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1.
Clin Transl Gastroenterol ; 13(10): e00522, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36000993

RESUMO

INTRODUCTION: Several complications of decompensated cirrhosis are believed to result from increased intestinal permeability. However, little is known about the relationship between mucosal bacteria and epithelial permeability in cirrhosis. We aimed to assess epithelial permeability and associations with mucosal bacteria in patients with compensated cirrhosis. METHODS: We obtained duodenal tissue biopsies from patients with compensated cirrhosis and controls. Patients were excluded if they used antibiotics or immunosuppression. The composition of mucosal microbiota was determined by 16S rRNA gene sequencing and epithelial permeability by transepithelial electrical resistance (TEER) and tight junction protein expression. RESULTS: We studied 24 patients with compensated cirrhosis and 20 controls. Patients with cirrhosis were older than controls (62 vs 52 years, P = 0.02) but had a similar number of extrahepatic comorbidities (2.2 vs 1.4, P = 0.13). Patients with compensated cirrhosis had lower duodenal TEER (i.e., increased epithelial permeability; 13.3 Ω/cm 2 ± 3.4 vs 18.9 Ω/cm 2 ± 7.1; P = 0.004). Patients with compensated cirrhosis trended toward a distinct mucosal microbiota community structure relative to controls ( P = 0.09). Clustering analysis identified two unique enterotypes. These enterotypes differed in bacterial composition and also TEER. A beta-binomial model found 13 individual bacteria associated with TEER, including Lactobacillus and Bifidobacterium taxa. Thirty-six taxa were associated with tight junction protein expression, including Lactobacillus and Bifidobacterium. DISCUSSION: Compensated cirrhosis is characterized by increased duodenal epithelial permeability with a distinct mucosal microbial community. Intriguingly, bacteria previously associated with health were protective of duodenal permeability.


Assuntos
Mucosa Intestinal , Microbiota , Humanos , RNA Ribossômico 16S/genética , Mucosa Intestinal/patologia , Permeabilidade , Cirrose Hepática/patologia , Proteínas de Junções Íntimas/metabolismo , Bactérias/genética
2.
Microbiol Mol Biol Rev ; 83(3)2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31167904

RESUMO

The gut microbiome is critical in providing resistance against colonization by exogenous microorganisms. The mechanisms via which the gut microbiota provide colonization resistance (CR) have not been fully elucidated, but they include secretion of antimicrobial products, nutrient competition, support of gut barrier integrity, and bacteriophage deployment. However, bacterial enteric infections are an important cause of disease globally, indicating that microbiota-mediated CR can be disturbed and become ineffective. Changes in microbiota composition, and potential subsequent disruption of CR, can be caused by various drugs, such as antibiotics, proton pump inhibitors, antidiabetics, and antipsychotics, thereby providing opportunities for exogenous pathogens to colonize the gut and ultimately cause infection. In addition, the most prevalent bacterial enteropathogens, including Clostridioides difficile, Salmonella enterica serovar Typhimurium, enterohemorrhagic Escherichia coli, Shigella flexneri, Campylobacter jejuni, Vibrio cholerae, Yersinia enterocolitica, and Listeria monocytogenes, can employ a wide array of mechanisms to overcome colonization resistance. This review aims to summarize current knowledge on how the gut microbiota can mediate colonization resistance against bacterial enteric infection and on how bacterial enteropathogens can overcome this resistance.


Assuntos
Anti-Infecciosos/farmacologia , Bactérias/metabolismo , Infecções Bacterianas/microbiologia , Microbioma Gastrointestinal , Animais , Bactérias/patogenicidade , Ácidos Graxos Voláteis/biossíntese , Humanos , Camundongos , Muco
3.
Clin Microbiol Infect ; 22(11): 905-909, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27619640

RESUMO

BACKGROUND: The growing appreciation of the potential role of indigenous microbiota in disease has resulted in a concomitant interest in manipulating the microbiome for therapeutic effect. The most successful example of microbiota manipulation for treatment of a disease is in recurrent infection with the bacterial pathogen Clostridium difficile. AIMS: This review provides historic perspectives on development of microbiota transplantation and reviews evidence for its use in recurrent C. difficile infection. SOURCES: A PubMed search of the terms ([fecal transplant OR fecal transplantation] AND difficile) to 9 June 2016 yielded 415 articles. CONTENT: Recent work has pointed to potential mechanisms by which microbiota restoration in the form of faecal transplantation has been efficacious. This includes studies of microorganisms associated with successful faecal transplantation in human and animal studies and a focus on bacterial bile acid metabolism as a mechanism that mediates colonization resistance against the pathogen. The potential use of microbiota manipulation for other diseases such as inflammatory bowel diseases and metabolic disorders will be discussed. The case will be made that the lessons learned from treatment of recurrent C. difficile infection may not necessarily translate to use of faecal transplantation or other methods to alter the microbiome for the treatment of other diseases. IMPLICATIONS: A key conclusion that can be drawn is that understanding of the precise role of the microbiota in the pathogenesis of a specific disease is necessary prior to determining if microbiota manipulation represents a novel treatment therapy.


Assuntos
Infecções por Clostridium/terapia , Transplante de Microbiota Fecal/métodos , Doenças Inflamatórias Intestinais/terapia , Microbiota , Animais , Clostridioides difficile , Modelos Animais de Doenças , Transplante de Microbiota Fecal/história , Fezes/microbiologia , História do Século XX , Humanos
4.
Anaerobe ; 27: 82-6, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24708941

RESUMO

Antibody levels to Clostridium difficile toxin A (TcdA), but not toxin B (TcdB), have been found to determine risk of C. difficile infection (CDI). Historically, TcdA was thought to be the key virulence factor; however the importance of TcdB in disease is now established. We re-evaluated the role of antibodies to TcdA and TcdB in determining patient susceptibility to CDI in two separate patient cohorts. In contrast to earlier studies, we find that CDI patients have lower pre-existing IgA titres to TcdB, but not TcdA, when compared to control patients. Our findings suggest that mucosal immunity to TcdB may be important in the early stages of infection and identifies a possible target for preventing CDI progression.


Assuntos
ADP Ribose Transferases/imunologia , Anticorpos Antibacterianos/análise , Antitoxinas/análise , Proteínas de Bactérias/imunologia , Infecções por Clostridium/imunologia , Infecções por Clostridium/prevenção & controle , Suscetibilidade a Doenças , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Imunidade nas Mucosas , Imunoglobulina A/análise , Masculino , Pessoa de Meia-Idade
5.
J Med Primatol ; 43(2): 89-99, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24266633

RESUMO

BACKGROUND: Use of a levonorgestrel-releasing intrauterine system (LNG-IUS) in humans may alter vaginal microbial populations and susceptibility to pathogens. This study evaluated the time-dependent effects of an LNG-IUS on the vaginal microbiome of the baboon, a useful animal model for reproductive studies. METHODS: Levonorgestrel-releasing intrauterine systems were inserted into three reproductively mature, female baboons. The animals were evaluated for 6 months by physical examination and Gram-stained cytology. The vaginal microbiota was characterized at each timepoint by culture-independent analysis of the 16S rRNA-encoding gene. RESULTS: Each baboon harbored a diverse vaginal microbiome. Interindividual variation exceeded intra-individual variation. Diversity declined over time in one baboon and showed mild fluctuations in the other two. There were no significant community differences from early to late post-LNG-IUS placement. CONCLUSIONS: The baboon vaginal microbiome is unique to each individual and is polymicrobial. In this pilot study, the vaginal microbiome remained stable from early to late post-LNG-IUS placement.


Assuntos
Anticoncepcionais Femininos/farmacologia , Dispositivos Intrauterinos Medicados , Levanogestrel/farmacologia , Microbiota/efeitos dos fármacos , Papio anubis/microbiologia , Vagina/efeitos dos fármacos , Vagina/microbiologia , Animais , Anticoncepcionais Femininos/administração & dosagem , Feminino , Levanogestrel/administração & dosagem , Modelos Animais , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Estudos Prospectivos , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/metabolismo , Análise de Sequência de DNA , Ultrassonografia , Útero/diagnóstico por imagem
6.
Vet Pathol ; 48(3): 713-25, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-20926734

RESUMO

Telomerase deficiency induces early senescence and defects in proliferating cell populations, but in mice it has not been associated with inflammatory bowel disease. Genetically engineered mice lacking either telomerase reverse transcriptase (TERT) or telomerase RNA were examined for chronic diarrhea and wasting. Affected mice had pasty stools, thickened nondistensible colon walls, and contracted ceca. Histologically, the cecal mucosa was largely replaced by inflammatory infiltrate consisting of plasma cells, neutrophils, lymphocytes, and macrophages with marked widespread fibrosis and ulceration. Remaining epithelium was disorganized and hyperplastic, with multifocal dysplasia. Colonic mucosa was markedly hyperplastic with similar inflammation and epithelial dysplasia. Multifocal adenomatous hyperplasia, but no inflammation, was present in the small intestine. Microaerophilic spiral bacteria with 16S rRNA gene sequences identical to Helicobacter mastomyrinus were isolated from the colon and cecum. Severe granulomatous typhlocolitis without epithelial dysplasia developed in germ-free recombination-activating gene (RAG) knockout (KO) recipients of CD4+ T cells and inoculated with cecal contents from affected TERT KO mice and in specific pathogen-free recipient RAG KO mice and interleukin-10 KO mice inoculated with H mastomyrinus. Typhlocolitis in mice given H mastomyrinus was more severe than in mice given Helicobacter hepaticus. Telomerase-deficient mice are susceptible to helicobacter-associated typhlocolitis. H mastomyrinus causes severe disease in susceptible mouse strains.


Assuntos
Colite Ulcerativa/microbiologia , Helicobacter/classificação , RNA/metabolismo , Telomerase/metabolismo , Animais , Colite Ulcerativa/genética , Colo/microbiologia , Colo/patologia , Feminino , Genes RAG-1/genética , Vida Livre de Germes , Infecções por Helicobacter , Interleucina-10/genética , Interleucina-10/metabolismo , Masculino , Camundongos , Camundongos Knockout , RNA/genética , Telomerase/genética
7.
Infect Immun ; 75(3): 1099-115, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17130251

RESUMO

Campylobacter jejuni is a globally distributed cause of human food-borne enteritis and has been linked to chronic joint and neurological diseases. We hypothesized that C. jejuni 11168 colonizes the gastrointestinal tract of both C57BL/6 mice and congenic C57BL/6 interleukin-10-deficient (IL-10(-/-)) mice and that C57BL/6 IL-10(-/-) mice experience C. jejuni 11168-mediated clinical signs and pathology. Individually housed mice were challenged orally with C. jejuni 11168, and the course of infection was monitored by clinical examination, bacterial culture, C. jejuni-specific PCR, gross pathology, histopathology, immunohistochemistry, and anti-C. jejuni-specific serology. Ceca of C. jejuni 11168-infected mice were colonized at high rates: ceca of 50/50 wild-type mice and 168/170 IL-10(-/-) mice were colonized. In a range from 2 to 35 days after infection with C. jejuni 11168, C57BL/6 IL-10(-/-) mice developed severe typhlocolitis best evaluated at the ileocecocolic junction. Rates of colonization and enteritis did not differ between male and female mice. A dose-response experiment showed that as little as 10(6) CFU produced significant disease and pathological lesions similar to responses seen in humans. Immunohistochemical staining demonstrated C. jejuni antigens within gastrointestinal tissues of infected mice. Significant anti-C. jejuni plasma immunoglobulin levels developed by day 28 after infection in both wild-type and IL-10-deficient animals; antibodies were predominantly T-helper-cell 1 (Th1)-associated subtypes. These results indicate that the colonization of the mouse gastrointestinal tract by C. jejuni 11168 is necessary but not sufficient for the development of enteritis and that C57BL/6 IL-10(-/-) mice can serve as models for the study of C. jejuni enteritis in humans.


Assuntos
Infecções por Campylobacter/microbiologia , Campylobacter jejuni/patogenicidade , Enterite/microbiologia , Interleucina-10/deficiência , Interleucina-10/genética , Animais , Animais Congênicos , Infecções por Campylobacter/genética , Infecções por Campylobacter/imunologia , Modelos Animais de Doenças , Enterite/genética , Enterite/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
9.
J Infect Dis ; 182(2): 620-3, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10915100

RESUMO

Helicobacter pullorum has been isolated from the feces and livers of poultry and is associated with human gastroenteritis. Discrimination of this organism from other enterohepatic Helicobacter species and Campylobacter species has proven difficult. H. pullorum from both avian and human clinical sources has DNA sequence homology and cytotoxic activity that represent a new member of the cytolethal distending toxin (CDT) family of bacterial toxins. CDT is a potential virulence factor in H. pullorum that may serve as a distinguishing phenotype and aid in identification of this organism in veterinary and human clinical samples.


Assuntos
Toxinas Bacterianas/isolamento & purificação , Helicobacter/patogenicidade , Animais , Toxinas Bacterianas/genética , Toxinas Bacterianas/toxicidade , Galinhas , Gastroenterite/microbiologia , Helicobacter/classificação , Helicobacter/genética , Humanos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Análise de Sequência de DNA
10.
Infect Immun ; 68(4): 2110-8, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10722608

RESUMO

Campylobacter fetus is a cause of enteritis and invasive extraintestinal disease in humans. In order to develop an animal model of C. fetus infection, outbred ICR SCID mice were orally challenged with a clinical isolate of C. fetus. The stomachs of SCID mice were heavily colonized with C. fetus, and colonization was associated with the development of chronic atrophic gastritis. This lesion was characterized by an inflammatory infiltrate of granulocytes and macrophages that over time resulted in a loss of specialized parietal and chief cells in the corpus and the appearance of a metaplastic mucous epithelium. This lesion bears similarity to that encountered during experimental murine infection with Helicobacter pylori or Helicobacter felis. Despite colonization of the cecum and colon tissues by C. fetus in SCID mice, no lesions were noted in these tissues. A follow-up study confirmed these findings for SCID mice and also demonstrated that C. fetus could also infect the gastric mucosa of wild-type, outbred ICR mice. However, in ICR mice, the anatomic extent of colonization was more limited and the severity of inflammation and epithelial alterations was significantly less than that observed in infected SCID mice. The stomach may represent an unrecognized environmental niche for Campylobacter species.


Assuntos
Campylobacter fetus , Gastrite Atrófica/imunologia , Gastrite Atrófica/microbiologia , Estômago/microbiologia , Animais , Ceco/microbiologia , Colo/microbiologia , Fezes/microbiologia , Feminino , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Gastrite Atrófica/patologia , Íleo/microbiologia , Fígado/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos SCID , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Estômago/patologia , Estômago/ultraestrutura , Fatores de Tempo
11.
Infect Immun ; 68(1): 184-91, 2000 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10603386

RESUMO

Little is known about the molecular pathogenesis of hepatitis and enterocolitis caused by enterohepatic Helicobacter species. Sonicates of the murine pathogen Helicobacter hepaticus were found to cause progressive cell distension, accumulation of filamentous actin, and G(2)/M cell cycle arrest in HeLa cell monolayers. The genes encoding this cytotoxic activity were cloned from H. hepaticus. Three open reading frames with closest homology to cdtA, cdtB, and cdtC from Campylobacter jejuni were identified. Sonicates of a laboratory strain of Escherichia coli carrying the cloned cdtABC gene cluster from H. hepaticus reproduced the cytotoxic activities seen with sonicates of H. hepaticus. Cytolethal distending toxin activity is a potential virulence determinant of H. hepaticus that may play a role in the pathogenesis of Helicobacter-associated hepatitis and enterocolitis.


Assuntos
Toxinas Bacterianas/genética , Toxinas Bacterianas/toxicidade , Helicobacter/genética , Helicobacter/patogenicidade , Sequência de Aminoácidos , Sequência de Bases , Campylobacter jejuni/genética , Ciclo Celular , DNA Bacteriano/genética , Enterocolite/etiologia , Genes Bacterianos , Células HeLa , Infecções por Helicobacter/etiologia , Hepatite/etiologia , Humanos , Dados de Sequência Molecular , Família Multigênica , Homologia de Sequência de Aminoácidos , Virulência/genética
12.
J Cell Biol ; 116(1): 197-207, 1992 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-1730744

RESUMO

Yersinia enterocolitica, a facultative intracellular pathogen of mammals, readily enters (i.e., invades) cultured eukaryotic cells, a process that can be conferred by the cloned inv locus of the species. We have studied the mechanism by which the product of inv, a microbial outer membrane protein termed "invasin," mediates the internalization of bacteria by HEp-2 cells and chicken embryo fibroblasts. Invasin-bearing bacteria initially bound the filopodia and the leading edges of cultured cells. Multiple points of contact between the bacterial surface and the surface of the cell ensued and led to the internalization of the bacterium within an endocytic vacuole; the same multi-step process could be induced by an inert particle coated with invasin-containing membranes. Both adherence and internalization were blocked by an antisera directed against the beta 1 integrin cell-adherence molecule. Ultrastructural studies of detergent-insoluble cytoskeletons from infected cells and immunofluorescence microscopy of phalloidin-labeled cells showed alterations in the structure of the cytoskeleton during the internalization process including the accumulation of polymerized actin around entering bacteria. Bacterial entry was prevented by cytochalasin D indicating that the internalization process requires actin microfilament function. Possible linkages between beta 1 containing integrins and the cytoskeleton were examined during the internalization process through the use of protein-specific antibodies and immunofluorescence microscopy. Like actin, the actin-associated proteins filamin, talin and the beta 1 integrin subunit were also found to accumulate around entering bacteria. These findings suggest that the invasin-mediated internalization process is associated with cytoskeletal reorganization.


Assuntos
Adesinas Bacterianas , Aderência Bacteriana , Proteínas de Bactérias/metabolismo , Citoesqueleto/fisiologia , Yersinia enterocolitica/fisiologia , Animais , Anticorpos , Proteínas de Bactérias/genética , Linhagem Celular , Membrana Celular/fisiologia , Células Cultivadas , Embrião de Galinha , Proteínas Contráteis/fisiologia , Citoesqueleto/ultraestrutura , Filaminas , Imunofluorescência , Humanos , Integrinas/imunologia , Integrinas/fisiologia , Proteínas dos Microfilamentos/fisiologia , Microscopia Eletrônica , Proteínas Recombinantes/metabolismo , Talina/fisiologia , Gravação em Vídeo
13.
Mol Microbiol ; 4(7): 1119-28, 1990 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-2233250

RESUMO

The inv locus of Yersinia enterocolitica is sufficient to convert a non-invasive Escherichia coli K12 strain into a microorganism that is able to penetrate cultured mammalian cells. The nucleotide sequence of inv reveals an open reading frame corresponding to an 835-amino-acid protein that is homologous to the invasin protein from Yersinia pseudotuberculosis. A polyclonal antiserum elicited by a synthetic peptide corresponding to the C-terminal 88 amino acids of this open reading frame detected a unique 100 kD protein in cell lysates of Y. enterocolitica strain 8081 c and in an E. coli strain harbouring the cloned inv gene. This protein localized to the outer membranes of both microorganisms and was cleaved by low concentrations of extracellular trypsin. HEp-2 cells were shown to attach to surfaces coated with bacterial outer membranes containing invasin and this attachment was destroyed by treatment of the membranes with trypsin. Thus it appears that the invasin protein from Y. enterocolitica is able to mediate both attachment to and entry of cultured epithelial cells.


Assuntos
Adesinas Bacterianas , Proteínas de Bactérias/genética , Yersinia enterocolitica/genética , Sequência de Aminoácidos , Proteínas de Bactérias/análise , Proteínas de Bactérias/metabolismo , Sequência de Bases , Clonagem Molecular , Genes Bacterianos , Dados de Sequência Molecular , Mapeamento por Restrição , Homologia de Sequência do Ácido Nucleico , Tripsina/metabolismo , Yersinia enterocolitica/metabolismo
14.
Proc Natl Acad Sci U S A ; 83(23): 8829-33, 1986 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-2947238

RESUMO

Following random mutagenesis of the bacteriophage lambda cro gene, we have isolated missense mutations that affect approximately half of the 66 residue positions of Cro. About two-thirds of the mutations change residues involved in the maintenance of Cro structure and stability. The corresponding mutant proteins are severely degraded in the cell but often have specific activities near that of wild-type Cro. The remaining mutations affect residues involved in DNA binding. These mutant proteins are present at moderately reduced intracellular levels, but their specific activities are much lower than that of wild type.


Assuntos
Bacteriófago lambda/genética , Proteínas de Ligação a DNA , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Sequência de Aminoácidos , Mutação , Regiões Promotoras Genéticas , Biossíntese de Proteínas , Conformação Proteica , Proteínas Repressoras/metabolismo , Relação Estrutura-Atividade , Proteínas Virais , Proteínas Virais Reguladoras e Acessórias
15.
Blood ; 50(2): 213-25, 1977 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-871526

RESUMO

The effects of the cationic anesthetic agents tetracaine and lidocaine on granulocyte function, morphology, and adherence to nylon fibers were studied in an attempt to improve current methods of granulocyte collection by filtration leukapheresis (FL). When dissolved in acid-citrate-dextrose (ACD) plasma, these drugs significantly increased granulocyte elution from the fibers in a dose-related fashion. Granulocytes exposed to tetracaine and lidocaine remained more than 95% viable, retained normal bactericidal capacity after the drugs were washed from the cells, and had preserved membrane integrity, as evidenced by the normal ultrastructural appearance of tetracaine-exposed cells and an absence of leakage of lysozyme or lactic dehydrogenase. Granulocytes eluted with the anesthetic agents were rounded in shape with a reduction in the number of filopodial cytoplasmic projections and a relative absence of cytoplasmic vacuolization when compared to granulocytes eluted with ACD plasma alone. Dose-related inhibition of phagocytosis and adherence, which was largely reversible after washing the granulocytes, was noted. Greater than 95% of the lidocaine could be removed from the eluate with a single centrifugation and resuspension, indicating that granulocytes prepared by FL with anesthetic-enhanced elution could be potentially transfusable.


Assuntos
Anestésicos Locais/farmacologia , Adesão Celular/efeitos dos fármacos , Granulócitos/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Plasmaferese , Separação Celular , Granulócitos/enzimologia , Granulócitos/ultraestrutura , Humanos , L-Lactato Desidrogenase/metabolismo , Lidocaína/farmacologia , Muramidase/metabolismo , Fagocitose/efeitos dos fármacos , Tetracaína/farmacologia
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