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1.
Chem Biol Interact ; 315: 108891, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31697926

RESUMO

BACKGROUND AND AIMS: Pregnane X receptor (PXR) is a ligand-activated transcription factor and nuclear receptor expressed ubiquitously along gut-liver-axis. Inflammatory bowel disorders have been reported to implicate PXR in maintaining tight junction (TJ) integrity and countering inflammation. However, the hepatoprotective role of PXR activation in soothing bacterial translocation in liver cirrhosis has not been explored. Ginkgolide A (GA), a terpene trilactone from Ginkgo Biloba extract, is a natural ligand of rodent and human PXR. This study aims to investigate the effect of GA in activating PXR and improving associated tight junction integrity and reducing bacterial translocation in gut-liver axis of CCl4 induced cirrhosis model. METHODS: Swiss albino mice were administered with CCl4 (0.5 ml/kg body weight, i.p) in corn oil for 12 weeks at an interval of two times a week. Following ascites induction, mice were randomized & administered 100 mg/kg body weight of GA through oral gavage for 2 weeks. At termination, blood, gut and liver tissues were collected for biochemical and molecular studies. RESULTS: When compared to naïve mice, protein expression of hepatic and small intestinal PXR, CYP3A, ZO-1 and occludin were found to be significantly (p < 0.01) decreased in CCl4 induced cirrhotic mice. Treatment with GA to cirrhotic mice significantly (p < 0.05) induced the expression of both hepatic and small intestinal PXR, CYP3A, ZO-1 and Occludin. Furthermore, increased (p < 0.01) hepatic and small intestinal NFκB was observed in CCl4 induced cirrhotic mice that was significantly (p < 0.05) lowered following GA treatment. Over expression of TLR4/MyD88/NFκB axis and its downstream pro-inflammatory mediators TNF-α, IL6 and IFN-γ were observed in CCl4 induced mice, and these indices were abrogated significantly after GA treatment. Furthermore, significantly increased plasma levels of bacterial translocation markers LBP and procalcitonin were found in CCl4 mice, which were reduced significantly (p < 0.05 & p < 0.0001) after GA treatment. CONCLUSION: In conclusion, our data supports the hypothesis that, GA treatment to CCl4 induced cirrhotic mice, activated hepatic and small intestinal PXR and diminished inflammation, thereby improving tight junction integrity and attenuating bacterial translocation.


Assuntos
Translocação Bacteriana/efeitos dos fármacos , Ginkgolídeos/farmacologia , Lactonas/farmacologia , Cirrose Hepática/metabolismo , Receptor de Pregnano X/metabolismo , Proteínas de Junções Íntimas/metabolismo , Animais , Citocromo P-450 CYP3A/metabolismo , Inflamação/metabolismo , Interferon gama/metabolismo , Interleucina-6/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Ligantes , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Proteína da Zônula de Oclusão-1/metabolismo
2.
Toxicol Lett ; 321: 73-82, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31862507

RESUMO

An enterogenic infection occurs when intestinal mucosal disruption is followed by the invasion of intestinal bacteria into the blood and distant organs, which can result in severe diseases or even death. Our previous study using Rhesus monkeys as an in vivo model revealed that methamphetamine (MA) induced intestinal mucosal barrier damage, which poses a high risk of enterogenic infection. However, how methamphetamine causes intestinal mucosal barrier damage remains largely unknown. In this study, we employed an in vitro model, and found that MA treatment could inhibit the expression of miR-181c, which directly targets and regulates TNF-α, and ultimately induces apoptosis and damages the intestinal barrier. Moreover, we measured TNF-α serum levels as well as the intestinal mucosal barrier damage indicators (diamine oxidase, d-lactic acid, and exotoxin) and found that their levels were significantly higher in MA-dependents than in healthy controls (P < 0.001). To the best of our knowledge, this is the first report evidencing that miR-181c is involved in MA-induced intestinal barrier injury via TNF-α regulation, which introduces novel potential therapeutic targets for MA-dependent intestinal diseases.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Estimulantes do Sistema Nervoso Central/efeitos adversos , Células Epiteliais/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Metanfetamina/efeitos adversos , MicroRNAs/metabolismo , Junções Íntimas/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Adolescente , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/sangue , Transtornos Relacionados ao Uso de Anfetaminas/genética , Transtornos Relacionados ao Uso de Anfetaminas/patologia , Animais , Apoptose/efeitos dos fármacos , Translocação Bacteriana/efeitos dos fármacos , Biomarcadores/sangue , Estudos de Casos e Controles , Linhagem Celular , Impedância Elétrica , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Microbioma Gastrointestinal , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Permeabilidade , Ratos , Transdução de Sinais , Junções Íntimas/metabolismo , Junções Íntimas/patologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Adulto Jovem
3.
Life Sci ; 239: 117021, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678552

RESUMO

OBJECTIVES: Clematichinenoside AR (AR) is a saponin extracted for traditional Chinese medicine with the effects of improving the expression of tight junction (TJ) proteins and mediating anti-inflammatory activities. However, its effect on Crohn's disease (CD) is still unknown. We aimed to investigate the impact of AR on CD-like colitis and determine the mechanism underlying its effects. METHODS: Interleukin-10 gene knockout (Il-10-/-) mice (male, fifteen weeks old) with spontaneous colitis were allocated to the positive control and AR-treated (32 mg/kg AR administered every other day by gavage for 4 weeks) groups. Wild-type (WT) mice (male, fifteen weeks old) composed the negative control group. The effects of AR on intestinal barrier function and structure and T cell responses as well as the potential mechanisms underlying these effects were investigated. RESULTS: AR treatment significantly improved spontaneous colitis in Il-10-/- mice as demonstrated by reductions in the inflammatory score, disease activity index (DAI) and levels of inflammatory factors. The effects of AR on colitis in Il-10-/- mice were related to protecting intestinal barrier function and maintaining immune system homeostasis (regulatory T cell (Treg)/T helper 17 (Th17) cell balance). The anticolitis effect of AR may partly act by downregulating PI3K/Akt signaling. CONCLUSIONS: AR may have therapeutic potential for treating CD in humans.


Assuntos
Colite/tratamento farmacológico , Colite/genética , Interleucina-10/genética , Intestinos/patologia , Saponinas/uso terapêutico , Triterpenos/uso terapêutico , Animais , Translocação Bacteriana/efeitos dos fármacos , Colite/patologia , Citocinas/metabolismo , Intestinos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos
4.
Artigo em Chinês | MEDLINE | ID: mdl-31245951

RESUMO

OBJECTIVE: To investigate the protective effects of shen-mai injection on intestinal barrier function in the early stage of 30% 3° scald, and to provide experimental basis for the prevention and control of enterogenic infection. METHODS: A total of 60 Wistar rats were randomly divided into 6 groups: normal control group (without treatment), model control group (with 30% total body surface area (TBSA) fully thickness burn on the back), hexadecadrol (5 mg/kg) group, Shenmai injection (5, 10, 15 mg/kg) groups, with 10 rats in each group. After burned by scald apparatus, rats in each group were treated with drugs immediately by intraperitoneal injection once a day. At 72 hours after burned, the levels of plasma endotoxin, diamine oxidase (DAO), tumor necrosis factor-alpha (TNF-α), interleukins-6(IL-6) in all rats were detected and the mesenteric lymph nodes, liver and spleen were homogenized to culture for bacteria. The change of secretory immunoglobulin A (sIgA) in intestinal mucosa was measured. RESULTS: Compared with normal control group, bacterial translocation quantity in mesenteric lymph nodes(MLN), liver, and spleen, and the plasma levels of DAO, endotoxin, TNF-α, IL-6 and the level of sIgA in intestinal mucosa in model control group were increased significantly (P<0.01); compared with model control group, bacterial translocation quantity in MLN, liver, and spleen, and the plasma levels of DAO, endotoxin, TNF-α, IL-6 and the level of sIgA in intestinal mucosa in hexadecadrol (5 mg/kg) group and shen-mai injection (5, 10, 15 mg/kg) groups were decreased significantly (P<0.05 or P<0.01). CONCLUSION: Shen-mai injection can alleviate intestinal mucosa injury caused by severe scald, and the effects are similar with those of dexamethasone, and the effect is better in the high-dose group.


Assuntos
Queimaduras , Medicamentos de Ervas Chinesas , Mucosa Intestinal , Animais , Translocação Bacteriana/efeitos dos fármacos , Queimaduras/complicações , Combinação de Medicamentos , Medicamentos de Ervas Chinesas/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Distribuição Aleatória , Ratos , Ratos Wistar
5.
Chin Med J (Engl) ; 132(10): 1179-1187, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31140989

RESUMO

BACKGROUND: Antibiotics are frequently used to treat critically ill patients, and its use is often accompanied by intestinal dysbiosis that might further lead to bacterial translocation (BT). Nevertheless, studies on the relationship between antibiotic therapy and BT are rare. In the present study, we investigated the effect of broad-spectrum antibiotics on BT in an experimental rat model of burn or sepsis injury. METHODS: The septic rat model was simulated by a second insult with lipopolysaccharides after burn injury. Ninety-two male Sprague-Dawley rats were randomly divided into control, burn, and sepsis groups (n = 8 or 9, each group), and the latter two groups were then treated with imipenem or ceftriaxone for 3 or 9 days. The mesenteric lymph nodes, liver, lungs, and blood were collected at each time point under sterile conditions for quantitative bacterial culture and strain identification. The differences between the groups were compared by Fisher exact test or Mann-Whitney U test. RESULTS: Only minimal Escherichia coli translocation to the mesenteric lymph nodes was observed in the normal control group, in which the BT rate was 12.5%. Burn injury did not affect the BT rate (Burn group vs. Control group, 12.5% vs. 12.5%, P = 1.000), whereas the BT rate showed an increased trend after the second insult with lipopolysaccharide (Sepsis group vs. Control group, 44.4% vs. 12.5%, P = 0.294), and many strains of Enterobacteria spp. were detected in distant organs (liver, lung, and blood) [Sepsis group vs. Control group, 0 (0,3) vs. 0 (0,0), U = 20, P = 0.045]. After the antibiotic treatment, BT to the distant organs was increased in burned rats [Burn IT3 group vs. Burn group, 0 (0,2) vs. 0 (0,0); Burn IT9 group vs. Burn group, 0 (0,1) vs. 0 (0,0); Burn CT9 group vs. Burn group, 0 (0,2) vs. 0 (0,0); all U = 20 and P = 0.076] but decreased in septic rats [Sepsis CT3 group vs. Sepsis group, 0 (0,0) vs. 0 (0,3), U = 20, P = 0.045]. The total amount of translocated bacteria, regardless of which antibiotic was used, was increased in burned rats [Burn IT9 group vs. Burn group, 2.389 (0,2.845) vs. 0 (0,2.301) Log10 colony-forming units (CFU)/g, U = 14, P = 0.034; Burn CT3 group vs. Burn group, 2.602 (0,3.633) vs. 0 (0,2.301) Log10 CFU/g, U = 10.5, P = 0.009], but there was a slightly decreased trend in septic rats [Sepsis IT9 group vs. Sepsis group, 2.301 (2,3.146) vs. 0 (0,4.185) Log10 CFU/g, U = 36, P = 0.721; Sepsis CT9 group vs. Sepsis group, 2 (0,3.279) vs. 0 (0,4.185) Log10 CFU/g, U = 32.5, P = 0.760]. Remarkably, the quantity of Enterococci spp. dramatically increased after broad-spectrum antibiotic treatment in both the burned and septic groups [Burn IT3 group vs. Burn group, 1 (0,5.164) vs. 0 (0,0) Log10 CFU/g, U = 16; Burn IT9 group vs. Burn group, 1 (0,2.845) vs. 0 (0,0) Log10 CFU/g, U = 16; Burn CT3 group vs. Burn group, 2.602 (0,3.633) vs. 0 (0,0) Log10 CFU/g, U = 8; Burn CT9 group vs. Burn group, 1 (0,4.326) vs. 0 (0,0) Log10 CFU/g, U = 16; Sepsis IT3 group vs. Sepsis group, 2.477 (0,2.903) vs. 0 (0,0) Log10 CFU/g, U = 4.5; Sepsis IT9 group vs. Sepsis group, 2 (0,3.146) vs. 0 (0,0) Log10 CFU/g, U = 9; Sepsis CT3 group vs. Sepsis group, 1.151 (0,2.477) vs. 0 (0,0) Log10 CFU/g, U = 18; Sepsis CT9 group vs. Sepsis group, 2 (0,3) vs. 0 (0,0) Log10 CFU/g, U = 13.5; all P < 0.05]. CONCLUSIONS: Broad-spectrum antibiotics promote BT in burned rats but prevent BT in septic rats, especially preventing BT to distant organs, such as the liver and lung. Moreover, Enterococci spp. with high drug resistance and high pathogenicity translocated most after antibiotic treatment.


Assuntos
Antibacterianos/uso terapêutico , Translocação Bacteriana/efeitos dos fármacos , Queimaduras/tratamento farmacológico , Queimaduras/microbiologia , Sepse/tratamento farmacológico , Sepse/microbiologia , Animais , Escherichia coli/efeitos dos fármacos , Escherichia coli/patogenicidade , Fígado/microbiologia , Pulmão/microbiologia , Linfonodos/microbiologia , Masculino , Ratos , Ratos Sprague-Dawley
6.
Oxid Med Cell Longev ; 2019: 3415682, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31007833

RESUMO

Aims: Vascular calcification (VC) is a primary risk factor for cardiovascular mortality in chronic renal failure (CRF) patients; thus, effective therapeutic targets are urgently needed to be explored. Here, we identified the role of intestinal bacterial translocation in CRF-related VC. Methods and Results: Antibiotic supplementation by oral gavage significantly suppressed intestinal bacterial translocation, CRF-related VC, and aortic osteogenic gene and Toll-like receptor (TLR) gene expression in CRF rats. Furthermore, TLR4 and TLR9 activation in vascular smooth muscle cells (VSMCs) aggravated inorganic phosphate- (Pi-) induced calcification. TLR9 inhibition, but not TLR4 inhibition, by both a pharmacological inhibitor and genetic methods could significantly reduce CRF rats' serum or CRF-induced VC. Interestingly, bone morphogenic protein-2 (BMP-2) levels were increased in the aorta and sera from CRF rats. Increased BMP-2 levels were also observed in VSMCs treated with TLR9 agonist, which was blocked by NF-κB inhibition. Both siRNA knockdown of BMP-2 and NF-κB inhibitor significantly blocked TLR9 agonist-induced VSMC calcification. Conclusions: Gut bacterial translocation inhibited by oral antibiotic significantly reduces CRF-related VC through inhibition of TLR9/NF-κB/BMP-2 signaling.


Assuntos
Translocação Bacteriana , Proteína Morfogenética Óssea 2/metabolismo , Microbioma Gastrointestinal , Receptor Toll-Like 9/metabolismo , Calcificação Vascular/metabolismo , Calcificação Vascular/microbiologia , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Translocação Bacteriana/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , DNA Bacteriano/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Osteoblastos/citologia , Ratos Wistar , Insuficiência Renal Crônica/microbiologia , Insuficiência Renal Crônica/patologia , Transdução de Sinais
7.
mBio ; 10(2)2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30862756

RESUMO

Cyclophosphamide (CTX) is widely used in cancer chemotherapy, but it often induces mucositis, in which the disruption of the gut microbiota might play a pivotal role. Whether the manipulation of the gut microbiota can be used as a strategy to improve CTX-induced mucositis remains to be studied. Here we observed the effects of a 4-week calorie restriction (CR) on CTX-induced mucositis. Compared with ad libitum-fed mice, CR mice showed significantly less mucositis in response to CTX, including lower intestinal permeability, less bacterial translocation, higher number of epithelial stem cells, and less epithelium damage. CTX induced significant shifts of the gut microbiota of the gut microbiota in ad libitum-fed control mice. In contrast, CR mice showed no significant change in their gut microbiota in responding to CTX treatment. CR significantly enriched the gut microbiota in Lactobacillus and Lachnospiraceae which are known to mitigate inflammation and improve gut barrier function. These findings suggest that CR remodeled gut microbiota is more robust and may contribute to attenuate the side effects of cyclophosphamide, which supports the concept that cancer chemotherapy would benefit from strategies targeting the gut microbiota.IMPORTANCE Improving the gut microbiota via calorie restriction is beneficial for human health. Our findings showed differential responses between calorie-restricted mice and ad libitum-fed mice. Compared with the ad libitum-fed mice, the calorie-restricted mice were less susceptible to cyclophosphamide side effects otherwise observed on the gut integrity and its microbiota. These results show the potential benefits of manipulating the gut microbiota with CR prior to cancer chemotherapy.


Assuntos
Antineoplásicos/efeitos adversos , Ciclofosfamida/efeitos adversos , Disbiose , Ingestão de Energia , Enterite/induzido quimicamente , Microbioma Gastrointestinal/efeitos dos fármacos , Mucosite/induzido quimicamente , Animais , Antineoplásicos/administração & dosagem , Translocação Bacteriana/efeitos dos fármacos , Ciclofosfamida/administração & dosagem , Modelos Animais de Doenças , Enterite/patologia , Enterite/prevenção & controle , Camundongos , Mucosite/patologia , Mucosite/prevenção & controle , Células-Tronco/fisiologia
8.
Virol J ; 16(1): 24, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30791956

RESUMO

BACKGROUND: As a low pathogenic influenza virus, avian influenza virus subtype H9N2 (H9N2 AIV) often induces high morbidity in association with secondary bacterial infections in chickens or mammals. To explore this phenomenon, the relationship between intestinal microflora changes and bacterial translocations was studied post H9N2 AIV challenge and post AIV infection plus Ageratum-liquid treatment. METHODS: Illumina sequencing, histological examination and Neongreen-tagged bacteria were used in this study to research the microbiota composition, intestinal barrier, and bacterial translocation in six weeks of BALB/c mice. RESULTS: H9N2 AIV infection caused intestinal dysbacteriosis and mucosal barrier damages. Notably, the villus length was significantly reduced (p < 0.01) at 12 dpi and the crypt depth was significantly increased (p < 0.01) at 5 dpi and 12 dpi with infection, resulting in the mucosal regular villus-length/crypt-depth (V/C) was significantly reduced (p < 0.01) at 5 dpi and 12 dpi. Moreover, degeneration and dissolution of the mucosal epithelial cells, loose of the connective tissue and partial glandular atrophy were found in infection group, indicating that intestinal barrier function was weakened. Eventually, intestinal microbiota (Staphylococcus, E. coli, etc.) overrun the intestinal barrier and migrated to liver and lung tissues of the mice at 5 and 12 dpi. Furthermore, the bacteria transferred in mesentery tissue sites from intestine at 36 h through tracking the Neongreen-tagged bacteria. Then the Neongreen-tagged bacteria were isolated from liver at 48 h post intragastrical administration. Simultaneously, Ageratum-liquid could inhibit the intestinal microbiota disorder post H9N2 AIV challenge via the respiratory tract. In addition, this study also illustrated that Ageratum-liquid could effectively prevent intestinal bacterial translocation post H9N2 AIV infection in mice. CONCLUSION: In this study, we report the discovery that H9N2 AIV infection could damage the ileal mucosal barrier and induce the disturbance of the intestinal flora in BALB/c mice resulting in translocation of intestinal bacteria. In addition, this study indicated that Ageratum-liquid can effectively prevent bacterial translocation following H9N2 infection. These findings are of important theoretical and practical significance in prevention and control of H9N2 AIV infection.


Assuntos
Ageratum/química , Infecções Bacterianas/tratamento farmacológico , Translocação Bacteriana/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Mucosa Intestinal/virologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Animais , Coinfecção/tratamento farmacológico , Microbioma Gastrointestinal , Genoma Bacteriano , Vírus da Influenza A Subtipo H9N2/patogenicidade , Vírus da Influenza A Subtipo H9N2/fisiologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos BALB C
9.
Benef Microbes ; 10(3): 265-278, 2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-30694100

RESUMO

The gut is hypothesised to play an important role in the development and progression of sepsis. It is however unknown whether the gut microbiome and the gut barrier function is already altered early in sepsis development and whether it is possible to modulate the microbiome in early sepsis. Therefore, a randomised, double blind, placebo-controlled pilot study to examine the alterations of the microbiome and the gut barrier in early sepsis and the influence of a concomitant probiotic intervention on dysbiosis at this early stage of the disease was conducted. Patients with early sepsis, defined as fulfilling the sepsis definition from the 2012 Surviving Sepsis Campaign guidelines but without signs of organ failure, received multispecies probiotic (Winclove 607 based on Omnibiotic® 10 AAD) for 28 days. Gut microbiome composition, function, gut barrier and bacterial translocation were studied. Patients with early sepsis had a significantly lower structural and functional alpha diversity, clustered differently and showed structural alterations on all taxonomic levels. Gut permeability was unaltered but endotoxin, endotoxin binding proteins and peptidoglycans were elevated in early sepsis patients compared to controls. Probiotic intervention successfully increased probiotic strains in stool and led to an improvement of functional diversity. Microbiome composition and function are altered in early sepsis. Probiotic intervention successfully modulates the microbiome and is therefore a promising tool for early intervention in sepsis.


Assuntos
Disbiose/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Probióticos/administração & dosagem , Probióticos/farmacologia , Sepse/tratamento farmacológico , Bactérias/classificação , Bactérias/genética , Translocação Bacteriana/efeitos dos fármacos , Biodiversidade , Método Duplo-Cego , Fezes/microbiologia , Feminino , Humanos , Mucosa Intestinal/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Resultado do Tratamento
10.
Free Radic Biol Med ; 131: 237-242, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30503401

RESUMO

Human and animal studies have shown that the colonic concentrations of lipid peroxidation products, such as 4-hydroxynonenal (4-HNE), are elevated in inflammatory bowel disease (IBD). However, the actions and mechanisms of these compounds on the development of IBD are unknown. Here, we show that a systemic treatment of low-dose 4-HNE exacerbates dextran sulfate sodium (DSS)-induced IBD in C57BL/6 mice, suggesting its pro-IBD actions in vivo. Treatment with 4-HNE suppressed colonic expressions of tight-junction protein occludin, impaired intestinal barrier function, enhanced translocation of lipopolysaccharide (LPS) and bacterial products from the gut into systemic circulation, leading to increased activation of Toll-like receptor 4 (TLR4) signaling in vivo. Furthermore, 4-HNE failed to promote DSS-induced IBD in Tlr4-/- mice, supporting that TLR4 signaling contributes to the pro-IBD effects of 4-HNE. Together, these results suggest that 4-HNE exacerbates the progression of IBD through activation of TLR4 signaling, and therefore could contribute to the pathogenesis of IBD.


Assuntos
Aldeídos/farmacologia , Colite/imunologia , Células Epiteliais/efeitos dos fármacos , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/genética , Animais , Translocação Bacteriana/efeitos dos fármacos , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Sulfato de Dextrana/administração & dosagem , Células Epiteliais/imunologia , Células Epiteliais/patologia , Regulação da Expressão Gênica , Injeções Intraperitoneais , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ocludina/genética , Ocludina/imunologia , Estresse Oxidativo/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/imunologia , Junções Íntimas/patologia , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/imunologia
11.
Infect Immun ; 87(2)2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30455200

RESUMO

Recent work has demonstrated that the polyketide natural product Aurodox from Streptomyces goldiniensis is able to block the pathogenesis of the murine pathogen Citrobacter rodentium In this work, we aimed to gain a better understanding of the mechanism of action of the compound. We show that Aurodox downregulates the expression of the type III secretion systems of enteropathogenic and enterohemorrhagic Escherichia coli Furthermore, we have used transcriptomic analysis to show that Aurodox inhibits the expression at the transcriptional level by repressing the master regulator, ler Our data support a model in which Aurodox acts upstream of ler and not directly on the secretion system itself. Finally, we have shown that Aurodox, unlike some traditional antibiotics, does not induce expression of RecA, which is essential for the production of Shiga toxin. We propose that these properties nominate Aurodox as a promising antivirulence therapy for the treatment of these infections.


Assuntos
Antibacterianos/farmacologia , Aurodox/farmacologia , Proteínas de Escherichia coli/metabolismo , Escherichia coli/efeitos dos fármacos , Streptomyces/metabolismo , Sistemas de Secreção Tipo III/antagonistas & inibidores , Translocação Bacteriana/efeitos dos fármacos , Escherichia coli/metabolismo , Virulência/efeitos dos fármacos
12.
Eur J Nutr ; 58(4): 1441-1451, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29574607

RESUMO

PURPOSE: Exercise-induced changes in intestinal permeability are exacerbated in the heat. The aim of this study was to determine the effect of 14 days of bovine colostrum (Col) supplementation on intestinal cell damage (plasma intestinal fatty acid-binding protein, I-FABP) and bacterial translocation (plasma bacterial DNA) following exercise in the heat. METHODS: In a double-blind, placebo-controlled, crossover design, 12 males completed two experimental arms (14 days of 20 g/day supplementation with Col or placebo, Plac) consisting of 60 min treadmill running at 70% maximal aerobic capacity (30 °C, 60% relative humidity). Blood samples were collected pre-exercise (Pre-Ex), post-exercise (Post-Ex) and 1 h post-exercise (1 h Post-Ex) to determine plasma I-FABP concentration, and bacterial DNA (for an abundant gut species, Bacteroides). RESULTS: Two-way repeated measures ANOVA revealed an arm × time interaction for I-FABP (P = 0.005, with greater Post-Ex increase in Plac than Col, P = 0.01: Plac 407 ± 194% of Pre-Ex vs Col, 311 ± 134%) and 1 h Post-Ex (P = 0.036: Plac 265 ± 80% of Pre-Ex vs Col, 229 ± 56%). There was no interaction (P = 0.904) but there was a main effect of arm (P = 0.046) for plasma Bacteroides/total bacterial DNA, with lower overall levels evident in Col. CONCLUSION: This is the first investigation to demonstrate that Col can be effective at reducing intestinal injury following exercise in the heat, but exercise responses (temporal pattern) of bacterial DNA were not influenced by Col (although overall levels may be lower).


Assuntos
Translocação Bacteriana/efeitos dos fármacos , Ácidos Nucleicos Livres/efeitos dos fármacos , Colostro , Suplementos Nutricionais , Temperatura Alta , Intestinos/efeitos dos fármacos , Corrida , Adulto , Animais , Bovinos , Ácidos Nucleicos Livres/sangue , Estudos Cross-Over , Método Duplo-Cego , Proteínas de Ligação a Ácido Graxo/sangue , Proteínas de Ligação a Ácido Graxo/efeitos dos fármacos , Humanos , Umidade , Intestinos/fisiopatologia , Masculino
13.
Pediatr Nephrol ; 34(1): 45-59, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29497824

RESUMO

Acute kidney injury (AKI) is a common accompaniment in patients with liver disease. The causes, risk factors, manifestations and management of AKI in these patients vary according to the liver disease in question (acute liver failure, acute-on-chronic liver failure, post-liver transplantation or metabolic liver disease). There are multiple causes of AKI in patients with liver disease-pre-renal, acute tubular necrosis, post-renal, drug-induced renal failure and hepatorenal syndrome (HRS). Definitions of AKI in liver failure are periodically revised and updated, but pediatric definitions have still to see the light of the day. As our understanding of the pathophysiology of liver disease and renal involvement improves, treatment modalities have become more advanced and rationalized. Treatment includes reversing precipitating factors, such as infections and gastrointestinal bleeding, volume expansion, paracentesis and vasoconstrictors. This approach is tried and tested in adults. A pediatric tailored approach is still lacking due to inadequate numbers of patients, differences in causes of AKI and paucity of literature. In this review, we attempt to explore the pathophysiological basis, treatment modalities and controversies in the diagnosis and treatment of AKI in pediatric patients with chronic liver disease and discuss our own personal practice. We recognize that, although it is not a very commonly encountered entity in pediatric population, HRS has specific diagnostic criteria and treatment modalities that differ from other causes of AKI in patients with chronic liver disease; hence among the etiologies of kidney injury in patients with chronic liver disease, we focus here on HRS.


Assuntos
Lesão Renal Aguda/etiologia , Síndrome Hepatorrenal/etiologia , Cirrose Hepática/complicações , Lesão Renal Aguda/diagnóstico , Lesão Renal Aguda/epidemiologia , Lesão Renal Aguda/terapia , Antibacterianos/uso terapêutico , Antibioticoprofilaxia/métodos , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Translocação Bacteriana/efeitos dos fármacos , Translocação Bacteriana/imunologia , Biomarcadores/análise , Criança , Síndrome Hepatorrenal/diagnóstico , Síndrome Hepatorrenal/epidemiologia , Síndrome Hepatorrenal/terapia , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Transplante de Rim , Cirrose Hepática/imunologia , Cirrose Hepática/terapia , Transplante de Fígado , Paracentese , Terapia de Substituição Renal/métodos , Fatores de Risco , Vasoconstritores/uso terapêutico
15.
Sci Rep ; 8(1): 17679, 2018 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-30518941

RESUMO

Perinatal HIV infection is characterized by faster HIV disease progression and higher initial rate of HIV replication compared to adults. While antiretroviral therapy (ART) has greatly reduced HIV replication to undetectable levels, there is persistent elevated inflammation associated with HIV disease progression. Alteration of gut microbiota is associated with increased inflammation in chronic adult HIV infection. Here, we aim to study the gut microbiome and its role in inflammation in treated and untreated HIV-infected children. Examination of fecal microbiota revealed that perinatally infected children living with HIV had significantly higher levels of genus Prevotella that persisted despite ART. These children also had higher levels of soluble CD14 (sCD14), a marker of microbial translocation, and IP-10 despite therapy. The Prevotella positively correlated with IP-10 levels in both treated and untreated HIV-infected children, while genus Prevotella and species Prevotella copri was inversely associated with CD4 count. Relative abundance of genus Prevotella and species Prevotella copri showed positive correlation with sCD14 in ART-suppressed perinatally HIV-infected children. Our study suggests that gut microbiota may serve as one of the driving forces behind the persistent inflammation in children despite ART. Reshaping of microbiota using probiotics may be recommended as an adjunctive therapy along with ART.


Assuntos
Terapia Antirretroviral de Alta Atividade , Quimiocina CXCL10/sangue , Microbioma Gastrointestinal , Infecções por HIV/tratamento farmacológico , Infecções por HIV/microbiologia , Prevotella/isolamento & purificação , Translocação Bacteriana/efeitos dos fármacos , Infecções por Bacteroidaceae/sangue , Infecções por Bacteroidaceae/microbiologia , Contagem de Linfócito CD4 , Criança , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Infecções por HIV/sangue , Humanos , Masculino , Prevotella/efeitos dos fármacos
16.
J Nutr Sci Vitaminol (Tokyo) ; 64(5): 357-366, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30381626

RESUMO

The effects of fructo-oligosaccharides (FOS) on gut-barrier function are still controversial in human and animal studies. Diet conditions would be a major factor for the controversy in animal studies. We fed rats a semi-purified (SP) or a non-purified diet (NP) with or without FOS (60 g/kg diet) for 9 (experiment 1) or 10 d (experiment 2). We assessed microbial fermentation, gut permeability, and inflammatory responses in the cecum (experiment 1), and mucus layer in the cecum, intestinal transit time and microbiota composition (experiment 2). FOS supplementation induced a very acidic fermentation due to the accumulation of lactate and succinate in SP, while short-chain fatty acids were major products in NP. Gut permeability estimated by urinary chromium-EDTA excretion, bacterial translocation into mesenteric lymph nodes, myeloperoxidase activity, and expressions of the inflammatory cytokine genes in the cecal mucosa were greater in SP+FOS than in SP, but these alterations were not observed between NP and NP+FOS (experiment 1). FOS supplementation destroyed the mucus layer on the epithelial surface in SP, but not in NP. Intestinal transit time was 3-fold longer in SP+FOS than in SP, but this was not the case between NP and NP+FOS. Lower species richness of cecal microbiota was manifest solely in SP+FOS (experiment 2). These factors suggest that impact of FOS on gut permeability and inflammatory responses in the cecal mucosa quite differs between SP and NP. Increased gut permeability in SP+FOS could be evoked by the disruption of the mucus layer due to stasis of the very acidic luminal contents.


Assuntos
Ração Animal , Ceco/efeitos dos fármacos , Dieta , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação , Mucosa Intestinal/efeitos dos fármacos , Oligossacarídeos/farmacologia , Animais , Translocação Bacteriana/efeitos dos fármacos , Ceco/metabolismo , Ceco/microbiologia , Ceco/patologia , Cromo/urina , Citocinas/metabolismo , Digestão , Ácido Edético/urina , Ácidos Graxos Voláteis/metabolismo , Fermentação , Frutose/farmacologia , Trânsito Gastrointestinal/efeitos dos fármacos , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/prevenção & controle , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Ácido Láctico/metabolismo , Masculino , Permeabilidade , Peroxidase/metabolismo , Prebióticos , Ratos Wistar , Ácido Succínico/metabolismo
17.
J Autoimmun ; 95: 47-57, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30340822

RESUMO

Gut microbiota and bacterial translocation have been implicated as significant contributors to mucosal immune responses and tolerance; alteration of microbial molecules, termed pathogen-associated molecular patterns (PAMP) and bacterial translocation are associated with immune pathology. However, the mechanisms by which dysregulated gut microbiota promotes autoimmunity is unclear. We have taken advantage of a well-characterized murine model of primary biliary cholangitis, dnTGFßRII mice, and an additional unique construct, toll-like receptor 2 (TLR2)-deficient dnTGFßRII mice coined dnTGFßRIITLR2-/- mice to investigate the influences of gut microbiota on autoimmune cholangitis. Firstly, we report that dnTGFßRII mice manifest altered composition of gut microbiota and that alteration of this gut microbiota by administration of antibiotics significantly alleviates T-cell-mediated infiltration and bile duct damage. Second, toll-like receptor 2 (TLR2)-deficient dnTGFßRII mice demonstrate significant exacerbation of autoimmune cholangitis when their epithelial barrier integrity was disrupted. Further, TLR2-deficiency mediates downregulated expression of tight junction-associated protein ZO-1 leading to increased gut permeability and bacterial translocation from gut to liver; use of antibiotics reduces microbiota translocation to liver and also decreases biliary pathology. In conclusion, our data demonstrates the important role of gut microbiota and bacterial translocation in the pathogenesis of murine autoimmune cholangitis.


Assuntos
Doenças Autoimunes/microbiologia , Translocação Bacteriana/imunologia , Ductos Biliares/imunologia , Cirrose Hepática Biliar/imunologia , Receptor do Fator de Crescimento Transformador beta Tipo II/imunologia , Receptor 2 Toll-Like/imunologia , Ampicilina/farmacologia , Animais , Antibacterianos/farmacologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/patologia , Translocação Bacteriana/efeitos dos fármacos , Ductos Biliares/efeitos dos fármacos , Ductos Biliares/microbiologia , Ductos Biliares/patologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/microbiologia , Colo/patologia , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Regulação da Expressão Gênica , Imunidade nas Mucosas/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/microbiologia , Fígado/patologia , Cirrose Hepática Biliar/tratamento farmacológico , Cirrose Hepática Biliar/microbiologia , Cirrose Hepática Biliar/patologia , Metronidazol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neomicina/farmacologia , Receptor do Fator de Crescimento Transformador beta Tipo II/deficiência , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Transdução de Sinais , Receptor 2 Toll-Like/deficiência , Receptor 2 Toll-Like/genética , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/imunologia
18.
Blood ; 132(23): 2506-2519, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30257880

RESUMO

The intestinal microbiota in allogeneic bone marrow transplant (allo-BMT) recipients modulates graft-versus-host disease (GVHD), a systemic inflammatory state initiated by donor T cells that leads to colitis, a key determinant of GVHD severity. Indole or indole derivatives produced by tryptophan metabolism in the intestinal microbiota limit intestinal inflammation caused by diverse stressors, so we tested their capacity to protect against GVHD in murine major histocompatibility complex-mismatched models of allo-BMT. Indole effects were assessed by colonization of allo-BMT recipient mice with tryptophanase positive or negative strains of Escherichia coli, or, alternatively, by exogenous administration of indole-3-carboxaldehyde (ICA), an indole derivative. Treatment with ICA limited gut epithelial damage, reduced transepithelial bacterial translocation, and decreased inflammatory cytokine production, reducing GVHD pathology and GVHD mortality, but did not compromise donor T-cell-mediated graft-versus-leukemia responses. ICA treatment also led to recipient-strain-specific tolerance of engrafted T cells. Transcriptional profiling and gene ontology analysis indicated that ICA administration upregulated genes associated with the type I interferon (IFN1) response, which has been shown to protect against radiation-induced intestinal damage and reduce subsequent GVHD pathology. Accordingly, protective effects of ICA following radiation exposure were abrogated in mice lacking IFN1 signaling. Taken together, these data indicate that indole metabolites produced by the intestinal microbiota act via type I IFNs to limit intestinal inflammation and damage associated with myeloablative chemotherapy or radiation exposure and acute GVHD, but preserve antitumor responses, and may provide a therapeutic option for BMT patients at risk for GVHD.


Assuntos
Transplante de Medula Óssea , Escherichia coli/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Doença Enxerto-Hospedeiro , Indóis , Interferon Tipo I/metabolismo , Mucosa Intestinal , Aloenxertos , Animais , Translocação Bacteriana/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/microbiologia , Indóis/farmacocinética , Indóis/farmacologia , Interferon Tipo I/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Camundongos , Camundongos Knockout
19.
Am J Hypertens ; 31(8): 941-944, 2018 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-30016413

RESUMO

Cardiovascular disease is the leading cause of death and is also a major cause of disability worldwide. Indeed, even in well-treated patients for hypertension or dyslipidemia, there is still a high cardiovascular risk called residual risk. It is of utmost importance to identify the pathway leading from risk factors to cardiovascular disease to further improve stroke and myocardial infarction prevention. In this review, we presented some of experimental and epidemiological evidences suggesting that microbiota-host crosstalk is involved in this pathway and bridges the gap between cardiovascular risk factors, diet, and cardiovascular residual risk. We considered the 3 participants in this dialogue: the gut microbiota, the intestinal barrier, and bacterial translocation. We analyzed their relations with cardiovascular risk factors and cardiovascular diseases. Also, we presented some of therapeutic strategies aiming to control microbiota to further prevent cardiovascular disease and the take home messages that can be drawn for clinical practice.


Assuntos
Translocação Bacteriana , Doenças Cardiovasculares/microbiologia , Dieta/efeitos adversos , Microbioma Gastrointestinal , Intestinos/microbiologia , Animais , Antibacterianos/uso terapêutico , Translocação Bacteriana/efeitos dos fármacos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/prevenção & controle , Dieta Mediterrânea , Disbiose , Microbioma Gastrointestinal/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Humanos , Intestinos/efeitos dos fármacos , Permeabilidade , Prebióticos/administração & dosagem , Prognóstico , Fatores de Risco
20.
Biomed Pharmacother ; 103: 1567-1576, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29864944

RESUMO

BACKGROUND: Studies have showed the protective effects of conjugated linoleic acid (CLA) on intestinal epithelium, modulating host immune and inflammatory responses on intestinal diseases. OBJECTIVE: To evaluate the preventive effects of CLA on the intestinal mucositis induced by 5-FU in a murine model. METHODS: Sixty-four BALB/c mice were randomly divided into four groups: Control (CTL), fed a standard chow diet; CLAs, fed a diet supplemented with CLA; Mucositis (5-FU), fed a standard chow diet and underwent mucositis induction and CLAs 5-FU, fed a diet supplemented with CLA and underwent mucositis induction. Mucositis was induced by intraperitoneal injection of 300 mg/kg 5-FU. After 72 h, the animals were euthanized and intestinal permeability, bacterial translocation, inflammatory mediators, and intestinal histology were evaluated. RESULTS: Mice in the CLAs 5-FU group showed reduced weight loss compared to those in the 5-FU group (p < 0.005). Furthermore, the results also showed that the treatment with CLA reduced intestinal permeability, bacterial translocation, and biomarkers of inflammatory response besides minor damage to ZO-1 and occludin with maintenance of the integrity of the intestinal epithelium and a favorable balance between the inflammatory and regulatory cytokines. CONCLUSION: This study suggests that CLA reduced the adverse effects from 5-FU administration on the intestinal mucosa.


Assuntos
Fluoruracila/efeitos adversos , Intestinos/patologia , Ácidos Linoleicos Conjugados/uso terapêutico , Mucosite/tratamento farmacológico , Mucosite/prevenção & controle , Animais , Translocação Bacteriana/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Quimiocinas/metabolismo , Modelos Animais de Doenças , Comportamento Alimentar , Imunoglobulina A/metabolismo , Inflamação/patologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Ácidos Linoleicos Conjugados/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Mucosite/microbiologia , Mucosite/patologia , Distribuição Tecidual/efeitos dos fármacos
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