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1.
Anim Sci J ; 91(1): e13468, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33025687

RESUMO

Here, we investigated the effect of prophylactic oral treatment with carbonate apatite-based particles (ID35caps) containing Lactobacillus rhamnosus GG-derived immunostimulatory oligodeoxynucleotides (ID35) when used in mice with acute colitis. Mice were administered orally with control particles (carbonate apatite particles, Caps), ID35, or ID35caps for 2 days, and then were given free access to drinking water containing 3% (w/v) dextran sodium sulfate (DSS) for 5 days (Days 0-5) to induce acute colitis. Body weight change, fecal bleeding, and stool consistency were monitored and scored as a disease activity index (DAI) to assess symptoms of colitis. On Day 10, animals were euthanized and the colon length was measured to evaluate inflammatory tissue injury. Prophylactic oral treatment with ID35caps significantly suppressed DSS-induced elevation of the DAI score and shortening of the colon compared to the respective parameters in DSS-exposed mice treated with Cap or ID35. We conclude that oral priming with ID35caps attenuates symptoms and inflammatory colonic injury in a mouse model of DSS-induced acute colitis. This finding suggests that ID35caps may be a new oral agent for preventing intestinal inflammation.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Colite/tratamento farmacológico , Sulfato de Dextrana/efeitos adversos , Lactobacillus rhamnosus/química , Oligodesoxirribonucleotídeos/administração & dosagem , Doença Aguda , Adjuvantes Imunológicos/isolamento & purificação , Administração Oral , Animais , Colite/induzido quimicamente , Colite/prevenção & controle , Modelos Animais de Doenças , Feminino , Camundongos Endogâmicos C57BL , Oligodesoxirribonucleotídeos/isolamento & purificação
2.
Nat Commun ; 11(1): 4457, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901017

RESUMO

Innate lymphoid cells (ILCs) and CD4+ T cells produce IL-22, which is critical for intestinal immunity. The microbiota is central to IL-22 production in the intestines; however, the factors that regulate IL-22 production by CD4+ T cells and ILCs are not clear. Here, we show that microbiota-derived short-chain fatty acids (SCFAs) promote IL-22 production by CD4+ T cells and ILCs through G-protein receptor 41 (GPR41) and inhibiting histone deacetylase (HDAC). SCFAs upregulate IL-22 production by promoting aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor 1α (HIF1α) expression, which are differentially regulated by mTOR and Stat3. HIF1α binds directly to the Il22 promoter, and SCFAs increase HIF1α binding to the Il22 promoter through histone modification. SCFA supplementation enhances IL-22 production, which protects intestines from inflammation. SCFAs promote human CD4+ T cell IL-22 production. These findings establish the roles of SCFAs in inducing IL-22 production in CD4+ T cells and ILCs to maintain intestinal homeostasis.


Assuntos
Ácidos Graxos Voláteis/imunologia , Microbioma Gastrointestinal/imunologia , Imunidade Inata , Interleucinas/biossíntese , Animais , Butiratos/imunologia , Butiratos/metabolismo , Butiratos/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/microbiologia , Citrobacter rodentium , Colite/imunologia , Colite/microbiologia , Colite/prevenção & controle , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/prevenção & controle , Ácidos Graxos Voláteis/metabolismo , Ácidos Graxos Voláteis/farmacologia , Microbioma Gastrointestinal/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Técnicas In Vitro , Interleucinas/deficiência , Interleucinas/genética , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Regiões Promotoras Genéticas , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo
3.
Proc Natl Acad Sci U S A ; 117(35): 21536-21545, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32817490

RESUMO

The building evidence for the contribution of microbiota to human disease has spurred an effort to develop therapies that target the gut microbiota. This is particularly evident in inflammatory bowel diseases (IBDs), where clinical trials of fecal microbiota transplantation have shown some efficacy. To aid the development of novel microbiota-targeted therapies and to better understand the biology underpinning such treatments, we have used gnotobiotic mice to model microbiota manipulations in the context of microbiotas from humans with inflammatory bowel disease. Mice colonized with IBD donor-derived microbiotas exhibit a stereotypical set of phenotypes, characterized by abundant mucosal Th17 cells, a deficit in the tolerogenic RORγt+ regulatory T (Treg) cell subset, and susceptibility to disease in colitis models. Transplanting healthy donor-derived microbiotas into mice colonized with human IBD microbiotas led to induction of RORγt+ Treg cells, which was associated with an increase in the density of the microbiotas following transplant. Microbiota transplant reduced gut Th17 cells in mice colonized with a microbiota from a donor with Crohn's disease. By culturing strains from this microbiota and screening them in vivo, we identified a specific strain that potently induces Th17 cells. Microbiota transplants reduced the relative abundance of this strain in the gut microbiota, which was correlated with a reduction in Th17 cells and protection from colitis.


Assuntos
Transplante de Microbiota Fecal , Doenças Inflamatórias Intestinais/microbiologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Colite/prevenção & controle , Colo/microbiologia , Doença de Crohn/metabolismo , Doença de Crohn/microbiologia , Citocinas/imunologia , Modelos Animais de Doenças , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/imunologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/microbiologia , Células Th17/microbiologia
4.
J Nutr ; 150(6): 1434-1442, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32286629

RESUMO

BACKGROUND: Chicken eggs and bovine colostrum contain proteins possessing antimicrobial, immunoregulatory, and growth factor activity. The ability of eggs to influence gut defense and repair is largely unexplored. OBJECTIVE: We examined the effect of pasteurized spray-dried egg on gastrointestinal injury using cell culture and animal models and sought to determine whether adding colostrum provided extra benefit. METHODS: Egg alone, colostrum alone, and a 40:60 egg: colostrum combination were tested for proliferative (Alamar blue) and migratory (wounded monolayer) activity at 1 mg.mL-1 using human colon adenocarcinoma (Caco-2), human gastric cancer (AGS), and rat intestinal epithelioid-1 (RIE1) cells. Four groups of adult male C57BL/6 mice received 20 mg.kg-1.d-1 test products in drinking water for 7 d and indomethacin (85 mg.kg-1, administered subcutaneously) on day 7. Villus height and morphology were assessed. Three groups of adult male Sprague Dawley rats received 20 mg.kg-1.d-1 test product by gavage for 9 d and dextran sodium sulfate (DSS, 4% in drinking water) for the final 7 d. Histology, microscopic damage scoring, and myeloperoxidase were assessed. RESULTS: Egg or colostrum alone caused 3-fold increases in cell proliferation and migration (P < 0.05 compared with baseline). Heating the egg removed its bioactivity. Addition of neutralizing antibodies or tyrphostin showed that ovomucoid, ovalbumin, and the epidermal growth factor receptor mediated the effects of egg (all P < 0.05 compared with egg). Egg reduced shortening of villi caused by indomethacin in mice by 34% and reduced DSS-induced colonic damage in rats by 44-61% (P < 0.05 compared with DSS). Similar results were seen using colostrum alone. In each assay, the 40:60 combination gave improved results compared with the same dose of egg or colostrum alone (P < 0.05). CONCLUSIONS: Studies using AGS, RIE1, and Caco-2 cells, C57BL/6 mice, and Sprague Dawley rats showed protective effects of egg against gut injury. Enhanced results were seen if colostrum and egg were coadministered. Egg powder with or without colostrum may have therapeutic value for prevention and treatment of gut injuries.


Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colite/prevenção & controle , Suplementos Nutricionais , Ovos , Animais , Linhagem Celular , Galinhas , Colite/induzido quimicamente , Modelos Animais de Doenças , Duodeno/efeitos dos fármacos , Duodeno/lesões , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pasteurização , Pós , Ratos
5.
Life Sci ; 249: 117470, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32135184

RESUMO

AIMS: Rigosertib (RGS) is a PI3K inhibitor that exerts protective effects against tumor progression and cancer-related inflammation. This study was aimed to explore the regulatory effects of RGS on proliferative, pro-fibrotic and inflammatory factors in DSS- induced colitis mice model. MATERIALS AND METHODS: The present study integrates systems and molecular biology approaches to investigate the therapeutic potency of RGS in an experimental model of colitis specifically examining its effects on the PI3K/AKT and NF-κB signaling pathways. KEY FINDINGS: Analysis of time-resolved proteome profiling showed that PI3K-AKT inhibitors regulate expression of many proteins in all stages of inflammation, fibrogenesis and extracellular matrix remodeling. Consistent with our in-silico findings, RGS improved colitis disease activity as assessed by changes in body weight, degree of stool consistency, rectal bleeding and prolapse. RGS also reduced oxidative stress markers and colon histopathological score by decreasing inflammatory responses in colon tissues. Moreover, expression of pro-fibrotic and pro-inflammatory factors including Acta 2, Col 1a1, Col 1a2, IL-1ß, TNF-α, INF-γ, and MCP-1 were suppressed in the mice treated with RGS compared to the control group. The protective effects of RGS were mediated by inactivation of PI3K/AKT and NF-kB signaling pathways. SIGNIFICANCE: This study clearly demonstrates the anti-proliferative, anti-inflammatory and anti-fibrotic effects of RGS in colitis that may have implications for the treatment of colitis and colitis-associated cancer.


Assuntos
Antineoplásicos/farmacologia , Colite/prevenção & controle , Inibidores Enzimáticos/farmacologia , Glicina/análogos & derivados , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfonas/farmacologia , Animais , Fibrose , Glicina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
6.
Nutrients ; 12(2)2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32013062

RESUMO

Galangin is a natural flavonoid that has been reported to provide substantial health benefits. Nevertheless, little is known about the potential effects of galangin against inflammatory bowel diseases. Here, an in vivo study was performed to investigate the preventive effects of galangin against dextran sulphate sodium (DSS)-induced acute murine colitis, which mimics the symptoms of human ulcerative colitis (UC). Pre-treatment with galangin (15 mg/kg, p.o.) resulted in a significant decreased in the macroscopic signs of DSS-induced colitic symptoms, including a decreased disease activity index, prevention of the colon length shortening, and alleviation of the pathological changes occurring in the colon. Colonic pro-inflammatory mediators, including tumor necrosis factor-alpha, interleukin (IL)-1 beta, and IL-6, as well as myeloperoxidase activities were decreased following galangin pre-treatment when compared with the DSS control group. Moreover, galangin pre-treatment significantly increased the expressions of autophagy-related proteins and promoted the formation of autophagosome in the colon. Galangin pre-treatment increased the diversity of the gut microbiota, and this was accompanied by increased levels of short-chain fatty acids. These observed changes could involve the modulating effects conferred by galangin in relation to some specific bacteria populations, including the recovery of Lactobacillus spp., and increased Butyricimonas spp. Overall, these results support the use of galangin in the prevention of UC.


Assuntos
Autofagia/efeitos dos fármacos , Colite/induzido quimicamente , Colite/prevenção & controle , Sulfato de Dextrana/toxicidade , Flavonoides/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Flavonoides/química , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Mutagênicos/farmacologia
7.
Nat Commun ; 11(1): 1056, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-32103006

RESUMO

NKp46+ innate lymphoid cells (ILC) modulate tissue homeostasis and anti-microbial immune responses. ILC development and function are regulated by cytokines such as Interleukin (IL)-7 and IL-15. However, the ILC-intrinsic pathways translating cytokine signals into developmental programs are largely unknown. Here we show that the anti-apoptotic molecule cellular FLICE-like inhibitory protein (c-FLIP) is crucial for the generation of IL-7/IL-15-dependent NKp46+ ILC1, including conventional natural killer (cNK) cells, and ILC3. Cytokine-induced phosphorylation of signal transducer and activator of transcription 5 (STAT5) precedes up-regulation of c-FLIP, which protects developing NKp46+ ILC from TNF-induced apoptosis. NKp46+ ILC-specific inactivation of c-FLIP leads to the loss of all IL-7/IL-15-dependent NKp46+ ILC, thereby inducing early-onset chronic colitis and subsequently microbial dysbiosis; meanwhile, the depletion of cNK, but not NKp46+ ILC1/3, aggravates experimental colitis. In summary, our data demonstrate a non-redundant function of c-FLIP for the generation of NKp46+ ILC, which protect T/B lymphocyte-sufficient mice from intestinal inflammation.


Assuntos
Antígenos Ly/metabolismo , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Colite/prevenção & controle , Interleucina-15/metabolismo , Interleucina-7/metabolismo , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Fator de Transcrição STAT5/metabolismo , Animais , Antígenos Ly/genética , Apoptose/fisiologia , Linfócitos B/imunologia , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Células Cultivadas , Colite/induzido quimicamente , Colite/patologia , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Knockout , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Fosforilação , Linfócitos T/imunologia
8.
PLoS One ; 15(2): e0220756, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32040478

RESUMO

Adipose tissue derived mesenchymal stem/stromal cell (ASC)-derived extracellular vesicles (EV) have been reported to be beneficial against dextran sulfate sodium (DSS)-induced colitis in mice. However, the underlying mechanisms have not been fully elucidated. We hypothesize that the tumor necrosis factor-α-stimulated gene/protein 6 (TSG-6) in EVs is a key factor influencing the alleviation of colitis symptoms. DSS-induced colitis mice (C57BL/6, male, Naïve = 6, Sham = 8, PBS = 8 EV = 8, CTL-EV = 8, TSG-6 depleted EV = 8) were intraperitoneally administered EVs (100 ug/mice) on day 1, 3, and 5; colon tissues were collected on day 10 for histopathological, RT-qPCR, western blot and immunofluorescence analyses. In mice injected with EV, inflammation was alleviated. Indeed, EVs regulated the levels of pro- and anti-inflammatory cytokines, such as TNF-α, IL-1ß, IFN-γ, IL-6, and IL-10 in inflamed colons. However, when injected with TSG-6 depleted EV, the degree of inflammatory relief was reduced. Furthermore, TSG-6 in EVs plays a key role in increasing regulatory T cells (Tregs) and polarizing macrophage from M1 to M2 in the colon. In conclusion, this study shows that TSG-6 in EVs is a major factor in the relief of DSS-induced colitis, by increasing the number of Tregs and macrophage polarization from M1 to M2 in the colon.


Assuntos
Moléculas de Adesão Celular/farmacologia , Colite/prevenção & controle , Vesículas Extracelulares/química , Células-Tronco Mesenquimais/química , Animais , Contagem de Células , Colite/induzido quimicamente , Colite/terapia , Citocinas/metabolismo , Sulfato de Dextrana/efeitos adversos , Cães , Vesículas Extracelulares/transplante , Inflamação/terapia , Macrófagos/citologia , Células-Tronco Mesenquimais/ultraestrutura , Camundongos , Linfócitos T Reguladores/citologia
9.
Chin Med J (Engl) ; 133(3): 292-300, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31904729

RESUMO

BACKGROUND: Baicalein has been shown to have anti-inflammatory and anti-tumor activities. However, the mechanisms underlying its anti-inflammatory effect on colitis remain unclear. METHODS: A dextran sodium sulfate (DSS)-induced model of acute colitis was established in BALB/c mice (6-8 weeks old, weighing 18-22 g). Six groups of mice received: (1) water for 10 days (control), n = 6; (2) DSS 4% solution in the drinking water for 7 days, followed by normal water for 3 days, n = 7; (3), (4), and (5) as for group 2 plus baicalein (10, 20, 40 mg/kg) administered once daily starting on day 1, n = 6; and (6) as for (2) plus 5-aminosalicylic acid (50 mg/kg) administered once daily starting on day 1, n = 6. Body weights, stool consistency, and hematochezia were recorded, and the severity of colitis was evaluated using a disease activity index. On day 11, the mice were euthanized, and organs and blood were collected for analysis. Serum inflammatory factors were detected by enzyme-linked immunosorbent assay; CD11b-positive cells were analyzed by immunofluorescence microscopy; expression of retinoic-acid-receptor-related orphan nuclear receptor gamma, sphingosine kinase 1 (SPHK1), and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) was detected by immunohistochemistry; and expression of nucleotide-binding oligomerization domain 2 (NOD2), SPHK1, sphingosine 1-phosphate receptor 1 (S1PR1), total STAT3, and p-STAT3 were detected by western blotting analysis. Inter-group differences were compared using Student's t test. RESULTS: Baicalein treatment dose-dependently reduced DSS-induced weight loss (P < 0.01 or P < 0.05), splenomegaly (P < 0.01), and colonic damage, as reflected by amelioration of diarrhea, rectal bleeding, and colonic ulceration, congestion, edema (shown as colon length, P < 0.05 or P < 0.01), and inflammatory cell infiltration. Baicalein also significantly decreased the levels of inflammatory mediators in the serum (P < 0.01) and colon, and significantly inhibited expression of NOD2 SPHK1, S1PR1, and p-STAT3 in the colon (P < 0.05). CONCLUSIONS: Baicalein treatment ameliorated colitis in mice by inhibiting S1P-STAT3 signaling, suggesting that this flavonoid might be beneficial in the treatment of colitis.


Assuntos
Colite/prevenção & controle , Flavanonas/uso terapêutico , Lisofosfolipídeos/fisiologia , Fator de Transcrição STAT3/fisiologia , Esfingosina/análogos & derivados , Animais , Colite/induzido quimicamente , Sulfato de Dextrana/farmacologia , Feminino , Flavanonas/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Proteína Adaptadora de Sinalização NOD2/análise , Fosfotransferases (Aceptor do Grupo Álcool)/análise , Fator de Transcrição STAT3/análise , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Esfingosina/fisiologia , Receptores de Esfingosina-1-Fosfato/análise
10.
Chem Biol Interact ; 317: 108943, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31926917

RESUMO

Epidemiological studies have shown that cigarette smoking is beneficial in ulcerative colitis and that nicotine may be responsible for this effect. However, the mechanism remains unclear. In a previous study, nicotine was found to induce autophagy in intestinal cells. Here, we evaluated the effect of nicotine-induced autophagy in a dextran sodium sulfate (DSS)-induced colitis mouse model. C57BL/6 adult male mice drank DSS water solution freely for seven consecutive days, and then tap water was administered. The effect of nicotine treatment was examined in the DSS model, including colon length, disease severity, histology of the colon tissue, and inflammation levels. Moreover, autophagy levels were detected by Western blot analysis (LC3II/LC3I, p62, and beclin-1). The levels of DSS-induced colitis were significantly decreased following nicotine treatment. The disease activity score, body weight, histologic damage scores, and the level of colonic inflammatory factors of nicotine-treated mice all decreased compared to those of the control mice. Additionally, nicotine enhanced the expression of LC3II/LC3I and beclin-1 but decreased the p62 protein level. Inhibiting autophagy by 3-MA attenuated the protective effects of nicotine on colitis. Additionally, both in vitro and in vivo experiments showed changes in AMPK-mTOR-P70S6K during this process. These results suggest that nicotine improved colitis by regulating autophagy and provided a protective effect against DSS-induced colitis.


Assuntos
Adenilato Quinase/metabolismo , Autofagia/efeitos dos fármacos , Colite/prevenção & controle , Nicotina/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Adenilato Quinase/genética , Animais , Colite/induzido quimicamente , Sulfato de Dextrana/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/genética
11.
Int J Mol Sci ; 21(2)2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31963519

RESUMO

Nerve injury-induced protein 1 (Ninjurin1, Ninj1) is a cell-surface adhesion molecule that regulates cell migration and attachment. This study demonstrates the increase in Ninj1 protein expression during development of intestinal inflammation. Ninj1-deficient mice exhibited significantly attenuated bodyweight loss, shortening of colon length, intestinal inflammation, and lesser pathological lesions than wild-type mice. Although more severe inflammation and serious lesions are observed in wild-type mice than Ninj1-deficient mice, there were no changes in the numbers of infiltrating macrophages in the inflamed tissues obtained from WT and Ninj1-deficient mice. Ninj1 expression results in activation of macrophages, and these activated macrophages secrete more cytokines and chemokines than Ninj1-deficient macrophages. Moreover, mice with conditional deletion of Ninj1 in myeloid cells (Ninj1fl/fl; Lyz-Cre+) alleviated experimental colitis compared with wild-type mice. In summary, we propose that the Ninj1 in myeloid cells play a pivotal function in intestinal inflammatory conditions.


Assuntos
Moléculas de Adesão Celular Neuronais/fisiologia , Adesão Celular , Movimento Celular , Colite/prevenção & controle , Inflamação/prevenção & controle , Enteropatias/prevenção & controle , Células Mieloides/metabolismo , Fatores de Crescimento Neural/fisiologia , Animais , Células Cultivadas , Colite/etiologia , Colite/metabolismo , Colite/patologia , Feminino , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Enteropatias/etiologia , Enteropatias/metabolismo , Enteropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais
12.
Mol Med Rep ; 21(3): 1181-1191, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31922249

RESUMO

Dysbiosis of the enteric microbiota causes gastrointestinal diseases, including colitis. The present study investigated the beneficial effect of Lactobacillus plantarum 06CC2 in experimental colitis in mice. An experimental colitis model in C57BL6 mice was induced using dextran sulfate sodium. Mice were orally administered 06CC2 (06CC2 group) or PBS only (control group) by gavage. The disease activity index (DAI), histological grading, and colon tissue and colonic lamina propria mononuclear cells (LPMCs) were examined macroscopically and histopathologically, and the expression levels of inflammation­associated cytokines (IL­6, IL­12, TNF­α and IL­10) in these samples were determined. Compared with the control group, the 06CC2 group exhibited a significantly lower DAI (1.5±0.8 vs. 0.2±0.3, respectively; P<0.05) and pathology score (6.3±1.5 vs. 3.8±1.3, respectively; P<0.05). IL­10 expression in colonic LPMCs was higher in the 06CC2 group than in the control group, although there was no significant difference in IFN­Î³, IL­6 or IL­12 expression in colonic LPMCs between the two groups. In addition, 06CC2 stimulated the production of IL­10 from CD11b­positive cells and CD11c­positive cells in the colon. The 06CC2 strain induced IL­10 production in the colon and attenuated colon inflammation.


Assuntos
Colite/prevenção & controle , Lactobacillus plantarum , Administração Oral , Animais , Colite/metabolismo , Colite/microbiologia , Colite/patologia , Colo/metabolismo , Colo/microbiologia , Colo/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/metabolismo , Inflamação/patologia , Inflamação/prevenção & controle , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Camundongos , Membrana Mucosa/metabolismo , Membrana Mucosa/microbiologia , Membrana Mucosa/patologia
13.
Planta Med ; 86(1): 61-69, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31627218

RESUMO

Opuntia ficus-indica extract has been used in traditional folk medicine for several purposes and exhibits anti-inflammatory properties. This study was directed to explore the prophylactic effect of O. ficus-indica fruit peel extract against irradiation-induced colitis in rats. GC/MS analysis of the petroleum ether extract led to recognition of 33 compounds in the unsaponifiable fraction and 15 fatty acid methyl esters in the saponifiable part. Thirteen terpenes and sterols were isolated and identified from which ten compounds were not isolated from any part of this species before. Data showed that irradiation induced colon injury as manifested by elevated contents of malondialdehyde, nitric oxide, myeloperoxidase, intercellular adhesion molecule-1, cyclooxygenase-2, tumor necrosis factor alpha, and nuclear factor kappa B, while it reduced superoxide dismutase activity and interleukin 10 content in colonic tissues, which was confirmed by histopathological examination. Pretreatment with O. ficus-indica extract attenuated the alteration in the measured parameters. It could be concluded that O. ficus-indica fruit peel extract can be regarded as a potential agent in limiting colonic complications due to irradiation, possibly by its antioxidant and anti-inflammatory properties.


Assuntos
Colite/prevenção & controle , Colo/efeitos da radiação , Opuntia/química , Extratos Vegetais/uso terapêutico , Protetores contra Radiação/isolamento & purificação , Animais , Colite/etiologia , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Feminino , Frutas/química , Cromatografia Gasosa-Espectrometria de Massas , Fitoterapia , Extratos Vegetais/isolamento & purificação , Profilaxia Pré-Exposição , Protetores contra Radiação/uso terapêutico , Ratos , Ratos Wistar
14.
Appl Microbiol Biotechnol ; 104(1): 335-349, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31758237

RESUMO

The potential of probiotics for treating ulcerative colitis (UC) has attracted increasing attention. However, more studies are still needed to guide physicians on the proper selection and use of probiotics. Here, we propose that combination of multiple probiotics with different functions can reduce intestinal inflammation. In this study, the effects of probiotics (Lactobacillus reuteri, Bacillus coagulans, Bifidobacterium longum, and Clostridium butyricum) on the physiology and histopathology of colon were evaluated in a dextran sulfate sodium (DSS)-induced colitis mouse model. The combined species, as well as the species individually, were tested and compared with sulfasalazine (SASP) and two Chinese herbal therapies. Results show that the functions of the four probiotic strains were different in regulating intestinal immunity and barrier function. The four-species probiotic cocktail was more effective than the species individually and anti-inflammatory drugs in repairing the dysbiosis of mucosal microbial ecology and reducing intestinal inflammation. The multi-strain probiotic mixture increased the proportion of beneficial bacteria and decreased the proportion of pro-inflammatory bacteria in the colonic mucosa. In addition, probiotic mixture significantly enhanced the expression of IL-10 and intestinal barrier function. These results suggest that a combination of multiple probiotics with different functions has synergistic effects and can restore the balance of interactions between microorganisms and immunological niches.


Assuntos
Colite/prevenção & controle , Colo/imunologia , Colo/microbiologia , Interleucina-10/imunologia , Probióticos/administração & dosagem , Animais , Colite/induzido quimicamente , Sulfato de Dextrana , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/administração & dosagem , Disbiose , Microbioma Gastrointestinal , Inflamação , Interleucina-10/genética , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Organismos Livres de Patógenos Específicos , Sulfassalazina/administração & dosagem
15.
Hum Exp Toxicol ; 39(4): 477-491, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31835924

RESUMO

BACKGROUND: Inflammatory bowel disease is a chronic immunoinflammatory disease of the gastrointestinal tract. Piperine, an alkaloid, has been reported to possess antioxidant, anti-inflammatory, antiapoptotic, and antiulcer potential. AIM: To elucidate the plausible mechanisms of action of piperine on experimental trinitrobenzenesufonic acid (TNBS)-induced colitis by assessing various biochemical, molecular, histological, and ultrastructural modifications. METHODS: Colitis was induced in male Sprague-Dawley rats via intrarectal instillation of TNBS. Then, the rats were treated with piperine (10, 20, and 40 mg/kg, p.o.) for 14 days. RESULTS: TNBS induced significant (p < 0.05) colonic damage, which was assessed by disease activity index, macroscopic score, and stool consistency. The administration of piperine (20 and 40 mg/kg) significantly inhibited (p < 0.05) these damages. Treatments with piperine (20 and 40 mg/kg) notably inhibited (p < 0.05) the TNBS-induced elevation of oxido-nitrosative stress (superoxide dismutase, glutathione, malondialdehyde, and nitric oxide), 5-hydroxytryptamine, and hydroxyproline content in the colon. Furthermore, colonic inducible nitric oxide synthase (iNOs), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1ß, IL-6, interferon-gamma, and cyclooxygenase-2 (COX-2) messenger RNA (mRNA) expressions were upregulated after TNBS instillation and piperine (20 and 40 mg/kg) significantly attenuated (p < 0.05) these elevated mRNA expressions. TNBS decreased the expressions of tight junction (TJ) protein (claudin-1, occludin, and zonula occludens-1 (ZO-1)) and increased the expressions of proapoptotic (caspase-1) protein. These expressions were markedly inhibited (p < 0.05) by piperine treatment. Histological and ultrastructural studies of transmission electron microscopy suggested that piperine significantly ameliorated (p < 0.05) TNBS-induced colonic aberrations. CONCLUSION: Piperine ameliorated the progression of TNBS-induced colitis by modulating the nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha/nuclear factor-kappa B signaling pathway, thus inhibiting the overexpression of proinflammatory cytokines (TNF-α and IL's), COX-2, iNOs, oxido-nitrosative stress, and proapoptotic proteins (caspase-1) that may improve the expression of TJ protein (claudin-1, occludin, and ZO-1).


Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Colite/prevenção & controle , Inibidor de NF-kappaB alfa/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Proteínas de Junções Íntimas/metabolismo , Animais , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Citocinas/genética , Modelos Animais de Doenças , Alimento Funcional , Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Ácido Trinitrobenzenossulfônico/toxicidade
16.
Parasitol Int ; 74: 101924, 2020 Feb.
Artigo em Espanhol | MEDLINE | ID: mdl-31075526

RESUMO

Inflammatory bowel disease (IBD) is an inflammatory disease caused by the activity of effector immune cells, such as the overproduction of inflammatory cytokines. Helminth immunomodulation in the host has been shown to have therapeutic implications in IBD. In the present study, we investigated whether Metagonimus miyatai infection could ameliorate inflammatory diseases. Mice were infected with M. miyatai, and colitis was then induced through oral administration of dextran sulfate sodium (DSS). Weight loss, stool consistency, gross bleeding, colon length, and tissue inflammation were assessed by macroscopic and microscopic examinations. In addition, regulatory cytokine expression was observed in colon tissue by reverse transcription polymerase chain reaction. The results showed that M. miyatai infection decreased the clinical severity of DSS-induced colitis, including weight loss, bloody diarrhea, shortening of the colon, and colon tissue damage in mice (p < .05). The expression levels of tumor necrosis factor-α, interleukin-1b, and cyclooxygenase-2 in mice infected with helminth were lower than those in DSS-treated mice without helminthic infection (p < .05). The results of the research showed that pre-infection with M. miyatai ameliorated DSS-induced colitis in mice and may be a novel therapeutic strategy for the treatment of immunological diseases.


Assuntos
Colite/induzido quimicamente , Colite/prevenção & controle , Heterophyidae , Imunomodulação , Animais , Colo/imunologia , Colo/parasitologia , Citocinas/imunologia , Sulfato de Dextrana , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL
17.
Life Sci ; 242: 117220, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881230

RESUMO

BACKGROUND/AIMS: Previous studies have demonstrated that Galactooligosaccharides (GOS), known as "bifidus factor", has anti-inflammatory effects. Colitis, a kind of colonic inflammatory damage could be induced by different chemicals. The pathogenesis and mechanism of colitis remains unclear, and may be related to intestinal microflora, genetic susceptibility or immune factors. The aim is to explore the effects of GOS on intestinal flora and its anti-inflammatory effects in Dextran Sulfate Sodium (DSS) induced murine colitis and extrapolate the underlying mechanism. MAIN METHODS: Initially, 5% DSS was used to induced colitis by free access to drinking water for 5-7 days. Then the mice were treated with GOS 1 day after DSS treatment. Colon samples were evaluated grossly using a microscope. The percentage of Treg and Th17 cells was analyzed by flow cytometry. The levels of cytokines secretion and mRNA expression were detected by ELISA and real-time PCR. The level of protein was detected by western blot. KEY FINDINGS: GOS attenuated DSS induced body weight loss and also reduced the increase in disease index caused by DSS. GOS ameliorated DSS induced colonic histological damage. The protective effect of GOS on DSS induced colitis may be partly attributed to intestinal flora regulation and Th17/Treg imbalance. Furthermore, GOS markedly decreased cytokines (IL-6, IL-18, IL-13 and IL-33) secretion and mRNA expression in colon tissues, through inhibiting activation of NF-κB pathways. SIGNIFICANCE: GOS could prevent the DSS induced colitis through intestinal flora regulation and reduce the secretion of inflammation related cytokines relying on the NF-κB signaling pathway.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , NF-kappa B/metabolismo , Oligossacarídeos/uso terapêutico , Panteteína/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Animais , Western Blotting , Colite/induzido quimicamente , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Microbioma Gastrointestinal/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Panteteína/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos
18.
J Nutr ; 150(5): 1291-1302, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31879786

RESUMO

BACKGROUND: ß-Glucans (BGs), a group of complex dietary polysaccharides (CDPs), are available as dietary supplements. However, the effects of orally administered highly purified BGs on gut inflammation are largely unknown. OBJECTIVES: The aim of this study was to investigate the impact of orally administering highly purified, yeast-derived BG (YBG; ß-1,3/1,6-d-glucan) on susceptibility to colitis. METHODS: Eight-week-old C57BL/6 (B6) mice were used in a series of experiments. Experiment (Expt) 1: male and female mice were treated every day, for 40 d, with saline (control) or 250 µg YBG, followed by 2.5% (wt:vol) dextran sulfate sodium (DSS) in drinking water during days 30-35; and colitis severity and intestinal immune phenotype were determined. Expt 2: female B6 mice were treated with saline or YBG for 30 d and intestinal immune phenotype, gut microbiota composition, and fecal SCFA concentrations were determined. Expt 3: female B6 mice were treated as in Expt 2, given drinking water with or without antibiotics [Abx; ampicillin (1 g/L), vancomycin (0.5 g/L), neomycin (1 g/L), and metronidazole (1 g/L)] during days 16-30, and gut immune phenotype and fecal SCFA concentrations were determined. Expt 4: female B6 Foxp3-green fluorescent protein (-GFP) reporter mice were treated as in Expt 3, and intestinal T-regulatory cell (Treg) frequencies and immune phenotypes were determined. Expt 5: female mice were treated as in Expt 1, given drinking water with or without antibiotics during days 16-40, and colitis severity and intestinal cytokine production were determined. RESULTS: Compared with controls, the YBG group in Expt 1 exhibited suppressive effects on features of colitis, such as loss of body weight (by 47%; P < 0.001), shortening of colon (by 24%; P = 0.016), and histopathology severity score (by 45%; P = 0.01). The YBG group of Expt 2 showed a shift in the abundance of gut microbiota towards Bacteroides (by 16%; P = 0.049) and Verrucomicrobia (mean ± SD: control = 7.8 ± 0.44 vs. YBG = 21.0 ± 9.6%) and a reduction in Firmicutes (by 66%; P < 0.001). The YBG group also showed significantly higher concentrations of fecal SCFAs such as acetic (by 37%; P = 0.016), propionic (by 47%; P = 0.026), and butyric (by 57%; P = 0.013) acids. Compared with controls, the YBG group of Expt 2 showed higher frequencies of Tregs (by 32%; P = 0.043) in the gut mucosa. Depletion of gut microbiota in the YBG group of mice caused diminished fecal SCFA concentrations (Expt 3) and intestinal Treg frequencies (Expt 4). Compared with the YBG group, the YBG-(Abx) group of Expt 5 showed aggravated colitis features including loss of body weight (by >100%; P < 0.01) and colonic inflammation score (by 42%; P = 0.04). CONCLUSIONS: Studies using B6 mice show that dietary BGs are beneficial for promoting intestinal health when the gut microbiota is intact. However, these CDPs may produce adverse effects if gut microbiota is compromised.


Assuntos
Colite/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Polissacarídeos/administração & dosagem , Saccharomyces cerevisiae/química , beta-Glucanas/administração & dosagem , Animais , Colite/induzido quimicamente , Colite/imunologia , Sulfato de Dextrana/farmacologia , Ácidos Graxos Voláteis/análise , Fezes/química , Fezes/microbiologia , Feminino , Fatores de Transcrição Forkhead/genética , Técnicas de Introdução de Genes , Proteínas de Fluorescência Verde/genética , Imunidade/efeitos dos fármacos , Intestinos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
19.
Nat Commun ; 10(1): 5650, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31827095

RESUMO

Alterations in gut microbiota composition are associated with metabolic syndrome and chronic inflammatory diseases such as inflammatory bowel disease. One feature of inflammation-associated gut microbiotas is enrichment of motile bacteria, which can facilitate microbiota encroachment into the mucosa and activate pro-inflammatory gene expression. Here, we set out to investigate whether elicitation of mucosal anti-flagellin antibodies by direct administration of purified flagellin might serve as a general vaccine against subsequent development of chronic gut inflammation. We show, in mice, that repeated injection of flagellin elicits increases in fecal anti-flagellin IgA and alterations in microbiota composition, reduces fecal flagellin concentration, prevents microbiota encroachment, protects against IL-10 deficiency-induced colitis, and ameliorates diet-induced obesity. Flagellin's impact on the microbiota is B-lymphocyte dependent and, in humans, obese subjects exhibit increased levels of fecal flagellin and reduced levels of fecal flagellin-specific IgA, relative to normal weight subjects. Thus, administration of flagellin, and perhaps other pathobiont antigens, may confer some protection against chronic inflammatory diseases.


Assuntos
Imunidade Adaptativa , Vacinas Bacterianas/imunologia , Colite/prevenção & controle , Flagelina/imunologia , Microbioma Gastrointestinal , Animais , Anticorpos Antibacterianos/imunologia , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/genética , Colite/genética , Colite/imunologia , Colite/microbiologia , Fezes/microbiologia , Flagelina/administração & dosagem , Flagelina/genética , Humanos , Imunoglobulina A/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Masculino , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/imunologia , Obesidade/microbiologia , Salmonella typhimurium/genética , Salmonella typhimurium/imunologia
20.
J Cell Mol Med ; 23(12): 8161-8172, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31565850

RESUMO

Numerous data show that taraxacum officinale extract (TOE) exerts protective effects on inflammatory diseases. However, the underlying mechanisms by which TOE affects dextran sulphate sodium (DSS)-induced colitis remain unclear. After DSS-induced colitis were treated with different concentrations of TOE for 8 days, the bodyweight, disease activity index (DAI), colon lengths and pathological scoring were assessed, and histopathological examination was confirmed by HE staining. Furthermore, a transcriptome sequencing was performed by using the colon tissues between TOE and DSS groups, and the differentially expressed genes were conducted for the Kyoto Encyclopaedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) and were validated by qRT-PCR and immunohistochemistry analysis. In addition, a 16S rDNA sequencing was carried out to distinguish the differential gut microbiota by using the mouse faecal samples between TOE and DSS groups. We found that TOE attenuated the clinical symptoms, lowered the inflammatory scoring and inhibited the secretion of proinflammatory factors TNF-α, IL-1ß and IL-6 in DSS-induced colitis. KEGG and GSEA analysis demonstrated that fatty acid degradation and cytokine-receptor signalling were predominantly enriched in TOE-treated colitis as compared with the DSS group. Further investigations revealed that TOE increased the expression levels of Adh5, Aldh3a2 and Acox3, but decreased those of CCL20, CCR6 and CXCL1/5 in DSS-induced colitis, where TOE also induced the enrichment of S24-7 and adlercreutzia, but decreased the amount of anaerostipes, enterococcus, enterobacteriaceae and peptostreptococcaceae. In conclusion, TOE ameliorated DSS-induced colitis by regulating fatty acid degradation and microbial dysbiosis.


Assuntos
Colite/prevenção & controle , Disbiose/prevenção & controle , Ácidos Graxos/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Extratos Vegetais/farmacologia , Taraxacum/química , Animais , Colite/induzido quimicamente , Colite/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Sulfato de Dextrana , Disbiose/fisiopatologia , Microbioma Gastrointestinal/fisiologia , Perfilação da Expressão Gênica/métodos , Masculino , Camundongos Endogâmicos C57BL , Fitoterapia/métodos , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética
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