulfato de Dextrana/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout
5.
Amyloid ; 26(3): 139-147, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31210531

RESUMO

Objective: Amyloid A (AA) amyloidosis is found in humans and non-human primates, but quantifying disease risk prior to clinical symptoms is challenging. We applied machine learning to identify the best predictors of amyloidosis in rhesus macaques from available clinical and pathology records. To explore potential biomarkers, we also assessed whether changes in circulating serum amyloid A (SAA) or lipoprotein profiles accompany the disease. Methods: We conducted a retrospective study using 86 cases and 163 controls matched for age and sex. We performed data reduction on 62 clinical, pathological and demographic variables, and applied multivariate modelling and model selection with cross-validation. To test the performance of our final model, we applied it to a replication cohort of 2,775 macaques. Results: The strongest predictors of disease were colitis, gastrointestinal adenocarcinoma, endometriosis, arthritis, trauma, diarrhoea and number of pregnancies. Sensitivity and specificity of the risk model were predicted to be 82%, and were assessed at 79 and 72%, respectively. Total, low density lipoprotein and high density lipoprotein cholesterol levels were significantly lower, and SAA levels and triglyceride-to-HDL ratios were significantly higher in cases versus controls. Conclusion: Machine learning is a powerful approach to identifying macaques at risk of AA amyloidosis, which is accompanied by increased circulating SAA and altered lipoprotein profiles.


Assuntos
Amiloidose/diagnóstico , Aprendizado de Máquina/estatística & dados numéricos , Modelos Estatísticos , Proteína Amiloide A Sérica/metabolismo , Adenocarcinoma/diagnóstico , Adenocarcinoma/fisiopatologia , Amiloidose/sangue , Amiloidose/fisiopatologia , Animais , Artrite/diagnóstico , Artrite/fisiopatologia , Biomarcadores/sangue , Estudos de Casos e Controles , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Colite/diagnóstico , Colite/fisiopatologia , Diarreia/diagnóstico , Diarreia/fisiopatologia , Modelos Animais de Doenças , Endometriose/diagnóstico , Endometriose/fisiopatologia , Feminino , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/fisiopatologia , Humanos , Macaca mulatta , Masculino , Estudos Retrospectivos , Fatores de Risco , Triglicerídeos/sangue , Ferimentos e Lesões/diagnóstico , Ferimentos e Lesões/fisiopatologia
6.
Life Sci ; 231: 116589, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31226416

RESUMO

AIMS: Despite the protective effect of galacto-oligosaccharides (GOS) on human colon has been widely-reported, the mechanism of its beneficial effect is still unclear. This paper aims to reveal the internal mechanism underlined the anti-colitis effect of GOS by studying its regulatory effect on miRNAs. MAIN METHODS: An in vitro model of colitis was constructed by using human colon epithelial FHC cells and lipopolysaccharide (LPS). An in vivo colitis model was established as well, by injecting Rag2-/- Sprague-Dawley (SD) rats with helicobacter hepaticus. The effects of GOS pre-treatment on these two models were tested, and the miRNAs involved in these effects were studied. KEY FINDINGS: The expression of miR-19b, miR-590-5p and miR-495 was up-regulated, and the expression of miR-29a, miR-31 and miR-142-5p was down-regulated by GOS treatment in both normal and LPS-stimulated FHC cells. Among which, miR-19b was the most varied miRNA. GOS pre-treatment significantly attenuated LPS-induced cell injury, as evidenced by the increase of cell viability, the decrease of apoptosis, as well as the suppressed release of TNF-α, IFN-γ and IL-1ß. GOS pre-treatment could also prevent Rag2-/- rats against helicobacter hepaticus injection induced diarrhea and inflammation, as the body weight and colon organ weight were recovered, diarrhea score was declined, and the release of pro-inflammatory cytokines was inhibited. The in vitro and in vivo effects of GOS abovementioned were all impeded when miR-19b was silenced. SIGNIFICANCE: In vitro and in vivo experiments showed that GOS have certain anti-colitis effect, and this effect may be achieved by up-regulating miR-19b.


Assuntos
MicroRNAs/genética , Oligossacarídeos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Colite/genética , Colite/fisiopatologia , Colo/efeitos dos fármacos , Colo/metabolismo , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Feminino , Humanos , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , MicroRNAs/metabolismo , Oligossacarídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Ativação Transcricional/efeitos dos fármacos , Regulação para Cima
7.
J Nippon Med Sch ; 86(2): 131-134, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31130565

RESUMO

Obstructive colitis (OC) is a nonspecific inflammatory condition that occurs at the proximal side of a completely or partially stenotic lesion typically caused by colorectal cancer. Impaired blood flow caused by these stenotic changes in the colon or rectum results in this condition. During surgery for sigmoid colon carcinoma with OC, complete surgical removal of the OC lesions is required. However, it is difficult to anticipate the range of OC before surgery. Diagnosing the potential ischemia during surgery would decrease the need for re-operation. This is the first report of HyperEye Medical System (HEMS) angiography for surgery of colon cancer with OC. We report a case of sigmoid colon carcinoma in which HEMS angiography was used and found to be useful for real-time detection of the OC lesion.


Assuntos
Angiografia/métodos , Colite/diagnóstico por imagem , Colite/cirurgia , Colo/irrigação sanguínea , Obstrução Intestinal/diagnóstico por imagem , Obstrução Intestinal/cirurgia , Isquemia/diagnóstico , Margens de Excisão , Reto/irrigação sanguínea , Neoplasias do Colo Sigmoide/irrigação sanguínea , Neoplasias do Colo Sigmoide/cirurgia , Idoso , Colite/etiologia , Colite/fisiopatologia , Humanos , Verde de Indocianina , Obstrução Intestinal/etiologia , Obstrução Intestinal/fisiopatologia , Período Intraoperatório , Masculino , Neoplasias do Colo Sigmoide/complicações , Neoplasias do Colo Sigmoide/diagnóstico por imagem
8.
Clin Sci (Lond) ; 133(8): 919-932, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-30944150

RESUMO

A dramatic increase in the incidence of inflammatory bowel disease (IBD) has been observed in the past two decades, mainly in developed countries and also in developing regions. Necroptosis has been found to play an important role in the pathogenesis of IBD, suggesting its inhibitors are promising in clinic. However, clinical drugs targeting necroptosis are seriously lacking. Through screening a clinical compound library that contains 611 inhibitors, a pan-RAF inhibitor LY3009120 was found to be promising as a necroptosis inhibitor. LY3009120 inhibited necroptosis in vitro, and its inhibition against necroptosis was independent of its well-known activity to inhibit RAF. Surprisingly, LY3009120 prevented phosphorylation of receptor interacting serine/threonine kinase 1 (RIPK1) and subsequently phosphorylation of receptor interacting serine/threonine kinase 3 (RIPK3) and mixed lineage kinase domain like pseudokinase (MLKL) which happened during necroptosis. In vivo, LY3009120 significantly alleviated dextran sulfate sodium (DSS)-induced colitis as indicated by prevention of body weight loss, colon shortening, and decreased mortality. Furthermore, LY3009120 inhibited necroptosis of intestinal epithelial cells (IECs) and prevented intestinal barrier function loss. Consistently, LY3009120 decreased DSS-induced colonic inflammation, as indicated by decreased infiltration of macrophages and neutrophils, and decreased colonic TNF-α, IL-6, and IL-1ß level in DSS treated mice. These results indicate that an anti-cancer pan-RAF inhibitor LY3009120 is a necroptosis inhibitor and may serve as a potential therapeutic drug for colitis.


Assuntos
Colite/tratamento farmacológico , Sulfato de Dextrana/efeitos adversos , Compostos de Fenilureia/administração & dosagem , Pirimidinas/administração & dosagem , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Colite/induzido quimicamente , Colite/metabolismo , Colite/fisiopatologia , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
9.
PLoS One ; 14(4): e0215387, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31002683

RESUMO

The dextran sulfate sodium (DSS) model of colitis is a common animal model of inflammatory bowel disease that causes pain and distress. In this study, we aimed to determine whether fluid supplementation can be used as a welfare-based intervention to minimize animal suffering. C57Bl/6 females undergoing acute colitis by administration of 3% DSS in drinking water were supplemented with 1 mL intraperitoneal injections of NaCl and compared to non-supplemented control mice. Mouse behavior and locomotive activity were assessed on days 5-6 after DSS initiation by means of tail suspension, novel object recognition and open field activity tests. Mice were euthanized after either the acute (day 7) or the recovery phase (day 12) of colitis and inflammation, epithelial proliferation, and differentiation were assessed by means of histology, immunohistochemistry, quantitative PCR, and western blot. We found that fluid-supplemented mice had reduced signs of colitis with no alterations in behavior or locomotive activity. Furthermore, we observed an accelerated epithelial repair response after fluid hydration during the acute phase of colitis, characterized by increased crypt proliferation, activation of ERK1/2, and modulation of TGF-ß1 expression. Consistent with these findings, fluid-supplemented mice had increased numbers of goblet cells, upregulated expression of differentiation markers for absorptive enterocytes, and reduced inflammation during the recovery phase. Our results show that fluid hydration does not reduce stress in DSS-treated mice but alters colitis evolution by reducing clinical signs and accelerating epithelial repair. These results argue against the routine use of fluid supplementation in DSS-treated mice.


Assuntos
Colite/terapia , Mucosa Intestinal/patologia , Solução Salina/farmacologia , Animais , Colite/induzido quimicamente , Colite/fisiopatologia , Sulfato de Dextrana , Modelos Animais de Doenças , Feminino , Hidratação/métodos , Injeções Intraperitoneais , Mucosa Intestinal/metabolismo , Camundongos Endogâmicos C57BL , Atividade Motora/fisiologia , Solução Salina/administração & dosagem , Cicatrização/fisiologia
10.
Neural Plast ; 2019: 2098083, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984253

RESUMO

Although referred pain or hypersensitivity has been repeatedly reported in irritable bowel syndrome (IBS) patients and experimental colitis rodents, little is known about the neural mechanisms. Spinal long-term potentiation (LTP) of nociceptive synaptic transmission plays a critical role in the development of somatic hyperalgesia in chronic pain conditions. Herein, we sought to determine whether spinal LTP contributes to the referral hyperalgesia in colitis rats and particularly whether electroacupuncture (EA) is effective to alleviate somatic hyperalgesia via suppressing spinal LTP. Rats in the colitis group (induced by colonic infusion of 2,4,6-trinitrobenzenesulfonic acid, TNBS), instead of the control and vehicle groups, displayed evident focal inflammatory destruction of the distal colon accompanied not only with the sensitized visceromotor response (VMR) to noxious colorectal distension (CRD) but also with referral hindpaw hyperalgesia indicated by reduced mechanical and thermal withdrawal latencies. EA at Zusanli (ST36) and Shangjuxu (ST37) attenuated the severity of colonic inflammation, as well as the visceral hypersensitivity and referral hindpaw hyperalgesia in colitis rats. Intriguingly, the threshold of C-fiber-evoked field potentials (CFEFP) was significantly reduced and the spinal LTP was exaggerated in the colitis group, both of which were restored by EA treatment. Taken together, visceral hypersensitivity and referral hindpaw hyperalgesia coexist in TNBS-induced colitis rats, which might be attributed to the enhanced LTP of nociceptive synaptic transmission in the spinal dorsal horn. EA at ST36 and ST37 could relieve visceral hypersensitivity and, in particular, attenuate referral hindpaw hyperalgesia by suppressing the enhanced spinal LTP.


Assuntos
Colite/fisiopatologia , Eletroacupuntura , Hiperalgesia/fisiopatologia , Potenciação de Longa Duração , Nociceptividade/fisiologia , Medula Espinal/fisiopatologia , Animais , Colite/induzido quimicamente , Colite/prevenção & controle , Modelos Animais de Doenças , Membro Posterior/fisiopatologia , Hiperalgesia/complicações , Masculino , Limiar da Dor , Ratos Sprague-Dawley , Ácido Trinitrobenzenossulfônico/administração & dosagem
11.
Nanoscale ; 11(11): 4970-4986, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30839018

RESUMO

Poor success rates and challenges associated with the current therapeutic strategies of inflammatory bowel disease (IBD) have accelerated the emergence of gene therapy as an alternative treatment option with great promise. However, oral delivery of nucleic acids (NAs) to an inflamed colon is challenged by multiple barriers presented by the gastrointestinal, extracellular and intracellular compartments. Therefore, we screened a series of polyaspartic acid-derived amphiphilic cationic polymers with varied hydrophobicity for their ability to deliver NAs into mammalian cells. Using the most effective TAC6 polymer, we then engineered biocompatible and stable nanogels composed of polyplexes (TAC6, NA) and an anionic polymer, sodium polyaspartate, that were able to deliver the NAs across mammalian cells using caveolae-mediated cellular uptake. We then utilized these nanogels for oral delivery of PIAS1 (protein inhibitor of activated STAT1), a SUMO 3 ligase, encoding plasmid DNA since PIAS1 is a key nodal therapeutic target for IBD due to its ability to control NF-κB-mediated inflammatory signaling. We show that plasmid delivery using TAC6-derived nanogels diminished gut inflammation in a murine colitis model. Therefore, our study presents engineering of orally deliverable nanogels that can target SUMOylation machinery to combat gut inflammation with very high efficacy.


Assuntos
Colite/terapia , Técnicas de Transferência de Genes/instrumentação , Terapia Genética/métodos , Polietilenoglicóis/administração & dosagem , Polietilenoimina/administração & dosagem , Sumoilação , Administração Oral , Animais , Cátions/química , Linhagem Celular Tumoral , Colite/patologia , Colite/fisiopatologia , Colo/metabolismo , Colo/patologia , Colo/fisiopatologia , Modelos Animais de Doenças , Endocitose , Expressão Gênica , Terapia Genética/instrumentação , Humanos , Inflamação , Camundongos , Peptídeos/química , Plasmídeos/administração & dosagem , Plasmídeos/química , Plasmídeos/genética , Polietilenoglicóis/química , Polietilenoglicóis/metabolismo , Polietilenoimina/química , Polietilenoimina/metabolismo , Polímeros/química , Proteínas Inibidoras de STAT Ativados/genética , Proteínas Inibidoras de STAT Ativados/metabolismo
12.
Cell Host Microbe ; 25(3): 377-388.e6, 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30850233

RESUMO

Inflammatory bowel disease (IBD) is characterized by alterations in the intestinal microbiota and altered immune responses to gut microbiota. Evidence is accumulating that IBD is influenced by not only commensal bacteria but also commensal fungi. We characterized fungi directly associated with the intestinal mucosa in healthy people and Crohn's disease patients and identified fungi specifically abundant in patients. One of these, the common skin resident fungus Malassezia restricta, is also linked to the presence of an IBD-associated polymorphism in the gene for CARD9, a signaling adaptor important for anti-fungal defense. M. restricta elicits innate inflammatory responses largely through CARD9 and is recognized by Crohn's disease patient anti-fungal antibodies. This yeast elicits strong inflammatory cytokine production from innate cells harboring the IBD-linked polymorphism in CARD9 and exacerbates colitis via CARD9 in mouse models of disease. Collectively, these results suggest that targeting specific commensal fungi may be a therapeutic strategy for IBD.


Assuntos
Colite/patologia , Colite/fisiopatologia , Doença de Crohn/patologia , Doença de Crohn/fisiopatologia , Trato Gastrointestinal/microbiologia , Malassezia/crescimento & desenvolvimento , Malassezia/isolamento & purificação , Animais , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Camundongos
14.
Biosci Biotechnol Biochem ; 83(5): 914-922, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30774006

RESUMO

This study aimed to evaluate the microbial compositions and gene expression related to inflammation in dextran sodium sulfate (DSS)-induced acute colitis and the effect of mulberry supplementation. Male BALB/c mice received a diet supplemented with mulberry juice freeze-dried powder (MFP) or not for 3 weeks. After 3 weeks, the mice received water containing 5% (w/v) DSS or not for 1 week. The disease activity index score in mice fed MFP was significantly decreased. A significant decrease in Bifidobacterium spp. and the Clostridium perfringens subgroup was observed in mice not fed MFP. The number of goblet cell and NLRP6 expression were observed in mice fed a diet supplemented with MFP compared with mice not fed MFP. These results may indicate that mulberry mitigates DSS-induced acute colitis by a changing the gut microbial flora and by improving mucosal conditions.


Assuntos
Bebidas , Colite/tratamento farmacológico , Sulfato de Dextrana/toxicidade , Liofilização , Mucosa Intestinal/efeitos dos fármacos , Morus , Pós , Doença Aguda , Animais , Colite/fisiopatologia , Mucosa Intestinal/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Índice de Gravidade de Doença
15.
Am J Physiol Gastrointest Liver Physiol ; 316(6): G692-G700, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30735453

RESUMO

Inflammatory bowel diseases (IBD) are characterized by repetition of flares and remission periods leading to chronic postinflammatory sequelae. Among postinflammatory sequelae, one-third of patients with IBD are suffering from functional symptoms or psychological comorbidities that persist during remission. The aim of our study was to assess functional and behavioral sequelae of chronic colitis in rats with quiescent intestinal inflammation. Chronic colitis was induced by a weekly intrarectal injection of increasing concentrations of trinitrobenzene sulfonic acid (TNBS) for 3 wk (15-45 mg of TNBS) in 30 rats, whereas the control rats (n = 24) received the vehicle. At 50 days post-TNBS, visceral sensitivity was assessed by visceromotor response to colorectal distension, and transient receptor potential vanilloid type 1 (TRPV1) expression was also quantified in the colon and dorsal root ganglia. Barrier function and inflammatory response were assessed by studying intestinal permeability, tight junction protein, myeloperoxidase activity, histological score, and cytokine production (IL-6, IL-10, and TNF-α). Anxiety behavioral tests were performed from 50 to 64 days after the last TNBS injection. Chronic TNBS induced 1) a visceral hypersensitivity (P = 0.03), 2) an increased colon weight-to-length ratio (P = 0.01), 3) higher inflammatory and fibrosis scores (P = 0.0390 and P = 0.0016, respectively), and 4) a higher colonic IL-6 and IL-10 production (P = 0.008 and P = 0.005, respectively) compared with control rats. Intestinal permeability, colonic production of TNF-α, myeloperoxidase activity, and TRPV1 expression did not differ among groups. Chronic TNBS increased anxiety-related behavior in the open-field test and in the acoustic stress test. In conclusion, chronic colitis induced functional sequelae such as visceral hypersensitivity and increased anxiety with a low-grade intestinal inflammation. Development of a representative animal model will allow defining novel therapeutic approaches to achieve a better management of IBD-related sequelae. NEW & NOTEWORTHY Patients with inflammatory bowel diseases have impaired quality of life. Therapeutic progress to control mucosal inflammation provides us an opportunity to develop novel approaches to understand mechanisms behind postinflammatory sequelae. We used a chronic colitis model to study long-term sequelae on visceral pain, gut barrier function, and psychological impact. Chronic colitis induced functional symptoms and increased anxiety in the remission period. It might define novel therapeutic approaches to achieve a better inflammatory bowel disease-related sequelae management.


Assuntos
Ansiedade , Colo , Motilidade Gastrointestinal , Doenças Inflamatórias Intestinais , Dor Visceral , Animais , Ansiedade/etiologia , Ansiedade/fisiopatologia , Comportamento Animal/fisiologia , Colite/imunologia , Colite/fisiopatologia , Colite/psicologia , Colo/inervação , Colo/metabolismo , Colo/fisiopatologia , Citocinas/análise , Modelos Animais de Doenças , Inflamação/imunologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/fisiopatologia , Doenças Inflamatórias Intestinais/psicologia , Masculino , Permeabilidade , Peroxidase/análise , Ratos , Proteínas de Junções Íntimas/análise , Dor Visceral/etiologia , Dor Visceral/imunologia , Dor Visceral/fisiopatologia , Dor Visceral/psicologia
16.
Infect Immun ; 87(5)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30782858

RESUMO

Chitin is a natural N-acetylglucosamine polymer and a major structural component of fungal cell walls. Dietary chitin is mucoadhesive; anti-inflammatory effects of chitin microparticles (CMPs; 1- to 10-µm diameters) have been demonstrated in models of inflammatory bowel disease (IBD). The goals of this study were to assess (i) whether CMPs among various chitin preparations are the most effective against colitis in male and female mice and (ii) whether host chitin-binding Toll-like receptor 2 (TLR2) and CD14 are required for the anti-inflammatory effect of chitin. We found that colitis in male mice was ameliorated by CMPs and large chitin beads (LCBs; 40 to 70 µm) but not by chitosan (deacetylated chitin) microparticles, oligosaccharide chitin, or glucosamine. In fact, LCBs were more effective than CMPs. In female colitis, on the other hand, CMPs and LCBs were equally and highly effective. Neither sex of TLR2-deficient mice showed anti-inflammatory effects when treated with LCBs. No anti-inflammatory effect of LCBs was seen in either CD14-deficient males or females. Furthermore, an in vitro study indicated that when LCBs and CMPs were digested with stomach acidic mammalian chitinase (AMC), their size-dependent macrophage activations were modified, at least in part, suggesting reduced particle sizes of dietary chitin in the stomach. Interestingly, stomach AMC activity was greater in males than females. Our results indicated that dietary LCBs were the most effective preparation for treating colitis in both sexes; these anti-inflammatory effects of LCBs were dependent on host TLR2 and CD14.


Assuntos
Candida albicans/química , Quitina/uso terapêutico , Colite/dietoterapia , Colite/fisiopatologia , Disbiose/fisiopatologia , Ativação de Macrófagos/efeitos dos fármacos , Receptor 2 Toll-Like/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
17.
Virulence ; 10(1): 97-117, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30665337

RESUMO

Citrobacter rodentium infection is a murine model for pathogenic intestinal Escherichia coli infection. C. rodentium infection causes an initial decrease in mucus layer thickness, followed by an increase during clearance. We aimed to identify the cause of these changes and to utilize this naturally occurring mucus stimulus to decrease pathogen impact and inflammation. We identified that mucin production and speed of transport from Golgi to secretory vesicles at the apical surface increased concomitantly with increased mucus thickness. Of the cytokines differentially expressed during increased mucus thickness, IFN-γ and TNF-α decreased the mucin production and transport speed, whereas IL-4, IL-13, C. rodentium and E. coli enhanced these aspects. IFN-γ and TNF-α treatment in combination with C. rodentium and pathogenic E. coli infection negatively affected mucus parameters in vitro, which was relieved by IL-4 treatment. The effect of IL-4 was more pronounced than that of IL-13, and in wild type mice, only IL-4 was present. Increased expression of Il-4, Il-4-receptor α, Stat6 and Spdef during clearance indicate that this pathway contributes to the increase in mucin production. In vivo IL-4 administration initiated 10 days after infection increased mucus thickness and quality and decreased colitis and pathogen contact with the epithelium. Thus, during clearance of infection, the concomitant increase in IL-4 protects and maintains goblet cell function against the increasing levels of TNF-α and IFN-γ. Furthermore, IL-4 affects intestinal mucus production, pathogen contact with the epithelium and colitis. IL-4 treatment may thus have therapeutic benefits for mucosal healing.


Assuntos
Citrobacter rodentium/imunologia , Colite/imunologia , Colite/microbiologia , Células Epiteliais/microbiologia , Interleucina-4/imunologia , Mucinas/metabolismo , Animais , Colite/fisiopatologia , Citocinas/genética , Escherichia coli/imunologia , Interações Hospedeiro-Patógeno , Interleucina-4/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
18.
Am J Physiol Gastrointest Liver Physiol ; 316(4): G495-G508, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30629469

RESUMO

Brachyspira spp. cause diarrheal disease in multiple animal species by colonization of the colon, resulting in colitis, mucus induction, and disrupted ion transport. Unique to spirochete pathogenesis is the immense production of mucus, resulting in a niche mucin environment likely favoring spirochete colonization. Mucin rheological properties are heavily influenced by anionic secretion, and loss of secretory function has been implicated in diseases such as cystic fibrosis. Here, the effects on the agonist-induced electrogenic anionic secretory response by infectious colonic spirochete bacteria Brachyspira hyodysenteriae and Brachyspira hampsonii were assessed in the proximal, apex, and distal sections of colon in Ussing chambers. Activation of secretion via isoproterenol, carbachol, and forskolin/3-isobutyl-1-methylxanthine demonstrated a significantly decreased change in short-circuit current ( Isc) in Brachyspira-infected pigs in all sections. Tissue resistances did not account for this difference, rather, it was attributed to a decrease in anionic secretion as indicated by a decrease in bumetanide inhibitable Isc. Quantitative RT-PCR and Western blot analyses determined that the major anionic channels of the epithelium were downregulated in diarrheic pigs paired with altered mucin gene expression. The investigated cytokines were not responsible for the downregulation of anion channel gene transcripts. Although IL-1α was upregulated in all segments, it did not alter cystic fibrosis transmembrane conductance regulator (CFTR) mRNA expression in Caco-2 monolayers. However, a whole cell Brachyspira hampsonii lysate significantly reduced CFTR mRNA expression in Caco-2 monolayers. Together, these findings indicate that these two Brachyspira spp. may directly cause a decreased anionic secretory response in the porcine colon, supporting an altered mucin environment likely favoring spirochete colonization. NEW & NOTEWORTHY This research demonstrates for the first time that the niche mucin environment produced by two infectious spirochete spp. is supported by a decrease in the electrogenic anionic secretory response throughout the porcine colon. Our findings suggest that the host's cytokine response is not likely responsible for the decrease in anionic secretory function. Rather, it appears that Brachyspira spp. directly impede ion channel transcription and translation, potentially altering colonic mucin rheological properties, which may favor spirochete colonization.


Assuntos
Ânions/metabolismo , Brachyspira hyodysenteriae , Colite , Colo , Canais Iônicos/fisiologia , Mucinas , Animais , Brachyspira hyodysenteriae/patogenicidade , Brachyspira hyodysenteriae/fisiologia , Colite/metabolismo , Colite/microbiologia , Colite/fisiopatologia , Colo/metabolismo , Colo/patologia , Colo/fisiopatologia , Regulação para Baixo , Transporte de Íons/fisiologia , Viabilidade Microbiana , Mucinas/biossíntese , Mucinas/metabolismo , Suínos
19.
Neurogastroenterol Motil ; 31(2): e13493, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30334342

RESUMO

BACKGROUND: Inflammatory bowel disease (IBD) is a functional disorder with chronic and relapsing clinical features. Vasopressin (VP) is a hormone responsible for water and stress homeostasis and also regulates gastrointestinal inflammation and motility. We explored whether VP was related to IBD pathogenesis and its possible pathway. METHODS: Colitis was induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) in mice. The disease activity and colonic damage were evaluated through a scoring system. Locations of the V1a receptor were revealed by immunochemistry method in colon. Ussing chamber technique was performed for the electrophysiological characterization by using rat ileum. The (Arg8 )-Vasopressin (AVP)-evoked short-circuit current (Isc) was recorded in the presence of conivaptan (V1a and V2 receptor antagonist), tolvaptan (V1b receptor antagonist), tetrodotoxin (TTX), atropine, cyclooxygenase (COX) inhibitors (indomethacin, nonspecific COX antagonist; SC560, COX-1 antagonist; NS560, COX-2 antagonist), and a stabilizer of mast cell (cromolyn sodium), respectively. KEY RESULTS: TNBS resulted in the obvious loss of body weight and tissue damages in mice. AVP significantly aggravated the TNBS-induced colitis, which was attenuated by conivaptan but not tolvaptan. V1a receptors were found immunopositive in neurons among the enteric nervous system. AVP evoked a pulsatile response in Isc. Its amplitude, frequency, and cycle duration were around 8-15 µA/cm2 , 10-11 mHz, and 1.5 minutes, respectively. Notably, the AVP-evoked change in Isc was abolished by TTX, atropine, conivaptan, indomethacin, NS560, and cromolyn sodium, respectively. CONCLUSIONS AND INFERENCES: VP-V1a receptor played the proinflammatory role in TNBS-induced colitis by promoting COX-2-dependent prostaglandin release from mucosal mast cells, which was mediated by the cholinergic pathway.


Assuntos
Colite/fisiopatologia , Mastócitos/metabolismo , Receptores de Vasopressinas/metabolismo , Vasopressinas/metabolismo , Animais , Colite/induzido quimicamente , Colite/metabolismo , Ciclo-Oxigenase 2/metabolismo , Sistema Nervoso Entérico/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/metabolismo , Prostaglandinas/metabolismo , Ratos , Ratos Wistar , Ácido Trinitrobenzenossulfônico/toxicidade
20.
Front Immunol ; 9: 2608, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30483266

RESUMO

Background: Accumulating evidence shows that high fat diet is closely associated with inflammatory bowel disease. However, the effects and underlying mechanisms of maternal high fat diet (MHFD) on the susceptibility of offspring to colitis in adulthood lacks confirmation. Methods: C57BL/6 pregnant mice were given either a high fat (60 E% fat, MHFD group) or control diet [10 E% fat, maternal control diet (MCD) group] during gestation and lactation. The intestinal development, mucosal barrier function, microbiota, and mucosal inflammation of 3-week old offspring were assessed. After weaning all mice were fed a control diet until 8 weeks of age when the microbiota was analyzed. Offspring were also treated with 2% DSS solution for 5 days and the severity of colitis was assessed. Results: The offspring in MHFD group were significantly heavier than those in MCD group only at 2-4 weeks of age, while no differences were found in the body weight between two groups at other measured time points. Compared with MCD group, MHFD significantly inhibited intestinal development and disrupted barrier function in 3-week old offspring. Although H&E staining showed no obvious microscopic inflammation in both groups of 3-week old offspring, increased production of inflammatory cytokines indicated low-grade inflammation was induced in MHFD group. Moreover, fecal analysis of the 3-week old offspring indicated that the microbiota compositions and diversity were significantly changed in MHFD group. Interestingly after 5 weeks consumption of control diet in both groups, the microbiota composition of offspring in MHFD group was still different from that in MCD group, although the bacterial diversity was partly recovered at 8 weeks of age. Finally, after DSS treatment in 8-week old offspring, MHFD significantly exacerbated the severity of colitis and increased the production of proinflammatory cytokine. Conclusions: Our data reveal that MHFD in early life can inhibit intestinal development, induce dysbiosis and low-grade inflammation and lead to the disruption of intestinal mucosal barrier in offspring, and enhance DSS-induced colitis in adulthood.


Assuntos
Colite/induzido quimicamente , Colite/microbiologia , Sulfato de Dextrana/farmacologia , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/fisiologia , Animais , Peso Corporal/fisiologia , Colite/fisiopatologia , Citocinas/metabolismo , Feminino , Inflamação/metabolismo , Inflamação/microbiologia , Inflamação/fisiopatologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez
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