RESUMEN
Antibiotics, among the most used medications in children, affect gut microbiome communities and metabolic functions. These changes in microbiota structure can impact host immunity. We hypothesized that early-life microbiome alterations would lead to increased susceptibility to allergy and asthma. To test this, mouse pups between postnatal days 5-9 were orally exposed to water (control) or to therapeutic doses of azithromycin or amoxicillin. Later in life, these mice were sensitized and challenged with a model allergen, house dust mite (HDM), or saline. Mice with early-life azithromycin exposure that were challenged with HDM had increased IgE and IL-13 production by CD4+ T cells compared to unexposed mice; early-life amoxicillin exposure led to fewer abnormalities. To test that the microbiota contained the immunological cues to alter IgE and cytokine production after HDM challenge, germ-free mice were gavaged with fecal samples of the antibiotic-perturbed microbiota. Gavage of adult germ-free mice did not result in altered HDM responses, however, their offspring, which acquired the antibiotic-perturbed microbiota at birth showed elevated IgE levels and CD4+ cytokines in response to HDM, and altered airway reactivity. These studies indicate that early-life microbiota composition can heighten allergen-driven Th2/Th17 immune pathways and airway responses in an age-dependent manner.
Asunto(s)
Alérgenos , Microbioma Gastrointestinal , Amoxicilina , Animales , Antibacterianos , Azitromicina , Citocinas/metabolismo , Inmunidad , Inmunoglobulina E , Ratones , Pyroglyphidae , Células Th2RESUMEN
In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs, and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in the stage IIIB-IV tumor-node-metastasis lung cancer group and is associated with poor prognosis, as shown by decreased survival among subjects with early-stage disease (I-IIIA) and worse tumor progression as measured by RECIST scores among subjects with stage IIIB-IV disease. In addition, this lower airway microbiota signature was associated with upregulation of the IL17, PI3K, MAPK, and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL17 inflammatory phenotype, and activation of checkpoint inhibitor markers. SIGNIFICANCE: Multiple lines of investigation have shown that the gut microbiota affects host immune response to immunotherapy in cancer. Here, we support that the local airway microbiota modulates the host immune tone in lung cancer, affecting tumor progression and prognosis.See related commentary by Zitvogel and Kroemer, p. 224.This article is highlighted in the In This Issue feature, p. 211.
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Adenocarcinoma/mortalidad , Disbiosis/complicaciones , Neoplasias Pulmonares/mortalidad , Adenocarcinoma/complicaciones , Adenocarcinoma/microbiología , Adenocarcinoma/secundario , Animales , Estudios de Cohortes , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/microbiología , Neoplasias Pulmonares/patología , Ratones , Ratones Transgénicos , Microbiota , Metástasis de la Neoplasia , Estadificación de Neoplasias , New York , Modelos de Riesgos Proporcionales , Análisis de SupervivenciaRESUMEN
BACKGROUND AND AIM: The metabolic syndrome (MetS) is a pathological condition comprised of abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. It has become a major threat globally, resulting in rapidly increasing rates of diabetes, coronary heart disease, and stroke. The polyphenol resveratrol (RES) is believed to improve glucose homeostasis and insulin resistance by activating sirtuin, which acetylates and coactivates downstream targets and affects glucose and lipid homeostasis in the liver, insulin secretion in the pancreas, and glucose uptake in skeletal muscle. We studied the effects of RES on insulin resistance, glucose homeostasis, and concomitant effects on adipose tissue metabolism and fecal microbiota in insulin-resistant subjects with the MetS. METHODS: A total of 28 obese men with the MetS were studied during a 35-day stay in the Rockefeller University Hospital metabolic unit. Subjects were randomized to receive RES 1 g orally twice daily or placebo while kept weight stable and consuming a western-style diet. At baseline, and after 30 days of RES or placebo administration, subjects underwent testing that included a euglycemic, hyperinsulinemic clamp, 2-h oral glucose tolerance test (GTT), resting energy expenditure, daily blood pressure monitoring, abdominal adipose tissue biopsy, and fecal and blood collections. RESULTS: RES induced no changes in insulin resistance but reduced the 120-min time point and the area under the curve for glucose concentration in the 2-h GTT. In post-hoc analysis, Caucasian subjects showed a significant improvement in insulin sensitivity and glucose homeostasis after GTT, whereas non-Caucasians showed no similar effects. Levels of fasting plasma RES and its primary metabolite dihydroresveratrol were variable and did not explain the racial differences in glucose homeostasis. RES administration to Caucasian subjects leads to an increase in several taxa including Akkermansia muciniphila. CONCLUSIONS: RES 2 g administered orally to obese men with MetS and insulin resistance marginally altered glucose homeostasis. However, in a small group of Caucasians, insulin resistance and glucose homeostasis improved. No concomitant changes in adipose tissue metabolism occurred, but fecal microbiota showed RES-induced changes. RELEVANCE FOR PATIENTS: The MetS increases the risk of diabetes, heart disease, and stroke. A major component of the syndrome is insulin resistance, resulting in systemic inflammation and hyperinsulinemia. The primary treatment consists of lifestyle changes, improved diet, and increased physical activity. This is often unsuccessful. In this study, RES was well tolerated. In Caucasian men, it significantly improved insulin sensitivity and glucose homeostasis. Similar results were found in studies that consisted exclusively of Caucasian men. However, RES presents a novel addition to the current treatment of the MetS and its sequelae.
RESUMEN
Despite that the human gastrointestinal tract is the most populated ecological niche by bacteria in the human body, much is still unknown about its characteristics. This site is highly susceptible to the effects of many external factors that may affect in the quality and the quantity of the microbiome. Specific factors such as diet, personal hygiene, pharmacological drugs and the use of antibiotics can produce a significant impact on the gut microbiota. The effect of these factors is more relevant early in life, when the gut microbiota has not yet fully established. In this review, we discussed the effect of type and doses of the antibiotics on the gut microbiota and what the major consequences in the use and abuse of these antimicrobial agents.
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Antibacterianos/efectos adversos , Microbioma Gastrointestinal/efectos de los fármacos , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/microbiología , Dieta , Humanos , Obesidad/inmunología , Obesidad/microbiología , Factores de RiesgoRESUMEN
Broad-spectrum antibiotics are frequently prescribed to children. Early childhood represents a dynamic period for the intestinal microbial ecosystem, which is readily shaped by environmental cues; antibiotic-induced disruption of this sensitive community may have long-lasting host consequences. Here we demonstrate that a single pulsed macrolide antibiotic treatment (PAT) course early in life is sufficient to lead to durable alterations to the murine intestinal microbiota, ileal gene expression, specific intestinal T-cell populations, and secretory IgA expression. A PAT-perturbed microbial community is necessary for host effects and sufficient to transfer delayed secretory IgA expression. Additionally, early-life antibiotic exposure has lasting and transferable effects on microbial community network topology. Our results indicate that a single early-life macrolide course can alter the microbiota and modulate host immune phenotypes that persist long after exposure has ceased.High or multiple doses of macrolide antibiotics, when given early in life, can perturb the metabolic and immunological development of lab mice. Here, Ruiz et al. show that even a single macrolide course, given early in life, leads to long-lasting changes in the gut microbiota and immune system of mice.
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Antibacterianos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Sistema Inmunológico/efectos de los fármacos , Tilosina/farmacología , Animales , Animales Recién Nacidos , Antibacterianos/administración & dosificación , Femenino , Microbioma Gastrointestinal/genética , Regulación de la Expresión Génica/efectos de los fármacos , Íleon/efectos de los fármacos , Íleon/inmunología , Inmunoglobulina A/metabolismo , Masculino , Ratones Endogámicos C57BL , Tilosina/administración & dosificaciónRESUMEN
To better characterize murine intestinal microbiota, a large number (187) of Gram-positive-staining, rod- and coccoid-shaped, and facultatively or strictly anaerobic bacteria were isolated from small and large intestinal contents from mice. Based on 16S rRNA gene sequencing, a total 115 isolates formed three phylogenetically distinct clusters located within the family Erysipelotrichaceae. Group 1, as represented by strain NYU-BL-A3T, was most closely related to Allobaculum stercoricanis, with 16S rRNA gene sequence similarity values of 87.7â%. A second group, represented by NYU-BL-A4T, was most closely related to Faecalibaculum rodentium, with 86.6â% 16S rRNA gene sequence similarity. A third group had a nearly identical 16S rRNA gene sequence (99.9â%) compared with the recently described Faecalibaculum rodentium, also recovered from a laboratory mouse; however, this strain had a few differences in biochemical characteristics, which are detailed in an emended description. The predominant (>10â%) cellular fatty acids of strain NYU-BL-A3T were C16â:â0 and C18â:â0, and those of strain NYU-BL-A4T were C10â:â0, C16â:â0, C18â:â0 and C18â:â1ω9c. The two groups could also be distinguished by multiple biochemical reactions, with the group represented by NYU-BL-A4T being considerably more active. Based on phylogenetic, biochemical and chemotaxonomic criteria, two novel genera are proposed, Ileibacterium valens gen. nov., sp. nov. with NYU-BL-A3T (=ATCC TSD-63T=DSM 103668T) as the type strain and Dubosiella newyorkensis gen. nov., sp. nov. with NYU-BL-A4T (=ATCC TSD-64T=DSM 103457T) as the type strain.
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Faecalibacterium/clasificación , Intestinos/microbiología , Ratones/microbiología , Filogenia , Tenericutes/clasificación , Animales , Técnicas de Tipificación Bacteriana , Composición de Base , ADN Bacteriano/genética , Ácidos Grasos/química , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADN , Tenericutes/genética , Tenericutes/aislamiento & purificaciónRESUMEN
BACKGROUND: Helicobacter pylori colonizes the human stomach of approximately 50% of the world's population, and increases the risk of several gastric diseases. The goal of this study is to compare the gastric microbiota in pediatric patients with and without H. pylori colonization. METHODS: We studied 51 children who underwent gastric endoscopy because of dyspeptic symptoms (18 H. pylori positive and 33 negative). Gastric biopsies were obtained for rapid urease test, culture, histology and DNA extraction. H. pylori was quantified by quantitative polymerase chain reaction and the gastric microbiome studied by V4-16S ribosomal RNA gene high-throughput sequencing. RESULTS: Bacterial richness and diversity of H. pylori-positive specimens were lower than those of negative, and both groups were clearly separated according to beta diversity. Taxonomic analysis confirmed that H. pylori-positive subjects had a higher relative abundance of Helicobacter genus (66.3%) than H. pylori-negative subjects (0.45%). Four phyla (proteobacteria, bacteroidetes, firmicutes and actinobacteria) accounted for >97% of all reads in both groups. Within proteobacteria, gamma- and betaproteobacteria were the most abundant for H. pylori-negative patients, whereas epsilonproteobacteria was for H. pylori positive. H. pylori-positive patients were associated with low body mass index. In the group of underweight patients (body mass index, <18.5), there were 46.1% of H. pylori-positive patients compared with 24% in the nonunderweight group (P = 0.049). Patients with active superficial gastritis in H. pylori-positive patients had the lowest alpha diversity (P = 0.035). CONCLUSIONS: We characterized the gastric microbiota for the first time in children with and without H. pylori and observed that when H. pylori is present, it tends to dominate the microbial community. In the H. pylori-negative patients, there was more relative abundance of gammaproteobacteria, betaproteobacteria, bacteroidia and clostridia classes and a higher bacterial richness and diversity.
Asunto(s)
Microbioma Gastrointestinal/genética , Infecciones por Helicobacter/microbiología , Helicobacter pylori/genética , Estómago/microbiología , Adolescente , Bacterias/clasificación , Bacterias/genética , Niño , Preescolar , Femenino , Helicobacter pylori/clasificación , Humanos , Lactante , Masculino , Proyectos PilotoRESUMEN
BACKGROUND: More than 50 years after the discovery of antibiotics, bacterial infections have decreased substantially; however, antibiotics also may have negative effects such as increasing susceptibility to pathogens. An intact microbiome is an important line of defense against pathogens. We sought to determine the effect of orally administered antibiotics both on susceptibility to pathogens and on impact to the microbiome. We studied Campylobacter jejuni, one of the most common causes of human diarrhea, and Acinetobacter baumannii, which causes wound infections. We examined the effects of antibiotic treatment on the susceptibility of mice to those pathogens as well as their influence on the mouse gut microbiome. RESULTS: In C57/BL6 mice models, we explored the effects of pathogen challenge, and antibiotic treatment on the intestinal microbiota. Mice were treated with either ciprofloxacin, penicillin, or water (control) for a 5-day period followed by a 5-day washout period prior to oral challenge with C. jejuni or A. baumannii to assess antibiotic effects on colonization susceptibility. Mice were successfully colonized with C. jejuni more than 118 days, but only transiently with A. baumannii. These challenges did not lead to any major effects on the composition of the gut microbiota. Although antibiotic pre-treatment did not modify pathogen colonization, it affected richness and community structure of the gut microbiome. However, the antibiotic dysbiosis was significantly reduced by pathogen challenge. CONCLUSIONS: We conclude that despite gut microbiota disturbance, susceptibility to gut colonization by these pathogens was unchanged. The major gut microbiome disturbance produced by antibiotic treatment may be reduced by colonization with specific microbial taxa.
RESUMEN
Eosinophilic esophagitis (EE) is an allergic inflammatory condition of the esophagus and is characterized by dense eosinophilic infiltration of the esophagus. There has been a dramatic increase in the diagnosis of EE in Western countries in recent years; however, in Japan, there are very few reports of EE. We present a rare case of EE in a 70-year-old Japanese woman, who had dysphasia for 2 years, but which worsened over a 6-month period. Laboratory examinations showed peripheral eosinophilia (1279/µl). Significant thickening of the esophageal wall was observed on computed tomography scan and many circular rings appeared when an esophagogastroduodenoscopy was carried out. From these circular rings, EE was suspected and a biopsy was then taken from the esophagus. As the histologic findings from the esophageal biopsy showed that >25 eosinophils existed per high-power field, the patient was diagnosed with EE. Oral corticosteroid (prednisolone 30 mg/day) therapy was administered and after 3 days of treatment her symptoms almost disappeared. EE needs to be considered as a differential diagnosis if patients with non-erosive reflux disease have dysphagia but do not respond to high-dose proton pump inhibitor therapy.
RESUMEN
Besides various gastroduodenal diseases, Helicobacter pylori infection may be involved in autoimmune disorders like rheumatoid arthritis (RA) or idiopathic thrombocytopenic purpura. Such autoimmune disorders are often associated with autoreactive antibodies produced by B-1 cells, a subpopulation of B lymphocytes. These B-1 cells are mainly located in the pleural cavity or mucosal compartment. The existence of H. pylori urease-specific immunoglobulin A (IgA)-producing B cells in the mucosal compartment and of their specific IgM in the sera of acutely infected volunteers suggests the possibility that urease stimulates mucosal innate immune responses. Here, we show for the first time that purified H. pylori urease predominantly stimulates the B-1-cell population rather than B-2 cells, which produce antigen-specific conventional antibodies among splenic B220(+) B cells. The fact that such stimulation of B-1 cells was not affected by the addition of polymyxin B indicates that the effect of purified H. pylori urease was not due to the contamination with bacterial lipopolysaccharide. Furthermore, the production of various B-1-cell-related autoreactive antibodies such as IgM-type rheumatoid factor, anti-single-stranded DNA antibody, and anti-phosphatidyl choline antibody was observed when the splenic B cells were stimulated with purified H. pylori urease in vitro. These findings suggest that H. pylori components, urease in particular, may be among the environmental triggers that initiate various autoimmune diseases via producing autoreactive antibodies through the activation of B-1 cells. The findings shown here offer important new insights into the pathogenesis of autoimmune disorders related to H. pylori infection.
Asunto(s)
Autoanticuerpos/biosíntesis , Linfocitos B/inmunología , Linfocitos B/microbiología , Helicobacter pylori/enzimología , Helicobacter pylori/inmunología , Activación de Linfocitos/inmunología , Ureasa/fisiología , Animales , Enfermedades Autoinmunes/enzimología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/microbiología , Linfocitos B/metabolismo , Proliferación Celular , Femenino , Ratones , Ratones Endogámicos BALB C , Ureasa/aislamiento & purificaciónRESUMEN
Gastric colonization of Helicobacter pylori (H. pylori) occurs in a very early age via infected mothers having H. pylori-specific IgG antibodies that would be transplacentally transferred to infants. In addition, H. pylori urease-specific IgG was associated with chronic gastric atrophy and post-immunization gastritis is usually correlated with a strong local IgG response. These findings indicate that H. pylori-specific IgG antibodies, in particular its urease-specific IgG, may induce unfavorable influence on host resistance against H. pylori. Here, we show that we have found a unique H. pylori urease-specific IgG monoclonal antibody (MAb), termed S3, recognizing the conformational structure of the small subunit Ure-A, which enhanced the urease enzymatic activity. Such enhancement of the H. pylori urease activity induced by 1 microg of S3 was almost completely cancelled by simultaneously added the same amount of L2 MAb, which has a strong and specific inhibitory activity against H. pylori urease and recognizes a liner epitope of 8-mer peptide (F8: SIKEDVQF) within its large subunit Ure-B (Infect. Immun. 69: 6597, 2001). Intravenous pre-administration of purified S3 into BALB/c mice showed significant augmentation for gastric colonization with the susceptible strain Sydney Strain-1 (SS-1). To our knowledge, this is the first demonstration that a H. pylori urease-specific IgG MAb induced an augmentation of their gastric colonization in vivo.
Asunto(s)
Helicobacter pylori/enzimología , Helicobacter pylori/inmunología , Ureasa/inmunología , Ureasa/metabolismo , Secuencia de Aminoácidos , Animales , Anticuerpos Antibacterianos/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Especificidad de Anticuerpos , Antígenos Bacterianos/genética , Mapeo Epitopo , Femenino , Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Gastritis/inmunología , Gastritis/microbiología , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/genética , Helicobacter pylori/crecimiento & desarrollo , Inmunoglobulina G/administración & dosificación , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Ureasa/genéticaRESUMEN
BACKGROUND: Endogenous and exogenous prostaglandins (PGs) have been shown to contribute to reducing the gastric injury caused by irritants given subsequently. The aim of this study was to clarify whether cyclooxygenase-2 (COX-2) protein induced by pretreatment was involved in the prevention of subsequent ethanol-caused gastric injury in mice. METHODS: Mice were pretreated with acidified ethanol or saline and then COX-2 protein expression in the stomach was immunohistochemically determined every 8h. Mice were administered 95% ethanol 24h after the acidified ethanol pretreatment, and gastric mucosal damage was evaluated macroscopically and histologically. The effects of NS-398 or indomethacin on the 95% ethanol-caused damage were also examined. RESULTS: Acidified ethanol pretreatment induced COX-2 protein expression in lamina propria macrophages of the gastric mucosa, with a peak level 24h after the pretreatment. The 95% ethanol treatment caused gastric mucosal damage. The degree of the damage was not different between mice pretreated with acidified ethanol and those pretreated with saline. However, NS-398 aggravated the ethanol-caused damage only in mice pretreated with acidified ethanol, while indomethacin aggravated the damage, evaluated histologically, irrespective of the pretreatment. CONCLUSIONS: Pretreatment-induced COX-2, in addition to COX-1, seemed to be involved in the defense mechanism through minimizing the damage caused by a subsequent irritant.