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1.
Nat Med ; 25(12): 1865-1872, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31792456

RESUMO

Viruses are implicated in autoimmune destruction of pancreatic islet ß cells, which results in insulin deficiency and type 1 diabetes (T1D)1-4. Certain enteroviruses can infect ß cells in vitro5, have been detected in the pancreatic islets of patients with T1D6 and have shown an association with T1D in meta-analyses4. However, establishing consistency in findings across studies has proven difficult. Obstacles to convincingly linking RNA viruses to islet autoimmunity may be attributed to rapid viral mutation rates, the cyclical periodicity of viruses7 and the selection of variants with altered pathogenicity and ability to spread in populations. ß cells strongly express cell-surface coxsackie and adenovirus receptor (CXADR) genes, which can facilitate enterovirus infection8. Studies of human pancreata and cultured islets have shown significant variation in enteroviral virulence to ß cells between serotypes and within the same serotype9,10. In this large-scale study of known eukaryotic DNA and RNA viruses in stools from children, we evaluated fecally shed viruses in relation to islet autoimmunity and T1D. This study showed that prolonged enterovirus B rather than independent, short-duration enterovirus B infections may be involved in the development of islet autoimmunity, but not T1D, in some young children. Furthermore, we found that fewer early-life human mastadenovirus C infections, as well as CXADR rs6517774, independently correlated with islet autoimmunity.

2.
J Neurotrauma ; 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31868094

RESUMO

Patients with chronic traumatic brain injury (TBI) requiring long-term, permanent care suffer a myriad of clinical symptoms (i.e. impaired cognition, fatigue, and other conditions) that persist for years beyond the acute brain injury. In addition to these comorbid clinical symptoms, chronic TBI patients exhibit altered amino acid and hormonal profiles with distinct cytokine patterns suggesting chronic inflammation. This metabolic link suggests a role of the gut-brain axis in chronic TBI. Thus, we utilized a two-site trial to investigate the role of the gut-brain axis in comorbidities of chronic TBI. The fecal microbiome profile of 22 moderate/severe TBI patients residing in permanent care facilities in Texas and California was compared to 18 healthy age-matched control subjects working within the participating facilities. Each fecal microbiome was characterized by 16S(V4) rRNA gene sequencing and metagenomic genome sequencing approaches followed by confirmatory full 16S rRNA gene sequencing or focused tuf gene speciation and specific qPCR evaluation of selected genera or species. The average chronic TBI patient fecal microbiome structure was significantly different compared to the control cohort, and these differences persisted after group stratification analysis to identify any unexpected confounders. Notably, the fecal microbiome of the chronic TBI cohort had absent or reduced Prevotella spp and Bacteroidies spp. Conversely, bacteria in the Ruminococcaceae family were higher in abundance in TBI compared to control profiles. Previously reported hypoaminoacidemia including significantly reduced levels of L-tryptophan, L-sarcosine, ß-alanine and alanine, positively correlated with the reduced levels of Prevotella spp in the TBI cohort samples compared to controls. Although the sequelae of gut-brain axis disruption following TBI is not fully understood, characterizing TBI-related alterations in the fecal microbiome may provide biomarkers and therapeutic targets to address patient morbidity.

3.
Cell ; 178(4): 795-806.e12, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398337

RESUMO

Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short-term survival (STS) and long-term survival (LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (Pseudoxanthomonas-Streptomyces-Saccharopolyspora-Bacillus clausii) highly predictive of long-term survivorship in both discovery and validation cohorts. Through human-into-mice fecal microbiota transplantation (FMT) experiments from STS, LTS, or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease.

4.
Am J Clin Nutr ; 110(3): 701-712, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31291462

RESUMO

BACKGROUND: Despite tremendous interest in modulating the microbiome to improve health, the association between diet and the colonic mucosa-associated gut microbiome in healthy individuals has not been examined. OBJECTIVE: To investigate the associations between Healthy Eating Index (HEI)-2005 and the colonic mucosa-associated microbiota. METHODS: In this cross-sectional observational study, we analyzed bacterial community composition and structure using 16S rRNA gene (V4 region) sequencing of 97 colonic mucosal biopsies obtained endoscopically from different colon segments of 34 polyp-free participants. Dietary consumption was ascertained using an FFQ. Differences in α- and ß-diversity and taxonomic relative abundances between the higher and lower score of total HEI and its components were compared, followed by multivariable analyses. RESULTS: The structure of the microbiota significantly differed by the scores for total HEI, total and whole fruits (HEI 1 and HEI 2), whole grains (HEI 6), milk products and soy beverages (HEI 7), and solid fat, alcohol, and added sugar (HEI 12). A lower score for total HEI and HEIs 2, 7, and 12 was associated with significantly lower richness. A lower score for total HEI was associated with significantly reduced relative abundance of Parabacteroides, Roseburia, and Subdoligranulum but higher Fusobacterium. A lower score for HEI 2 was associated with lower Roseburia but higher Bacteroides. A lower score for HEI 7 was associated with lower Faecalibacterium and Fusobacterium but higher Bacteroides. A lower score for HEI 12 was associated with lower Subdoligranulum but higher Escherichia and Fusobacterium (false discovery rate-adjusted P values <0.05). The findings were confirmed by multivariate analysis. Less abundant bacteria such as Alistipes, Odoribacter, Bilophila, and Tyzzerella were also associated with dietary quality. CONCLUSIONS: A lower score for total HEI-2005 was significantly associated with reduced relative abundance of potentially beneficial bacteria but increased potentially harmful bacteria in the colonic mucosa of endoscopically normal individuals.

5.
Nat Commun ; 10(1): 3273, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332169

RESUMO

Severe respiratory syncytial virus (RSV) infection is a major cause of morbidity and mortality in infants <2 years-old. Here we describe that high-fiber diet protects mice from RSV infection. This effect was dependent on intestinal microbiota and production of acetate. Oral administration of acetate mediated interferon-ß (IFN-ß) response by increasing expression of interferon-stimulated genes in the lung. These effects were associated with reduction of viral load and pulmonary inflammation in RSV-infected mice. Type 1 IFN signaling via the IFN-1 receptor (IFNAR) was essential for acetate antiviral activity in pulmonary epithelial cell lines and for the acetate protective effect in RSV-infected mice. Activation of Gpr43 in pulmonary epithelial cells reduced virus-induced cytotoxicity and promoted antiviral effects through IFN-ß response. The effect of acetate on RSV infection was abolished in Gpr43-/- mice. Our findings reveal antiviral effects of acetate involving IFN-ß in lung epithelial cells and engagement of GPR43 and IFNAR.

6.
PLoS One ; 14(6): e0216557, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31188837

RESUMO

BACKGROUND: Understanding the role of the gut microbiome is pivotal for the future development of therapies for the prevention and management of autoimmune conditions such as type 1 diabetes when sampling during early life may be particularly important. The current standard methods for collecting gut microbiome samples for research is to extract fresh samples or freeze samples immediately after collection. This is often impractical however for population-based studies. The aim of this study was to determine the optimal method for the stabilization of stool bacterial DNA obtained from nappies and transported by post in ambient conditions to the research centre for a national birth cohort study. METHODS: Four methods to collect samples were compared to immediate freezing of samples: 1) collecting faeces onto a swab which was immediately frozen, 2) using a commercially available kit with stabilisation solution (OMNIgene•GUT kit) at ambient temperature, 3) collecting onto a swab and 4) collecting into a sterile plain tube. Samples 3) and 4) were returned to the laboratory by post at ambient temperatures. A Bland Altman analysis was used to assess the agreement between the different methods and the frozen standard. RESULTS: Stool samples were collected by parents. For samples transported in ambient conditions, the limits of agreement showed that the OMNIgene•GUT kit had the narrowest 95% limits of agreement with the frozen standard as measured by the number of operational taxonomic units and the Shannon diversity index. CONCLUSIONS: All methods assessed for preserving samples collected from nappies at a distance and delivered by post for gut microbiome analysis showed variation / disagreement from the frozen standard. Overall, the OMNIgene•GUT kit preserved the samples with minimal changes compared to other methods and was practical for parents to use.

7.
J Virol Methods ; 271: 113677, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31195032

RESUMO

Dengue virus (DENV) is the causative agent of one of the most important febrile illnesses worldwide. Four DENV serotypes are responsible for a broad clinical spectrum of the disease. Positive controls are costly and required for the validation of molecular test results of DENV serotyping. In this study, we describe the in silico design of the qDENV-Control plasmid with the target sequences to oligonucleotides and probes widely used for DENV serotyping, and the subsequent production of qDENV Control RNA by T7-driven run-off in vitro transcription. The qDENV Control RNA was successfully used to validate the positive and negative DENV serotyping results, allowing its incorporation in routine in-house protocols for virologic surveillance. This Control RNA allowed the absolute quantification of viral RNA copies from unknown samples as required in several fundamental studies.

8.
Am J Perinatol ; 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31242511

RESUMO

OBJECTIVE: This article determines the differences in the distal gut and vaginal microbiome in African American (AA) women by prepregnancy body mass index and gestational weight gain (GWG) comparing women with and without obesity and by obesity class. STUDY DESIGN: We prospectively sampled the vaginal and distal gut microbiome in pregnant AA women at two time points during pregnancy. Samples were analyzed using high-throughput sequencing of the V4 region of the 16S ribosomal ribonucleic acid gene. RESULTS: Distinct differences in vaginal and distal gut α-diversity were observed at time point 1 between women with and without obesity by total GWG. Significant differences in distal gut ß-diversity were also found at time point 1 in obese women by GWG. Within the Bacteroides genus, a significant association was observed by total GWG among obese women which was absent in nonobese women. Women with class III obesity who experienced low GWG had the lowest abundance of distal gut Bacteroides and appreciably higher relative abundance of a consortia of vaginal taxa including Atopobium, Gardnerella, Prevotella, and Sneathia. CONCLUSION: These results contribute new evidence showing that GWG in combination with obesity and obesity class is associated with an altered distal gut and vaginal composition early in pregnancy among AA women.

9.
Thorax ; 74(6): 592-599, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31076501

RESUMO

BACKGROUND: Emerging evidence shows that airway microbiota may modulate local immune responses, thereby contributing to the susceptibility and severity of acute respiratory infections (ARIs). However, there are little data on the longitudinal relationships between airway microbiota and susceptibility to ARIs in children. OBJECTIVE: We aimed to investigate the association of early nasal microbiota and the subsequent risk of ARIs during the first years of life. METHODS: In this prospective population-based birth-cohort study in Finland, we followed 839 healthy infants for ARIs from birth to age 24 months. Nasal microbiota was tested using 16S rRNA gene sequencing at age 2 months. We applied an unsupervised clustering approach to identify early nasal microbiota profiles, and examined the association of profiles with the rate of ARIs during age 2-24 months. RESULTS: We identified five nasal microbiota profiles dominated by Moraxella, Streptococcus, Dolosigranulum, Staphylococcus and Corynebacteriaceae, respectively. Incidence rate of ARIs was highest in children with an early Moraxella-dominant profile and lowest in those with a Corynebacteriaceae-dominant profile (738 vs 552/100 children years; unadjusted incidence rate ratio (IRR), 1.34; 95% CI 1.16 to 1.54; p < 0.001). After adjusting for nine potential confounders, the Moraxella-dominant profile-ARI association persisted (adjusted IRR (aIRR), 1.19; 95% CI 1.04 to 1.37; p = 0.01). Similarly, the incidence rate of lower respiratory tract infections (a subset of all ARIs) was significantly higher in children with an early Moraxella-dominant profile (aIRR, 2.79; 95% CI 1.04 to 8.09; p = 0.04). CONCLUSION: Moraxella-dominant nasal microbiota profile in early infancy was associated with an increased rate of ARIs during the first 2 years of life.


Assuntos
Microbiota , Cavidade Nasal/microbiologia , Infecções Respiratórias/microbiologia , Doença Aguda , Corynebacterium/isolamento & purificação , Suscetibilidade a Doenças , Feminino , Finlândia/epidemiologia , Bactérias Gram-Positivas/isolamento & purificação , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Moraxella/isolamento & purificação , Estudos Prospectivos , Infecções Respiratórias/epidemiologia , Staphylococcus/isolamento & purificação , Streptococcus/isolamento & purificação
10.
Virol J ; 16(1): 62, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068191

RESUMO

Dengue is hyperendemic in Colombia, where a cyclic behavior of serotype replacement leading to periodic epidemics has been observed for decades. This level of endemicity favors accumulation of dengue virus genetic diversity and could be linked to disease outcome. To assess the genetic diversity of dengue virus type 2 in Colombia, we sequenced the envelope gene of 24 virus isolates from acute cases of dengue or severe dengue fever during the period 2013-2016. The phylogenetic analysis revealed the circulation of the Asian-American genotype of dengue virus type 2 in Colombia during that period, the intra-genotype variability leading to divergence in two recently circulating lineages with differential geographic distribution, as well as the presence of nonsynonymous substitutions accompanying their emergence and diversification.


Assuntos
Vírus da Dengue/genética , Dengue/virologia , Variação Genética , Genótipo , RNA Viral/sangue , Adolescente , Adulto , Bancos de Espécimes Biológicos , Criança , Pré-Escolar , Colômbia/epidemiologia , Dengue/epidemiologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , RNA Viral/genética , Estudos Retrospectivos , Sorogrupo , Proteínas do Envelope Viral/genética , Adulto Jovem
11.
Nature ; 569(7758): 655-662, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31142855

RESUMO

Inflammatory bowel diseases, which include Crohn's disease and ulcerative colitis, affect several million individuals worldwide. Crohn's disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study's infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi'omics Database ( http://ibdmdb.org ), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases.

12.
Cancers (Basel) ; 11(4)2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974798

RESUMO

Helicobacter pylori (H. pylori) related chronic gastritis is a well-known major etiological factor for gastric cancer development. However, H. pylori-negative gastritis (HpN) is not well described. We aimed to examine gastric mucosal microbiota in HpN compared to H. pylori-positive gastritis (HpP) and H. pylori-negative non-gastritis group (control). Here, we studied 11 subjects with HpN, 40 with HpP and 24 controls. We performed endoscopy with six gastric biopsies. Comparison groups were defined based on strict histological criteria for the disease and H. pylori diagnosis. We used 16S rRNA gene amplicon sequencing to profile the gastric microbiota according to comparison groups. These results demonstrate that the HpP group had significantly lower bacterial richness by the operational taxonomic unit (OTU) counts, and Shannon and Simpson indices as compared to HpN or controls. The linear discriminant analysis effect size analysis showed the enrichment of Firmicutes, Fusobacteria, Bacteroidetes and Actinobacteria at phylum level in the HpN group. In the age-adjusted multivariate analysis, Streptococcus sp. and Haemophilus parainfluenzae were at a significantly increased risk for HpN (odds ratio 18.9 and 12.3, respectively) based on abundance. Treponema sp. was uniquely found in HpN based on occurrence. In this paper, we conclude that Streptococcus sp., Haemophilus parainfluenzae and Treponema sp. are candidate pathogenic bacterial species for HpN. These results if confirmed may have important clinical implications.

13.
Artigo em Inglês | MEDLINE | ID: mdl-30881924

RESUMO

The oral microbiome has the potential to provide an important symbiotic function in human blood pressure physiology by contributing to the generation of nitric oxide (NO), an essential cardiovascular signaling molecule. NO is produced by the human body via conversion of arginine to NO by endogenous nitric oxide synthase (eNOS) but eNOS activity varies by subject. Oral microbial communities are proposed to supplement host NO production by reducing dietary nitrate to nitrite via bacterial nitrate reductases. Unreduced dietary nitrate is delivered to the oral cavity in saliva, a physiological process termed the enterosalivary circulation of nitrate. Previous studies demonstrated that disruption of enterosalivary circulation via use of oral antiseptics resulted in increases in systolic blood pressure. These previous studies did not include detailed information on the oral health of enrolled subjects. Using 16S rRNA gene sequencing and analysis, we determined whether introduction of chlorhexidine antiseptic mouthwash for 1 week was associated with changes in tongue bacterial communities and resting systolic blood pressure in healthy normotensive individuals with documented oral hygiene behaviors and free of oral disease. Tongue cleaning frequency was a predictor of chlorhexidine-induced changes in systolic blood pressure and tongue microbiome composition. Twice-daily chlorhexidine usage was associated with a significant increase in systolic blood pressure after 1 week of use and recovery from use resulted in an enrichment in nitrate-reducing bacteria on the tongue. Individuals with relatively high levels of bacterial nitrite reductases had lower resting systolic blood pressure. These results further support the concept of a symbiotic oral microbiome contributing to human health via the enterosalivary nitrate-nitrite-NO pathway. These data suggest that management of the tongue microbiome by regular cleaning together with adequate dietary intake of nitrate provide an opportunity for the improvement of resting systolic blood pressure.


Assuntos
Antibacterianos/administração & dosagem , Clorexidina/administração & dosagem , Microbiota/efeitos dos fármacos , Nitratos/metabolismo , Língua/microbiologia , Pressão Sanguínea/efeitos dos fármacos , Análise por Conglomerados , DNA Ribossômico/química , DNA Ribossômico/genética , Voluntários Saudáveis , Humanos , Antissépticos Bucais/administração & dosagem , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA
14.
Gastroenterology ; 157(1): 163-178, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30885780

RESUMO

BACKGROUND & AIMS: The peroxisome proliferator-activated receptor delta (PPARD) regulates cell metabolism, proliferation, and inflammation and has been associated with gastric and other cancers. Villin-positive epithelial cells are a small population of quiescent gastric progenitor cells. We expressed PPARD from a villin promoter to investigate the role of these cells and PPARD in development of gastric cancer. METHODS: We analyzed gastric tissues from mice that express the Ppard (PPARD1 and PPARD2 mice) from a villin promoter, and mice that did not carry this transgene (controls), by histology and immunohistochemistry. We performed cell lineage-tracing experiments and analyzed the microbiomes, chemokine and cytokine production, and immune cells and transcriptomes of stomachs of these mice. We also performed immunohistochemical analysis of PPARD levels in 2 sets of human gastric tissue microarrays. RESULTS: Thirty-eight percent of PPARD mice developed spontaneous, invasive gastric adenocarcinomas, with severe chronic inflammation. Levels of PPARD were increased in human gastric cancer tissues, compared with nontumor tissues, and associated with gastric cancer stage and grade. We found an inverse correlation between level of PPARD in tumor tissue and patient survival time. Gastric microbiomes from PPARD and control mice did not differ significantly. Lineage-tracing experiments identified villin-expressing gastric progenitor cells (VGPCs) as the origin of gastric tumors in PPARD mice. In these mice, PPARD up-regulated CCL20 and CXCL1, which increased infiltration of the gastric mucosa by immune cells. Immune cell production of inflammatory cytokines promoted chronic gastric inflammation and expansion and transformation of VGPCs, leading to tumorigenesis. We identified a positive-feedback loop between PPARD and interferon gamma signaling that sustained gastric inflammation to induce VGPC transformation and gastric carcinogenesis. CONCLUSIONS: We found PPARD overexpression in VPGCs to result in inflammation, dysplasia, and tumor formation. PPARD and VGPCs might be therapeutic targets for stomach cancer.


Assuntos
Carcinogênese/genética , Transformação Celular Neoplásica/genética , Citocinas/imunologia , Mucosa Gástrica/metabolismo , Interferon gama/imunologia , Receptores Citoplasmáticos e Nucleares/genética , Células-Tronco/metabolismo , Estômago/imunologia , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Animais , Carcinogênese/imunologia , Linhagem da Célula , Transformação Celular Neoplásica/imunologia , Quimiocina CCL20/metabolismo , Quimiocina CXCL1/metabolismo , Quimiocinas , Retroalimentação Fisiológica , Perfilação da Expressão Gênica , Inflamação , Camundongos , Microbiota/imunologia , Proteínas dos Microfilamentos/genética , Células-Tronco/imunologia , Estômago/microbiologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia
15.
Nutrients ; 11(3)2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30871224

RESUMO

One carbon (1C) metabolism nutrients influence epigenetic regulation and they are supplied by diet and synthesized by gut microbiota. We examined the association between dietary consumption of methyl donors (methionine, betaine and choline) and B vitamins (folate, B2, B6, and B12) and the community composition and structure of the colonic mucosa-associated gut microbiota determined by 16S rRNA gene sequencing in 97 colonic biopsies of 35 men. We used the food frequency questionnaire to assess daily consumption of nutrients, and the UPARSE and SILVA databases for operational taxonomic unit classification. The difference in bacterial diversity and taxonomic relative abundance were compared between low versus high consumption of these nutrients. False discover rate (FDR) adjusted p value < 0.05 indicated statistical significance. The bacterial richness and composition differed significantly by the consumption of folate and B vitamins (p < 0.001). Compared with higher consumption, a lower consumption of these nutrients was associated with a lower abundance of Akkermansia (folate), Roseburia (vitamin B2), and Faecalibacterium (vitamins B2, B6, and B12) but a higher abundance of Erysipelatoclostridium (vitamin B2) (FDR p values < 0.05). The community composition and structure of the colonic bacteria differed significantly by dietary consumption of folate and B vitamins.


Assuntos
Bactérias/metabolismo , Colo/microbiologia , Dieta , Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Idoso , Estudos Transversais , Análise de Alimentos , Microbioma Gastrointestinal/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
16.
Innate Immun ; 25(2): 132-143, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30774010

RESUMO

Crohn's disease (CD) is a chronic disorder of the gastrointestinal tract characterized by inflammation and intestinal epithelial injury. Loss of function mutations in the intracellular bacterial sensor NOD2 are major risk factors for the development of CD. In the absence of robust bacterial recognition by NOD2 an inflammatory cascade is initiated through alternative PRRs leading to CD. In the present study, MCC950, a specific small molecule inhibitor of NLR pyrin domain-containing protein 3 (NLRP3), abrogated dextran sodium sulfate (DSS)-induced intestinal inflammation in Nod2-/- mice. NLRP3 inflammasome formation was observed at a higher rate in NOD2-deficient small intestinal lamina propria cells after insult by DSS. NLRP3 complex formation led to an increase in IL-1ß secretion in both the small intestine and colon of Nod2ko mice. This increase in IL-1ß secretion in the intestine was attenuated by MCC950 leading to decreased disease severity in Nod2ko mice. Our work suggests that NLRP3 inflammasome activation may be a key driver of intestinal inflammation in the absence of functional NOD2. NLRP3 pathway inhibition can prevent intestinal inflammation in the absence of robust NOD2 signaling.

17.
Cell Host Microbe ; 25(2): 285-299.e8, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30763538

RESUMO

Bacteriophages are the most abundant members of the microbiota and have the potential to shape gut bacterial communities. Changes to bacteriophage composition are associated with disease, but how phages impact mammalian health remains unclear. We noted an induction of host immunity when experimentally treating bacterially driven cancer, leading us to test whether bacteriophages alter immune responses. Treating germ-free mice with bacteriophages leads to immune cell expansion in the gut. Lactobacillus, Escherichia, and Bacteroides bacteriophages and phage DNA stimulated IFN-γ via the nucleotide-sensing receptor TLR9. The resultant immune responses were both phage and bacteria specific. Additionally, increasing bacteriophage levels exacerbated colitis via TLR9 and IFN-γ. Similarly, ulcerative colitis (UC) patients responsive to fecal microbiota transplantation (FMT) have reduced phages compared to non-responders, and mucosal IFN-γ positively correlates with bacteriophage levels. Bacteriophages from active UC patients induced more IFN-γ compared to healthy individuals. Collectively, these results indicate that bacteriophages can alter mucosal immunity to impact mammalian health.


Assuntos
Bactérias/virologia , Bacteriófagos , Colite Ulcerativa/imunologia , Colite Ulcerativa/microbiologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/microbiologia , Microbioma Gastrointestinal , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Colite Ulcerativa/patologia , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Transplante de Microbiota Fecal , Humanos , Interferon gama/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Projetos Piloto , Estudos Prospectivos , Organismos Livres de Patógenos Específicos
18.
Mol Nutr Food Res ; 63(8): e1801064, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30667580

RESUMO

SCOPE: The effects of green tea polyphenols, Polyphenon E (PPE), and black tea polyphenols, theaflavins (TFs), on gut microbiota and development of diabetes in db/db mice are investigated and compared. METHODS AND RESULTS: Supplementation of PPE (0.1%) in the diet of female db/db mice for 7 weeks decreases fasting blood glucose levels and mesenteric fat while increasing the serum level of insulin, possibly through protection against ß-cell damage. However, TFs are less or not effective. Microbiome analysis through 16S rRNA gene sequencing shows that PPE and TFs treatments significantly alter the bacterial community structure in the cecum and colon, but not in the ileum. The key bacterial phylotypes responding to the treatments are then clustered into 11 co-abundance groups (CAGs). CAGs 6 and 7, significantly increased by PPE but not by TFs, are negatively associated with blood glucose levels. The operational taxonomic units in these CAGs are from two different phyla, Firmicutes and Bacteroidetes. CAG 10, decreased by PPE and TFs, is positively associated with blood glucose levels. CONCLUSION: Gut microbiota respond to tea polyphenol treatments as CAGs instead of taxa. Some of the CAGs associated with the blood glucose lowering effect are enriched by PPE, but not TFs.


Assuntos
Glicemia/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Polifenóis/farmacologia , Chá/química , Animais , Biflavonoides/farmacologia , Peso Corporal/efeitos dos fármacos , Catequina/análogos & derivados , Catequina/farmacologia , Feminino , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/fisiologia , Hipoglicemiantes/farmacologia , Insulina/sangue , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/patologia , Camundongos Mutantes , Tamanho do Órgão/efeitos dos fármacos , RNA Ribossômico 16S
19.
J Infect Dis ; 219(12): 2005-2014, 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-30629185

RESUMO

BACKGROUND: Emerging evidence suggests relationships between the nasopharyngeal metabolome and both the microbiota and severity of bronchiolitis. However, the influence of host systemic metabolism on disease pathobiology remains unclear. We aimed to examine metabolome profiles and their association with more-severe disease, defined by use of positive pressure ventilation (PPV), in infants hospitalized for bronchiolitis. METHODS: In 140 infants with bronchiolitis, metabolomic profiling was performed on serum; samples from 70 were in a training data set, and samples from 70 were in an independent test data set. We also profiled the nasopharyngeal airway microbiota and examined its association with the serum metabolites. RESULTS: Serum metabolome profiles differed by bronchiolitis severity (P < .001). In total, 20 metabolites in the training data set were significantly associated with the risk of PPV, of which 18 remained significant following adjustment for confounders (false-discovery rate [FDR], < 0.10). Phosphatidylcholine metabolites were associated with higher risks of PPV use, while metabolites from the plasmalogen subpathway were associated with lower risks. The test data set validated these findings (FDR < 0.05). Streptococcus abundance was positively associated with metabolites that are associated with higher risks of PPV. CONCLUSIONS: Serum metabolomic signatures were associated with both the nasopharyngeal microbiota and the severity of bronchiolitis. Our findings advance research into the complex interrelations between the airway microbiome, host systemic response, and pathobiology of bronchiolitis.

20.
Nat Commun ; 9(1): 5010, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30479342

RESUMO

Neonatal rotavirus infections are predominantly asymptomatic. While an association with gastrointestinal symptoms has been described in some settings, factors influencing differences in clinical presentation are not well understood. Using multidisciplinary approaches, we show that a complex interplay between human milk oligosaccharides (HMOs), milk microbiome, and infant gut microbiome impacts neonatal rotavirus infections. Validating in vitro studies where HMOs are not decoy receptors for neonatal strain G10P[11], population studies show significantly higher levels of Lacto-N-tetraose (LNT), 2'-fucosyllactose (2'FL), and 6'-siallylactose (6'SL) in milk from mothers of rotavirus-positive neonates with gastrointestinal symptoms. Further, these HMOs correlate with abundance of Enterobacter/Klebsiella in maternal milk and infant stool. Specific HMOs also improve the infectivity of a neonatal strain-derived rotavirus vaccine. This study provides molecular and translational insight into host factors influencing neonatal rotavirus infections and identifies maternal components that could promote the performance of live, attenuated rotavirus vaccines.


Assuntos
Microbioma Gastrointestinal , Leite Humano/química , Leite Humano/microbiologia , Oligossacarídeos/metabolismo , Infecções por Rotavirus/microbiologia , Fezes/microbiologia , Humanos , Recém-Nascido , Rotavirus/patogenicidade , Infecções por Rotavirus/imunologia , Vacinas contra Rotavirus/imunologia
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