RESUMO
Although the impact of host genetics on gut microbial diversity and the abundance of specific taxa is well established1-6, little is known about how host genetics regulates the genetic diversity of gut microorganisms. Here we conducted a meta-analysis of associations between human genetic variation and gut microbial structural variation in 9,015 individuals from four Dutch cohorts. Strikingly, the presence rate of a structural variation segment in Faecalibacterium prausnitzii that harbours an N-acetylgalactosamine (GalNAc) utilization gene cluster is higher in individuals who secrete the type A oligosaccharide antigen terminating in GalNAc, a feature that is jointly determined by human ABO and FUT2 genotypes, and we could replicate this association in a Tanzanian cohort. In vitro experiments demonstrated that GalNAc can be used as the sole carbohydrate source for F. prausnitzii strains that carry the GalNAc-metabolizing pathway. Further in silico and in vitro studies demonstrated that other ABO-associated species can also utilize GalNAc, particularly Collinsella aerofaciens. The GalNAc utilization genes are also associated with the host's cardiometabolic health, particularly in individuals with mucosal A-antigen. Together, the findings of our study demonstrate that genetic associations across the human genome and bacterial metagenome can provide functional insights into the reciprocal host-microbiome relationship.
Assuntos
Bactérias , Microbioma Gastrointestinal , Interações entre Hospedeiro e Microrganismos , Metagenoma , Humanos , Acetilgalactosamina/metabolismo , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Estudos de Coortes , Simulação por Computador , Faecalibacterium prausnitzii/genética , Microbioma Gastrointestinal/genética , Genoma Humano/genética , Genótipo , Interações entre Hospedeiro e Microrganismos/genética , Técnicas In Vitro , Metagenoma/genética , Família Multigênica , Países Baixos , TanzâniaRESUMO
OBJECTIVE: Gut microbiome composition is associated with multiple diseases, but relatively little is known about its relationship with long-term outcome measures. While gut dysbiosis has been linked to mortality risk in the general population, the relationship with overall survival in specific diseases has not been extensively studied. In the current study, we present results from an in-depth analysis of the relationship between gut dysbiosis and all-cause and cause-specific mortality in the setting of solid organ transplant recipients (SOTR). DESIGN: We analysed 1337 metagenomes derived from faecal samples of 766 kidney, 334 liver, 170 lung and 67 heart transplant recipients part of the TransplantLines Biobank and Cohort-a prospective cohort study including extensive phenotype data with 6.5 years of follow-up. To analyze gut dysbiosis, we included an additional 8208 metagenomes from the general population of the same geographical area (northern Netherlands). Multivariable Cox regression and a machine learning algorithm were used to analyse the association between multiple indicators of gut dysbiosis, including individual species abundances, and all-cause and cause-specific mortality. RESULTS: We identified two patterns representing overall microbiome community variation that were associated with both all-cause and cause-specific mortality. The gut microbiome distance between each transplantation recipient to the average of the general population was associated with all-cause mortality and death from infection, malignancy and cardiovascular disease. A multivariable Cox regression on individual species abundances identified 23 bacterial species that were associated with all-cause mortality, and by applying a machine learning algorithm, we identified a balance (a type of log-ratio) consisting of 19 out of the 23 species that were associated with all-cause mortality. CONCLUSION: Gut dysbiosis is consistently associated with mortality in SOTR. Our results support the observations that gut dysbiosis is associated with long-term survival. Since our data do not allow us to infer causality, more preclinical research is needed to understand mechanisms before we can determine whether gut microbiome-directed therapies may be designed to improve long-term outcomes.
RESUMO
OBJECTIVES: The genus Faecalibacterium is one of the most important butyrate producers in the human intestinal tract and has been widely linked to health. Recently, several different species have been described, but still more phylogroups have been identified, suggesting that additional species may exist. Four strains HTF-FT, HTF-128, HTF-75H and HTF-76H, representing two different phylogenetic clusters, are evaluated in this study. METHODS: Phylogenomic analysis was performed using whole-genome sequences and 16S rRNA gene sequences. Chemotaxonomic analysis was done based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Physiological and phenotypical characteristics of these strains were also determined. All characteristics of these strains were compared with other validly published species within the genus Faecalibacterium. RESULTS: On a genomic level, the strains HTF-FT and HTF-128 shared an average nucleotide identity (ANI) of <95.0 % and digital DNA-DNA hybridization (dDDH) of <70.0 with other Faecalibacterium species, while between HTF-FT and HTF-128 the ANI-value was 97.18 % and the dDDH was 76.8 %. HTF-75H and HTF-76H had an ANI and dDDH value of 100 % (99.96 %) and 100 % (99.99 %) respectively. Both HTF-75H and HTF-76H were closely related to Faecalibacterium taiwanense HLW78T. 16S rRNA gene and chemotaxonomic analysis were in accordance with the genomic data, confirming that HTF-FT and HTF-128 represent a novel Faecalibacterium species and HTF-75H and HTF-76H belong to F. taiwanense. CONCLUSIONS: Faecalibacterium strains HTF-FT (=DSM 117771T = NCIMB 15531T) and HTF-128 represent a novel species. The name Faecalibacterium wellingii with HTF-FT as type strain is proposed. Two novel isolates HTF-75H (=DSM 17770 = NCIMB 15530) and HTF-76H are described in this study and belong to the recently described Faecalibacterium taiwanense.
RESUMO
Gastrointestinal mucositis could potentially compromise drug absorption due to functional loss of mucosa and other pathophysiological changes in the gastrointestinal microenvironment. Little is known about this effect on commonly used anti-infectives. This study aimed to explore the association between different stages of gastrointestinal mucositis, drug exposure, and gut microbiota. A prospective, observational pilot study was performed in HSCT patients aged ≥ 18 years receiving anti-infectives orally. Left-over blood samples and fecal swabs were collected from routine clinical care until 14 days after HSCT to analyze drug and citrulline concentrations and to determine the composition of the gut microbiota. 21 patients with a median age of 58 (interquartile range 54-64) years were included with 252 citrulline, 155 ciprofloxacin, 139 fluconazole, and 76 acyclovir concentrations and 48 fecal swabs obtained. Severe gastrointestinal mucositis was observed in all patients. Due to limited data correlation analysis was not done for valacyclovir and fluconazole, however we did observe a weak correlation between ciprofloxacin and citrulline concentrations. This could suggest that underexposure of ciprofloxacin can occur during severe mucositis. A follow-up study using frequent sampling rather than the use of left-over would be required to investigate the relationship between gastrointestinal mucositis, drug exposure, and gut microbiome.
Assuntos
Anti-Infecciosos , Microbioma Gastrointestinal , Mucosite , Humanos , Pessoa de Meia-Idade , Mucosite/induzido quimicamente , Projetos Piloto , Fluconazol/efeitos adversos , Seguimentos , Estudos Prospectivos , Citrulina/farmacologia , Transplante de Células-Tronco , Anti-Infecciosos/efeitos adversos , Ciprofloxacina/efeitos adversosRESUMO
Dystonia is a movement disorder in which patients have involuntary abnormal movements or postures. Non-motor symptoms, such as psychiatric symptoms, sleep problems and fatigue, are common. We hypothesise that the gut microbiome might play a role in the pathophysiology of the (non-)motor symptoms in dystonia via the gut-brain axis. This exploratory study investigates the composition of the gut microbiome in dystonia patients compared to healthy controls. Furthermore, the abundance of neuro-active metabolic pathways, which might be implicated in the (non-)motor symptoms, was investigated. We performed both metagenomic and 16S rRNA sequencing on the stool samples of three subtypes of dystonia (27 cervical dystonia, 20 dopa-responsive dystonia and 24 myoclonus-dystonia patients) and 25 controls. While microbiome alpha and beta diversity was not different between dystonia patients and controls, dystonia patients had higher abundances of Ruminococcus torques and Dorea formicigenerans, and a lower abundance of Butyrivibrio crossotus compared to controls. For those with dystonia, non-motor symptoms and the levels of neurotransmitters in plasma explained the variance in the gut microbiome composition. Several neuro-active metabolic pathways, especially tryptophan degradation, were less abundant in the dystonia patients compared to controls. This suggest that the gut-brain axis might be involved in the pathophysiology of dystonia. Further studies are necessary to confirm our preliminary findings.
Assuntos
Discinesias , Distonia , Distúrbios Distônicos , Microbioma Gastrointestinal , Transtornos Mentais , Humanos , Microbioma Gastrointestinal/genética , RNA Ribossômico 16S/genéticaRESUMO
BACKGROUND: Vancomycin-resistant enterococci (VRE) are successful nosocomial pathogens able to cause hospital outbreaks. In the Netherlands, core-genome MLST (cgMLST) based on short-read sequencing is often used for molecular typing. Long-read sequencing is more rapid and provides useful information about the genome's structural composition but lacks the precision required for SNP-based typing and cgMLST. Here we compared prophages among 50 complete E. faecium genomes belonging to different lineages to explore whether a phage signature would be usable for typing and identifying an outbreak caused by VRE. As a proof of principle, we investigated if long-read sequencing data would allow for identifying phage signatures and thereby outbreak-related isolates. RESULTS: Analysis of complete genome sequences of publicly available isolates showed variation in phage content among different lineages defined by MLST. We identified phage present in multiple STs as well as phages uniquely detected within a single lineage. Next, in silico phage typing was applied to twelve MinION sequenced isolates belonging to two different genetic backgrounds, namely ST117/CT24 and ST80/CT16. Genomic comparisons of the long-read-based assemblies allowed us to correctly identify isolates of the same complex type based on global genome architecture and specific phage signature similarity. CONCLUSIONS: For rapid identification of related VRE isolates, phage content analysis in long-read sequencing data is possible. This allows software development for real-time typing analysis of long-read sequencing data, which will generate results within several hours. Future studies are required to assess the discriminatory power of this method in the investigation of ongoing outbreaks over a longer time period.
Assuntos
Infecção Hospitalar , Enterococcus faecium , Infecções por Bactérias Gram-Positivas , Enterococos Resistentes à Vancomicina , Tipagem de Bacteriófagos , Simulação por Computador , Surtos de Doenças , Enterococcus faecium/genética , Infecções por Bactérias Gram-Positivas/epidemiologia , Humanos , Tipagem de Sequências Multilocus , Vancomicina , Enterococos Resistentes à Vancomicina/genéticaRESUMO
BACKGROUND: The intestinal microbiome in preterm infants differs markedly from term infants. It is unclear whether the microbiome develops over time according to infant specific factors. METHODS: We analysed (clinical) metadata - to identify the main factors influencing the microbiome composition development - and the first meconium and faecal samples til the 4th week via 16 S rRNA amplican sequencing. RESULTS: We included 41 infants (gestational age 25-30 weeks; birth weight 430-990 g. Birth via Caesarean section (CS) was associated with placental insufficiency during pregnancy and lower BW. In meconium samples and in samples from weeks 2 and 3 the abundance of Escherichia and Bacteroides (maternal faecal representatives) were associated with vaginal delivery while Staphylococcus (skin microbiome representative) was associated with CS. Secondly, irrespective of the week of sampling or the mode of birth, a transition was observed as children children gradually increased in weight from a microbiome dominated by Staphylococcus (Bacilli) towards a microbiome dominated by Enterobacteriaceae (Gammaproteobacteria). CONCLUSIONS: Our data show that the mode of delivery affects the meconium microbiome composition. They also suggest that the weight of the infant at the time of sampling is a better predictor for the stage of progression of the intestinal microbiome development/maturation than postconceptional age as it less confounded by various infant-specific factors.
Assuntos
Bactérias/classificação , Biodiversidade , Peso Corporal , Fezes/microbiologia , Microbioma Gastrointestinal/genética , Bactérias/genética , Peso ao Nascer , Humanos , Recém-Nascido , Recém-Nascido Prematuro , RNA Ribossômico 16S/genéticaRESUMO
BACKGROUND: Diarrhea is a well-known side effect of mycophenolic acid (MPA) use in kidney transplant recipients (KTRs). It is unknown whether self-reported diarrhea using the Modified Transplant Symptom Occurrence and Symptom Distress Scale (MTSOSD-59R) corresponds to stool water content and how both relate to MPA usage. METHODS: MTSOSD-59R questionnaires filled out by 700 KTRs from the TransplantLines Biobank and Cohort Study (NCT03272841) were analyzed and compared with stool water content. Stool samples (N = 345) were freeze-dried, and a water content ≥80% was considered diarrhea. RESULTS: Self-perceived diarrhea was reported by 46%, while stool water content ≥80% was present in 23% of KTRs. MPA use was not associated with self-perceived diarrhea (odds ratio(OR) 1.32; 95% confidence interval(CI), 0.87-1.99, p = .2), while it was associated with stool water content ≥80% (OR 2.88; 95%CI, 1.41-5.89, p = .004), independent of potential confounders. Adjustment for prior MPA discontinuation because of severe diarrhea, uncovered an association between MPA use and self-perceived diarrhea (OR 1.80; 95%CI, 1.13-2.89, p = .01). CONCLUSIONS: These results suggest that reporting bias could add to the discrepancy between both methods for diarrhea assessment. We recommend use of objective biomarkers or more extensive questionnaires which assess information on stool frequency and stool consistency, to investigate post-transplantation diarrhea.
Assuntos
Transplante de Rim , Ácido Micofenólico , Estudos de Coortes , Diarreia/induzido quimicamente , Humanos , Imunossupressores , Transplante de Rim/efeitos adversos , Ácido Micofenólico/efeitos adversosRESUMO
Experimental autoimmune encephalomyelitis (EAE) in common marmosets is a translationally relevant model of the chronic neurologic disease multiple sclerosis. Following the introduction of a new dietary supplement in our purpose-bred marmoset colony, the percentage of marmosets in which clinically evident EAE could be induced by sensitization against recombinant human myelin oligodendrocyte glycoprotein in IFA decreased from 100 to 65%. The reduced EAE susceptibility after the dietary change coincided with reduced Callitrichine herpesvirus 3 expression in the colony, an EBV-related γ1-herpesvirus associated with EAE. We then investigated, in a controlled study in marmoset twins, which disease-relevant parameters were affected by the dietary change. The selected twins had been raised on the new diet for at least 12 mo prior to the study. In twin siblings reverted to the original diet 8 wk prior to EAE induction, 100% disease prevalence (eight out of eight) was restored, whereas in siblings remaining on the new diet the EAE prevalence was 75% (six out of eight). Spinal cord demyelination, a classical hallmark of the disease, was significantly lower in new-diet monkeys than in monkeys reverted to the original diet. In new-diet monkeys, the proinflammatory T cell response to recombinant human myelin oligodendrocyte glycoprotein was significantly reduced, and RNA-sequencing revealed reduced apoptosis and enhanced myelination in the brain. Systematic typing of the marmoset gut microbiota using 16S rRNA sequencing demonstrated a unique, Bifidobacteria-dominated composition, which changed after disease induction. In conclusion, targeted dietary intervention exerts positive effects on EAE-related parameters in multiple compartments of the marmoset's gut-immune-CNS axis.
Assuntos
Bifidobacterium/genética , Encéfalo/fisiologia , Células/imunologia , Suplementos Nutricionais , Encefalomielite Autoimune Experimental/dietoterapia , Esclerose Múltipla/dietoterapia , Medula Espinal/patologia , Animais , Apoptose , Callithrix , Células Cultivadas , Doenças Desmielinizantes , Dietoterapia , Modelos Animais de Doenças , Microbioma Gastrointestinal/genética , Herpesvirus Humano 3 , Humanos , Glicoproteína Mielina-Oligodendrócito/imunologia , RNA Ribossômico 16S/genética , Análise de Sequência de RNARESUMO
OBJECTIVE: The aim of the present study is to investigate the association of gut microbiota, depending on treatment method, with the development of colorectal anastomotic leakage (AL). BACKGROUND: AL is a major cause for morbidity and mortality after colorectal surgery, but the mechanism behind this complication still is not fully understood. METHODS: Bacterial DNA was isolated from 123 "donuts" of patients where a stapled colorectal anastomosis was made and was analyzed using 16S MiSeq sequencing. In 63 patients, this anastomosis was covered with a C-seal, a bioresorbable sheath stapled to the anastomosis. RESULTS: In non-C-seal patients, AL development was associated with low microbial diversity (P = 0.002) and correspondingly with a high abundance of the dominant Bacteroidaceae and Lachnospiraceae families (P = 0.008 and 0.010, respectively). In C-seal samples, where AL rates were slightly higher (25% vs 17%), an association with the gut microbiota composition was almost undetectable. Only a few opportunistic pathogenic groups of low abundance were associated with AL in C-seal patients, in particular Prevotella oralis (P = 0.007). CONCLUSIONS: AL in patients without a C-seal can be linked to the intestinal microbiota, in particular with a low microbial diversity and a higher abundance of especially mucin-degrading members of the Bacteroidaceae and Lachnospiraceae families. In C-seal patients, however, it seems that any potential protective benefits or harmful consequences of the gut microbiota composition in regard to wound healing are negated, as progression to AL is independent of the initially dominant bacterial composition.
Assuntos
Fístula Anastomótica/epidemiologia , Bactérias/isolamento & purificação , Colo/cirurgia , Microbioma Gastrointestinal , Muco/microbiologia , Reto/cirurgia , Feminino , Humanos , Cuidados Intraoperatórios , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos TestesRESUMO
OBJECTIVE: Alterations in the microbiota composition of the gastro-intestinal tract are suspected to be involved in the etiopathogenesis of two closely related systemic inflammatory autoimmune diseases: primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE). Our objective was to assess whether alterations in gut and oral microbiota compositions are specific for pSS and SLE. METHODS: 16S ribosomal RNA gene sequencing was performed on fecal samples from 39 pSS patients, 30 SLE patients and 965 individuals from the general population, as well as on buccal swab and oral washing samples from the same pSS and SLE patients. Alpha-diversity, beta-diversity and relative abundance of individual bacteria were used as outcome measures. Multivariate analyses were performed to test associations between individual bacteria and disease phenotype, taking age, sex, body-mass index, proton-pump inhibitor use and sequencing-depth into account as possible confounding factors. RESULTS: Fecal microbiota composition from pSS and SLE patients differed significantly from population controls, but not between pSS and SLE. pSS and SLE patients were characterized by lower bacterial richness, lower Firmicutes/Bacteroidetes ratio and higher relative abundance of Bacteroides species in fecal samples compared with population controls. Oral microbiota composition differed significantly between pSS patients and SLE patients, which could partially be explained by oral dryness in pSS patients. CONCLUSIONS: pSS and SLE patients share similar alterations in gut microbiota composition, distinguishing patients from individuals in the general population, while oral microbiota composition shows disease-specific differences between pSS and SLE patients.
Assuntos
Microbioma Gastrointestinal , Lúpus Eritematoso Sistêmico/etiologia , Microbiota , Mucosa Bucal/microbiologia , Síndrome de Sjogren/etiologia , Adulto , Biodiversidade , Estudos de Casos e Controles , Suscetibilidade a Doenças , Disbiose , Fezes/microbiologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/metabolismo , Masculino , Metagenoma , Metagenômica/métodos , Pessoa de Meia-Idade , Fenótipo , RNA Ribossômico 16S/genética , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/metabolismoRESUMO
Objectives: Environmental factors in the aetiology of primary Sjögren's syndrome (pSS) are largely unknown. Host-microbiome interaction at mucosal surfaces is presumed to be involved in the aetiopathogenesis of pSS. Here, we assessed whether the microbiome of the buccal mucosa is specific for pSS compared with symptom-controls. Methods: The bacterial composition of buccal swab samples from 37 pSS patients, 86 non-SS sicca patients (with similar dryness symptoms to pSS patients, but not fulfilling the classification criteria) and 24 healthy controls (HCs) was determined with 16S rRNA sequencing. Multivariate Association with Linear Models was used to find associations between individual taxa and pSS, taking into account smoking and dental status. Associations were replicated in a general population cohort (n = 103). Results: The buccal mucosa microbiome of pSS and non-SS sicca patients both differed from HCs. A higher Firmicutes/Proteobacteria ratio was characteristic for both pSS and non-SS sicca patients. Disease status (pSS, non-SS sicca, HCs) and salivary secretion rate contributed almost equally to the variation in bacterial composition between individuals (3.8 and 4.3%, respectively). Two taxa were associated with pSS compared with non-SS sicca patients and 19 compared with HCs. When salivary secretion rate was taken into account, no taxon was associated with pSS compared with non-SS sicca. Twelve of the 19 pSS-associated taxa were correlated with salivary secretion. Conclusion: Dysbiosis of the buccal mucosa microbiome in pSS patients resembles that of symptom-controls. The buccal mucosa microbiome in pSS patients is determined by a combination of reduced salivary secretion and disease-specific factors.
Assuntos
Disbiose/microbiologia , Microbiota , Mucosa Bucal/microbiologia , Síndrome de Sjogren/microbiologia , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , RNA Ribossômico 16S , Saliva/microbiologiaRESUMO
The 2017 annual symposium organized by the University Medical Center Groningen in The Netherlands focused on the role of the gut microbiome in human health and disease. Experts from academia and industry examined interactions of prebiotics, probiotics, or vitamins with the gut microbiome in health and disease, the development of the microbiome in early-life and the role of the microbiome on the gut-brain axis. The gut microbiota changes dramatically during pregnancy and intrinsic factors (such as stress), in addition to extrinsic factors (such as diet, and drugs) influence the composition and activity of the gut microbiome throughout life. Microbial metabolites, e.g. short-chain fatty acids affect gut-brain signaling and the immune response. The gut microbiota has a regulatory role on anxiety, mood, cognition and pain which is exerted via the gut-brain axis. Ingestion of prebiotics or probiotics has been used to treat a range of conditions including constipation, allergic reactions and infections in infancy, and IBS. Fecal microbiota transplantation (FMT) highly effective for treating recurrent Clostridium difficile infections. The gut microbiome affects virtually all aspects of human health, but the degree of scientific evidence, the models and technologies and the understanding of mechanisms of action vary considerably from one benefit area to the other. For a clinical practice to be broadly accepted, the mode of action, the therapeutic window, and potential side effects need to thoroughly be investigated. This calls for further coordinated state-of-the art research to better understand and document the human gut microbiome's effects on human health.
Assuntos
Nível de Saúde , Microbiota/fisiologia , Encéfalo/fisiologia , Infecções por Clostridium , Dieta , Ácidos Graxos Voláteis , Feminino , Fermentação , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Humanos , Hipersensibilidade , Imunidade , Doenças Inflamatórias Intestinais , Intestinos/crescimento & desenvolvimento , Intestinos/microbiologia , Países Baixos , Prebióticos/administração & dosagem , Gravidez , Probióticos/administração & dosagem , Transdução de Sinais , Vitaminas/administração & dosagemRESUMO
The microbiota of the gut has many crucial functions in human health. Dysbiosis of the microbiota has been correlated to a large and still increasing number of diseases. Recent studies have mostly focused on analyzing the associations between disease and an aberrant microbiota composition. Functional studies using (in vitro) gut models are required to investigate the precise interactions that occur between specific bacteria (or bacterial mixtures) and gut epithelial cells. As most gut bacteria are obligate or facultative anaerobes, studying their effect on oxygen-requiring human gut epithelial cells is technically challenging. Still, several (anaerobic) bacterial-epithelial co-culture systems have recently been developed that mimic host-microbe interactions occurring in the human gut, including 1) the Transwell "apical anaerobic model of the intestinal epithelial barrier", 2) the Host-Microbiota Interaction (HMI) module, 3) the "Human oxygen-Bacteria anaerobic" (HoxBan) system, 4) the human gut-on-a-chip and 5) the HuMiX model. This review discusses the role of gut microbiota in health and disease and gives an overview of the characteristics and applications of these novel host-microbe co-culture systems.
Assuntos
Técnicas de Cocultura/métodos , Trato Gastrointestinal/microbiologia , Interações Hospedeiro-Patógeno , Modelos Biológicos , Aerobiose , Anaerobiose , HumanosRESUMO
BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or promoting colonisation by pathogens. In this study, we investigated the influence of PPI use on the gut microbiome. METHODS: The gut microbiome composition of 1815 individuals, spanning three cohorts, was assessed by tag sequencing of the 16S rRNA gene. The difference in microbiota composition in PPI users versus non-users was analysed separately in each cohort, followed by a meta-analysis. RESULTS: 211 of the participants were using PPIs at the moment of stool sampling. PPI use is associated with a significant decrease in Shannon's diversity and with changes in 20% of the bacterial taxa (false discovery rate <0.05). Multiple oral bacteria were over-represented in the faecal microbiome of PPI-users, including the genus Rothia (p=9.8×10(-38)). In PPI users we observed a significant increase in bacteria: genera Enterococcus, Streptococcus, Staphylococcus and the potentially pathogenic species Escherichia coli. CONCLUSIONS: The differences between PPI users and non-users observed in this study are consistently associated with changes towards a less healthy gut microbiome. These differences are in line with known changes that predispose to C. difficile infections and can potentially explain the increased risk of enteric infections in PPI users. On a population level, the effects of PPI are more prominent than the effects of antibiotics or other commonly used drugs.
Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Inibidores da Bomba de Prótons/farmacologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Anomalous intestinal microbiota development is supposedly associated with development of necrotizing enterocolitis (NEC). Our aim in this study was to identify the intestinal microbiota of patients at risk for NEC. METHODS: In a prospective trial that investigated prognostic factors for development of NEC in high-risk neonates (NTR4153), 11 NEC cases were gestational age/birthweight matched with controls (ratio of 1:2). Feces were collected twice a week. We used the first feces sample of each patient (meconium), as well as the last 2 feces samples prior to development of NEC. DNA was extracted, and the bacterial 16S rRNA genes were analyzed on a MiSeq sequencer. RESULTS: The presence and abundance of Clostridium perfringens (8.4%) and Bacteroides dorei (0.9%) in meconium were increased in neonates who developed NEC compared with controls (0.1% and 0.2%; both species, P < .001). In post-meconium samples, the abundance of staphylococci became negatively associated with NEC development (P = .1 and P = .01 for consecutive samples); Clostridium perfringens continued to be more prevalent in NEC cases. Early enteral feeding and, in particular, breast milk were correlated with an increase in lactate-producing bacilli in post-meconium samples (ρ = -0.45; P = .004). CONCLUSIONS: A NEC-associated gut microbiota can be identified in meconium samples; C. perfringens continues to be associated with NEC from the first meconium till just before NEC onset. In contrast, in post-meconium, increased numbers of staphylococci were negatively associated with NEC. These findings suggest causality but this causality should be verified in trials of induced infection in animals, targeted antibiotics, and/or probiotics. CLINICAL TRIALS REGISTRATION: CALIFORNIA trial, registered under trial number NTR4153 in the Dutch Trial Registry.
Assuntos
Enterocolite Necrosante/epidemiologia , Enterocolite Necrosante/microbiologia , Microbioma Gastrointestinal , Doenças do Recém-Nascido/epidemiologia , Doenças do Recém-Nascido/microbiologia , Mecônio/microbiologia , Adulto , Cesárea/estatística & dados numéricos , Corioamnionite/epidemiologia , DNA Bacteriano/análise , DNA Bacteriano/genética , Enterocolite Necrosante/mortalidade , Feminino , Humanos , Lactente , Recém-Nascido , Doenças do Recém-Nascido/mortalidade , Masculino , Gravidez , Análise de Componente Principal , Estudos Prospectivos , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Anastomotic leakage (AL) after colorectal surgery is a severe complication, resulting in morbidity, reinterventions, prolonged hospital stay and, in some cases, death. Some technical and patient-related aetiological factors of AL are well established. In many cases, however, none of these factors seem to explain the occurrence of AL. Recent studies suggest that the intestinal microbiome plays a role in wound healing, diabetes and Crohn's disease. The aim of this study was to compare the intestinal microbiota of patients who developed AL with matched patients with healed colorectal anastomoses. METHODS: We investigated the microbiome in the doughnuts collected from 16 patients participating in the C-seal trial. We selected eight patients who developed AL requiring reintervention and eight matched controls without AL. We analysed the bacterial 16S rDNA of both groups with MiSeq sequencing. RESULTS: The abundance of Lachnospiraceae is statistically higher (P = 0.001) in patient group who did develop AL, while microbial diversity levels were higher in the group who did not develop AL (P = 0.037). Body mass index (BMI) was also positively associated with the abundance of the Lachnospiraceae family (P = 0.022). CONCLUSION: A correlation between the bacterial family Lachnospiraceae, low microbial diversity and anastomotic leakage, possibly in association with the BMI, was found. The relative abundance of the Lachnospiraceae family is possibly explained by the higher abundance of mucin-degrading Ruminococci within that family in AL cases (P = 0.011) as is similarly the case in IBD.
Assuntos
Fístula Anastomótica/microbiologia , Colo/microbiologia , Cirurgia Colorretal/efeitos adversos , Microbioma Gastrointestinal , Enteropatias/cirurgia , Complicações Pós-Operatórias/microbiologia , Reto/microbiologia , Idoso , Fístula Anastomótica/etiologia , Bactérias/isolamento & purificação , Estudos de Casos e Controles , Colo/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Reto/cirurgiaRESUMO
The microbiota in our gut performs many different essential functions that help us to stay healthy. These functions include vitamin production, regulation of lipid metabolism and short chain fatty acid production as fuel for epithelial cells and regulation of gene expression. There is a very numerous and diverse microbial community present in the gut, especially in the colon, with reported numbers of species that vary between 400 and 1500, for some those we even do not yet have culture representatives.A healthy gut microbiota is important for maintaining a healthy host. An aberrant microbiota can cause diseases of different nature and at different ages ranging from allergies at early age to IBD in young adults. This shows that our gut microbiota needs to be treated well to stay healthy. In this chapter we describe what we consider a healthy microbiota and discuss what the role of the microbiota is in various diseases. Research into these described dysbiosis conditions could lead to new strategies for treatment and/or management of our microbiota to improve health.
Assuntos
Diabetes Mellitus Tipo 1/microbiologia , Disbiose/microbiologia , Microbioma Gastrointestinal/fisiologia , Trato Gastrointestinal/microbiologia , Doenças Inflamatórias Intestinais/microbiologia , Obesidade/microbiologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Disbiose/metabolismo , Disbiose/patologia , Ácidos Graxos Voláteis/biossíntese , Interações Hospedeiro-Patógeno , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Metabolismo dos Lipídeos , Obesidade/metabolismo , Obesidade/patologia , Simbiose/fisiologia , Vitaminas/biossínteseRESUMO
OBJECTIVE: Crohn's disease (CD) is caused by a complex interplay among genetic, microbial and environmental factors. ATG16L1 is an important genetic factor involved in innate immunity, including autophagy and phagocytosis of microbial components from the gut. We investigated the effect of inflammation on the composition of microbiota in the ileal mucosa of CD patients in relation to the ATG16L1 risk status. DESIGN: Biopsies (n=35) were obtained from inflamed and non-inflamed regions of the terminal ileum of 11 CD patients homozygous for the ATG16L1 risk allele (ATG16L1-T300A) and 9 CD patients homozygous for the ATG16L1 protective allele (ATG16L1-T300). Biopsy DNA was extracted and the bacterial composition analysed by pyrosequencing. Intracellular survival rates of adherent-invasive Escherichia coli (AIEC) were analysed by determining colony forming units after exposure to monocytes isolated from healthy volunteers homozygous for the ATG16L1 risk or protective allele. RESULTS: Inflamed ileal tissue from patients homozygous for the ATG16L1 risk allele contained increased numbers of Fusobacteriaceae, whereas inflamed ileal tissue of patients homozygous for the ATG16L1 protective allele showed decreased numbers of Bacteroidaceae and Enterobacteriaceae and increased Lachnospiraceae. The ATG16L1 allele did not affect the bacterial composition in the non-inflamed ileal tissue. Monocytes homozygous for the ATG16L1 risk allele showed impaired killing of AIEC under inflammatory conditions compared with those homozygous for the ATG16L1 protective allele. CONCLUSIONS: CD patients homozygous for the ATG16L1-T300A risk allele show impaired clearance of pathosymbionts in ileal inflammation indicating that ATG16L1 is essential for effective elimination of pathosymbionts upon inflammation.
Assuntos
Proteínas de Transporte/genética , Doença de Crohn/genética , DNA/genética , Íleo/patologia , Polimorfismo de Nucleotídeo Único , Alelos , Autofagia/genética , Proteínas Relacionadas à Autofagia , Biópsia , Proteínas de Transporte/metabolismo , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Feminino , Homozigoto , Humanos , Íleo/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo RealRESUMO
PURPOSE: Earlier, we showed in acute myeloid leukemia (AML) patients that the microbiota changes dramatically during anticancer treatment, coinciding with gastrointestinal mucositis: The commensal anaerobic populations reduce in favor of potential pathogens. Therefore, interventions targeting the microbiota during mucositis might be interesting but can better be tested in animals than in vulnerable mucositis patients. Here, we aimed to study the potential microbial changes during methotrexate (MTX)-induced gastrointestinal mucositis in a well-established rat model and to study whether this model can be used for future microbial intervention studies. METHODS: After injection with MTX or saline (day 0), rats were sacrificed between days 2 and 11. Plasma citrulline level, jejunal histology, and the number and diversity of intestinal bacteria in feces (using fluorescence in situ hybridization (FISH)) were determined. RESULTS: Mucositis was most severe on day 4 when food intake, plasma citrulline, and villus length were the lowest, compared with controls (P < 0.0125). At the same time, MTX-treated rats showed an overall decrease (705-fold) in most bacteria (using a universal probe), compared with controls (P < 0.125). Reduced bacterial presence was related with the presence of diarrhea and a reduced villus length (rho = 0.38, P < 0.05). At day 4, there was an absolute and relative decrease of anaerobes (13-fold and -58 %, respectively) and streptococci (296-fold and -1 %, respectively) but a relative increase of Bacteroides (+49 %), compared with controls (P < 0.125). CONCLUSIONS: In the mucositis rat model, we found substantial decreases in the number and diversity of microbiota, resembling earlier findings in humans. The model therefore seems well suited to study the effects of different microbial interventions on mucositis, prior to performing human studies.