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The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson's disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial re-colonization promotes, pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates disease. Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms. Remarkably, colonization of αSyn-overexpressing mice with microbiota from PD-affected patients enhances physical impairments compared to microbiota transplants from healthy human donors. These findings reveal that gut bacteria regulate movement disorders in mice and suggest that alterations in the human microbiome represent a risk factor for PD.
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Enfermedad de Parkinson/microbiología , Enfermedad de Parkinson/patología , Animales , Encéfalo/patología , Disbiosis/patología , Ácidos Grasos/metabolismo , Microbioma Gastrointestinal , Tracto Gastrointestinal/microbiología , Tracto Gastrointestinal/fisiopatología , Humanos , Inflamación/metabolismo , Inflamación/microbiología , Inflamación/patología , Ratones , Microglía/patología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , alfa-Sinucleína/metabolismoRESUMEN
The role of the gut microbiota in human health calls for a better understanding of its determinants. In particular, the possible effects of chemicals with widespread exposure other than pharmaceuticals are little known. Our aim was to characterize the sensitivity of the early-life gut microbiota to specific chemicals with possible antimicrobial action. Within the SEPAGES French couple-child cohort, we assessed 12 phenols in repeated urine samples from 356 pregnant women and their offspring and 19 poly- and perfluoroalkyl substances (PFASs) in serum from the pregnant women. We collected stool samples from the children at one year of age, in which the V3-V4 region of the 16S rRNA gene was sequenced, allowing for gut bacterial profiling. Associations of each chemical with α- and ß-diversity indices of the gut microbiota and with the relative abundance of the most abundant taxa were assessed using single-pollutant and mixture (BKMR) models. Perinatal exposure to certain parabens was associated with gut microbiota α- and ß-diversity and with Firmicutes and Proteobacteria. Suggestive associations of certain phenols with genera of the Lachnospiraceae and Enterobacteriaceae families were observed, but these were not maintained after correction for multiple testing. Parabens, which have known antimicrobial properties, might disrupt the child gut microbiota, but larger studies are required to confirm these findings.
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Pd0 catalysis and microbially catalyzed reduction of nitrate (NO3--N) were combined as a strategy to increase the kinetics of NO3- reduction and control selectivity to N2 gas versus ammonium (NH4+). Two H2-based membrane biofilm reactors (MBfRs) were tested in continuous mode: one with a biofilm alone (H2-MBfR) and the other with biogenic Pd0 nanoparticles (Pd0NPs) deposited in the biofilm (Pd-H2-MBfR). Solid-state characterizations of Pd0NPs in Pd-H2-MBfR documented that the Pd0NPs were uniformly located along the outer surfaces of the bacteria in the biofilm. Pd-H2-MBfR had a higher rate of NO3- reduction compared to H2-MBfR, especially when the influent NO3- concentration was high (28 mg-N/L versus 14 mg-N/L). Pd-H2-MBfR enriched denitrifiers of Dechloromonas, Azospira, Pseudomonas, and Stenotrophomonas in the microbial community and also increased abundances of genes affiliated with NO3--N reductases, which reflected that the denitrifying bacteria could channel their respiratory electron flow to NO3- reduction to NO2-. N2 selectivity in Pd-H2-MBfR was regulated by the H2/NO3- flux ratio: 100% selectivity to N2 was achieved when the ratio was less than 1.3 e- equiv of H2/e- equiv N, while the selectivity toward NH4+ occurred with larger H2/NO3- flux ratios. Thus, the results with Pd-H2-MBfR revealed two advantages of it over the H2-MBfR: faster kinetics for NO3- removal and controllable selectivity toward N2 versus NH4+. By being able to regulate the H2/NO3- flux ratio, Pd-H2-MBfR has significant implications for improving the efficiency and effectiveness of the NO3- reduction processes, ultimately leading to more environmentally benign wastewater treatment.
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Matriz Extracelular de Sustancias Poliméricas , Nanopartículas del Metal , Desnitrificación , Paladio , Reactores Biológicos/microbiología , Nitratos , Biopelículas , Bacterias , Catálisis , Oxidación-ReducciónRESUMEN
Anti-seizure medications (ASMs) are the first line of treatment for seizure control in children with epilepsy. Cumulative evidence suggests an imbalanced gut microbiota in refractory epilepsy patients. We systematically investigated the differential antimicrobial impacts of nine ASM active ingredients, seven common excipients of ASMs, and four syrup formulations on core early-life gut microbiota strains. Additionally, we evaluated the toxicity and gene expression profiles of HT-29 colon epithelial cells when exposed to active ingredients with or without bacterial supernatants. The physicochemical structure of ASM active ingredients and bacterial phylogeny were found to be related to ASM toxicity. Carbamazepine, lamotrigine, and topiramate reduced the growth of more than ten strains along with syrup excipient propyl-paraben. Various artificial sweeteners present in ASM formulations stimulated the growth of gut bacterial strains. The active ingredients that were more toxic to bacterial strains also exhibited toxicity towards HT-29 cells, yet Bifidobacterium longum supernatant reduced cytotoxic effects of carbamazepine and lamotrigine. Akkermansia muciniphila or mixed community supernatants reduced the expression of drug resistance genes in HT-29 cell lines. In summary, our results indicate that several ASM active ingredients and their excipients regulate the growth of gut bacterial strains in a species-specific manner. Interactions between ASMs and gut epithelial cells might be modulated by gut microbial metabolites.
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Epilepsia , Microbioma Gastrointestinal , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Niño , Epilepsia/tratamiento farmacológico , Humanos , Lamotrigina/farmacología , Lamotrigina/uso terapéutico , TopiramatoRESUMEN
BACKGROUND: Prevotella species are commonly isolated from the reproductive tract of women with obstetric/gynecologic health complications. However, contributions of this genus to changes in local microenvironment are not well characterized. Our objective was to evaluate species-specific effects of Prevotella on the human endometrial epithelium. METHODS: Thirteen Prevotella strains, originally isolated from the human oral cavity, amniotic fluid, endometrium, or vagina (including women with bacterial vaginosis), were obtained from BEI and ATCC resources. Bacteria were evaluated in silico and in vitro using human endometrial epithelial cells (EEC) grown as monolayers or a 3-dimensional (3D) model. RESULTS: Genomic characterization illustrated metabolic and phylogenetic diversity of Prevotella genus. Among tested species, P. disiens exhibited cytotoxicity. Scanning electron microscopy analysis of the 3D EEC model revealed species-specific colonization patterns and alterations of ultracellular structures. Infection with sialidase-producing P. timonensis resulted in elongated microvilli, and increased MUC3 and MUC4 expression. Infections with Prevotella species, including P. bivia, did not result in significant proinflammatory activation of EEC. CONCLUSIONS: Collectively, findings indicate that Prevotella species are metabolically diverse and overall not cytotoxic or overtly inflammatory in EEC; however, these bacteria can form biofilms, alter barrier properties of the endometrial epithelium, and ultimately impact colonization of secondary colonizers.
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Células Epiteliales/microbiología , Inmunidad Innata , Prevotella/genética , Prevotella/patogenicidad , Línea Celular Tumoral , Endometrio/citología , Células Epiteliales/inmunología , Femenino , Humanos , Microscopía Electrónica de Rastreo , Mucinas/genética , Prevotella/inmunología , Especificidad de la EspecieRESUMEN
Evidence supporting that gut problems are linked to ASD symptoms has been accumulating both in humans and animal models of ASD. Gut microbes and their metabolites may be linked not only to GI problems but also to ASD behavior symptoms. Despite this high interest, most previous studies have looked mainly at microbial structure, and studies on fecal metabolites are rare in the context of ASD. Thus, we aimed to detect fecal metabolites that may be present at significantly different concentrations between 21 children with ASD and 23 neurotypical children and to investigate its possible link to human gut microbiome. Using 1H-NMR spectroscopy and 16S rRNA gene amplicon sequencing, we examined metabolite profiles and microbial compositions in fecal samples, respectively. Of the 59 metabolites detected, isopropanol concentrations were significantly higher in feces of children with ASD after multiple testing corrections. We also observed similar trends of fecal metabolites to previous studies; children with ASD have higher fecal p-cresol and possibly lower GABA concentrations. In addition, Fisher Discriminant Analysis (FDA) with leave-out-validation suggested that a group of metabolites-caprate, nicotinate, glutamine, thymine, and aspartate-may potentially function as a modest biomarker to separate ASD participants from the neurotypical group (78% sensitivity and 81% specificity). Consistent with our previous Arizona cohort study, we also confirmed lower gut microbial diversity and reduced relative abundances of phylotypes most closely related to Prevotella copri in children with ASD. After multiple testing corrections, we also learned that relative abundances of Feacalibacterium prausnitzii and Haemophilus parainfluenzae were lower in feces of children with ASD. Despite a relatively short list of fecal metabolites, the data in this study support that children with ASD have altered metabolite profiles in feces when compared with neurotypical children and warrant further investigation of metabolites in larger cohorts.
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Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/microbiología , Bacterias/metabolismo , Heces/química , Microbioma Gastrointestinal , 2-Propanol/análisis , 2-Propanol/metabolismo , Adolescente , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Biodiversidad , Biomarcadores/análisis , Biomarcadores/metabolismo , Niño , Preescolar , Estudios de Cohortes , Heces/microbiología , Femenino , Humanos , Masculino , Neurotransmisores/análisis , Neurotransmisores/metabolismoRESUMEN
Identifying specific gut microorganisms associated with chronic constipation may be useful for diagnostic and therapeutic purposes. The objective of this study was to evaluate whether or not the gut microbial community of constipated subjects had specific microbial signatures and to assess the effects of lubiprostone treatment on the gut microbial community. Stool diaries, breath H2 and CH4 levels, and stool samples were collected from ten healthy subjects and nine patients meeting the Rome III criteria for chronic functional constipation. Constipated subjects received lubiprostone for four weeks, during which stool diaries were maintained. Stool samples were evaluated for gut microbial communities using pyrosequencing and quantitative real-time PCR (qPCR) targeting 16S-rRNA gene, along with concentrations of short-chain fatty acids (SCFAs) using high-performance liquid chromatography. Prior to treatment, gut microbial profiles were similar between constipated subjects and healthy subjects, while iso-butyrate levels were significantly higher in constipated subjects compared with healthy subjects. Despite increases in stool frequency and improvements in consistency after lubiprostone treatment, gut microbial profiles and community diversity after treatment showed no significant change compared to before treatment. While we did not observe a significant difference in either breath methane or archaeal abundance between the stool samples of healthy and constipated subjects, we confirmed a strong correlation between archaeal abundance measured by qPCR and the amount of methane gas exhaled in the fasting breath. Butyrate levels, however, were significantly higher in the stool samples of constipated subjects after lubiprostone treatment, suggesting that lubiprostone treatment had an effect on the net accumulation of SCFAs in the gut. In conclusion, lubiprostone treatment improved constipation symptoms and increased levels of butyrate without substantial modification of the gut microbial structure.
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Estreñimiento/metabolismo , Estreñimiento/microbiología , Ácidos Grasos Volátiles/metabolismo , Microbioma Gastrointestinal , Adulto , Anciano , Biodiversidad , Estudios de Casos y Controles , Agonistas de los Canales de Cloruro/uso terapéutico , Enfermedad Crónica , Estreñimiento/tratamiento farmacológico , Femenino , Dosificación de Gen , Humanos , Lubiprostona/uso terapéutico , Masculino , Metagenoma , Persona de Mediana Edad , ARN Ribosómico 16S/genética , Resultado del TratamientoRESUMEN
We evaluated a strategy for achieving complete reduction of perchlorate (ClO(4)(-)) in the presence of much higher concentrations of sulfate (SO(4)(2-)) and nitrate (NO(3)(-)) in a hydrogen-based membrane biofilm reactor (MBfR). Full ClO(4)(-) reduction was achieved by using a two-stage MBfR with controlled NO(3)(-) surface loadings to each stage. With an equivalent NO(3)(-) surface loading larger than 0.65 ± 0.04 g N/m(2)-day, the lead MBfR removed about 87 ± 4% of NO(3)(-) and 30 ± 8% of ClO(4)(-). This decreased the equivalent surface loading of NO(3)(-) to 0.34 ± 0.04-0.53 ± 0.03 g N/m(2)-day for the lag MBfR, in which ClO(4)(-) was reduced to nondetectable. SO(4)(2-) reduction was eliminated without compromising full ClO(4)(-) reduction using a higher flow rate that gave an equivalent NO(3)(-) surface loading of 0.94 ± 0.05 g N/m(2)-day in the lead MBfR and 0.53 ± 0.03 g N/m(2)-day in the lag MBfR. Results from qPCR and pyrosequencing showed that the lead and lag MBfRs had distinctly different microbial communities when SO(4)(2-) reduction took place. Denitrifying bacteria (DB), quantified using the nirS and nirK genes, dominated the biofilm in the lead MBfR, but perchlorate-reducing bacteria (PRB), quantified using the pcrA gene, became more important in the lag MBfR. The facultative anaerobic bacteria Dechloromonas, Rubrivivax, and Enterobacter were dominant genera in the lead MBfR, where their main function was to reduce NO(3)(-). With a small NO(3)(-) surface loading and full ClO(4)(-) reduction, the dominant genera shifted to ClO(4)(-)-reducing bacteria Sphaerotilus, Rhodocyclaceae, and Rhodobacter in the lag MBfR.
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Biopelículas , Reactores Biológicos/microbiología , Hidrógeno/farmacología , Membranas Artificiales , Nitratos/aislamiento & purificación , Percloratos/aislamiento & purificación , Sulfatos/aislamiento & purificación , Bacterias/efectos de los fármacos , Bacterias/genética , Biodegradación Ambiental/efectos de los fármacos , Biopelículas/efectos de los fármacos , ElectronesRESUMEN
To investigate interactions among multiple electron acceptors in a H2-fed biofilm, we operated a membrane biofilm reactor with H2-delivery capacity sufficient to reduce all acceptors. ClO4(-) and O2 were input electron acceptors in all stages at surface loadings of 0.08 ± 0.006 g/m(2)-d (1.0 ± 0.7 e(-) meq/m(2)-d) for ClO4(-) and 0.51 g/m(2)-d (76 e(-) meq/m(2)-d) for O2. SO4(2-) was added in Stage 2 at 3.77 ± 0.39 g/m(2)-d (331 ± 34 e(-) meq/m(2)-d), and NO3(-) was further added in Stage 3 at 0.72 ± 0.03 g N/m(2)-d (312 ± 13 e(-) meq/m(2)-d). At steady state for each stage, ClO4(-), O2, and NO3(-) (when present in the influent) were completely reduced; measured SO4(2-) reduction decreased from 78 ± 4% in Stage 2 to 59 ± 4% in Stage 3, when NO3(-) was present. While perchlorate-reducing bacteria (PRB), assayed by qPCR targeting the pcrA gene, remained stable throughout, sulfate-reducing bacteria (SRB), assayed by the dsrA gene, increased almost 3 orders of magnitude when significant SO4(2-) reduction occurred in stage 2. The abundance of denitrifying bacteria (DB), assayed by the nirK and nirS genes, increased in Stage 3, while SRB remained at high numbers, but did not increase. Based on pyrosequencing analyses, ß-Proteobacteria dominated in Stage 1, but ε-Proteobacteria became more important in Stages 2 and 3, when the input of multiple electron acceptors favored genera with broader electron-accepting capabilities. Sulfuricurvum (a sulfur oxidizer and NO3(-) reducer) and Desulfovibrio (a SO4(2-) reducer) become dominant in Stage 3, suggesting redox cycling of sulfur in the biofilm.
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Fenómenos Fisiológicos Bacterianos , Biopelículas , Reactores Biológicos , Hidrógeno/química , Oxígeno/química , Proteínas Bacterianas/genética , ADN Bacteriano/genética , Nitratos/química , Oxidación-Reducción , Percloratos/química , Reacción en Cadena de la Polimerasa , ARN Ribosómico 16S/genética , Sulfatos/químicaRESUMEN
BACKGROUND: Necrotizing enterocolitis (NEC) is still one of the leading causes of neonatal death. The present study reports the data from a French case-control prospective multicenter study. METHODS: A total of 146 preterm neonates (PNs) with or without NEC were included. Bacterial 16S rRNA gene sequencing was performed on stool samples (n = 103). Specific culture media were used to isolate Escherichia coli, Clostridium butyricum, and Clostridium neonatale, and strains were phenotypically characterized. RESULTS: The gut microbiota of PNs was dominated by Firmicutes and Proteobacteria, and five enterotypes were identified. The microbiota composition was similar between NEC cases and PN controls. However, differences were observed in the relative abundance of Lactobacillus genus, which was significantly lower in the NEC group, whereas that of the Clostridium cluster III was significantly higher (p < 0.05). Within enterotypes, several phylotypes were significantly more abundant in NEC cases (p < 0.05). Regarding perinatal factors, a statistical association was found between the gut microbiota and cesarean delivery and antifungal therapy. In NEC cases and PN controls, the carriage rates and virulence genes of uropathogenic E. coli were equivalent based on culture. No correlation was found between E. coli, C. butyricum, and C. neonatale carriages, beta-lactam resistance, and antibiotic treatment. CONCLUSIONS: At disease onset, our data support a microbiota dysbiosis between NEC and control infants at the genus level. In addition, it provides valuable information on bacterial antimicrobial susceptibility.
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Traditional research on biodegradation of emerging organic pollutants involves slow and labor-intensive experimentation. Currently, fast-developing metagenome, metatranscriptome, and metabolome technologies promise to expedite mechanistic research on biodegradation of emerging organic pollutants. Integrating the metagenome, metatranscriptome, and metabolome (i.e., tri-omics) makes it possible to link gene abundance and expression with the biotransformation of the contaminant and the formation of metabolites from this biotransformation. In this study, we used this tri-omics approach to study the biotransformation pathways for cetyltrimethylammonium bromide (CTAB) under aerobic conditions. The tri-omics analysis showed that CTAB undergoes three parallel first-step mono-/di-oxygenations (to the α, ß, and ω-carbons); intermediate metabolites and expressed enzymes were identified for all three pathways, and the ß-carbon mono-/di-oxygenation is a novel pathway; and the genes related to CTAB biodegradation were associated with Pseudomonas spp. Four metabolites - palmitic acid, trimethylamine N-oxide (TMAO), myristic acid, and betaine - were the key identified biodegradation intermediates of CTAB, and they were associated with first-step mono-/di-oxygenations at the α/ß-C. This tri-omics approach with CTAB demonstrates its power for identifying promising paths for future research on the biodegradation of complex organics by microbial communities.
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Contaminantes Ambientales , Metagenoma , Cetrimonio , Compuestos de Cetrimonio , MetabolomaRESUMEN
Hydrogen (H2) is a crucial electron donor for many processes in the environment including nitrate-, sulfate- and, iron-reduction, homoacetogenesis, and methanogenesis, and is a major determinant of microbial competition and metabolic pathways in groundwater, sediments, and soils. Despite the importance of H2 for many microbial processes in the environment, the total H2 consuming capacity (or H2 demand) of soils is generally unknown. Using soil microcosms with added H2, the aims of this study were 1) to measure the H2 demand of geochemically diverse soils and 2) to define the processes leading to this demand. Study results documented a large range of H2 demand in soil (0.034-1.2 millielectron equivalents H2 g-1 soil). The measured H2 demand greatly exceeded the theoretical demand predicted based on measured concentrations of common electron acceptors initially present in a library of 15 soils. While methanogenesis accounted for the largest fraction of H2 demand, humic acid reduction and acetogenesis were also significant contributing H2-consuming processes. Much of the H2 demand could be attributed to CO2 produced during incubation from fermentation and/or acetoclastic methanogenesis. The soil initial total organic carbon showed the strongest correlation to H2 demand. Besides external additions, H2 was likely generated or cycled in the microcosms. Apart from fermentative H2 production, carboxylate elongation to produce C4-C7 fatty acids may have accounted for additional H2 production in these soils. Many of these processes, especially the organic carbon contribution is underestimated in microbial models for H2 consumption in natural soil ecosystems or during bioremediation of contaminants in soils.
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Carbono , Suelo , Anaerobiosis , Ecosistema , Hidrógeno , Microbiología del SueloRESUMEN
Quaternary ammonium compounds (QAC, e.g., cetyltrimethylammonium bromide, (CTAB)) are widely used as surfactants and disinfectants. QAC already are commonly found in wastewaters, and their concentration could increase, since QAC are recommended to inactivate the SARS-CoV-2 (COVID-19) virus. Exposure of bacteria to QAC can lead to proliferation of antibiotic resistance genes (ARG). In particular, O2-based membrane biofilm reactors (O2-MBfRs) achieved excellent CTAB biodegradation, but ARG increased in their biofilms. Here, we applied meta-transcriptomic analyses to assess the impacts of CTAB exposure and operating conditions on microbial community's composition and ARG expression in the O2-MBfRs. Two opportunistic pathogens, Pseudomonas aeruginosa and Stenotrophomonas maltophilia, dominated the microbial communities and were associated with the presence of ARG. Operating conditions that imposed stress on the biofilms, i.e., limited supplies of O2 and nitrogen or a high loading of CTAB, led to large increases in ARG expression, particularly for genes conferring antibiotic-target protection. Important within the efflux pumps was the Resistance-Nodulation-Division (RND) family, which may have been active in exporting CTAB from cells. Oxidative stress appeared to be the key factor that triggered ARG proliferation by selecting intrinsically resistant species and accentuating the expression of ARG. Our findings suggest that means to mitigate the spread of ARG, such as shown here in a O2-based membrane biofilm reactor, need to consider the impacts of stressors, including QAC exposure and stressful operating conditions.
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Antibacterianos , COVID-19 , Antibacterianos/toxicidad , Biopelículas , Cetrimonio , Farmacorresistencia Microbiana/genética , Humanos , Pruebas de Sensibilidad Microbiana , SARS-CoV-2RESUMEN
Menopause in human females and subsequent ovarian hormone deficiency, particularly concerning 17ß-estradiol (E2), increase the risk for metabolic dysfunctions associated with obesity, diabetes type 2, cardiovascular diseases, and dementia. Several studies indicate that these disorders are also strongly associated with compositional changes in the intestinal microbiota; however, how E2 deficiency and hormone therapy affect the gut microbial community is not well understood. Using a rat model, we aimed to evaluate how ovariectomy (OVX) and subsequent E2 administration drive changes in metabolic health and the gut microbial community, as well as potential associations with learning and memory. Findings indicated that OVX-induced ovarian hormone deficiency and E2 treatment had significant impacts on several health-affecting parameters, including (a) the abundance of some intestinal bacterial taxa (e.g., Bifidobacteriaceae and Porphyromonadaceae), (b) the abundance of microbial short-chain fatty acids (SCFAs) (e.g., isobutyrate), (c) weight/BMI, and (d) high-demand spatial working memory following surgical menopause. Furthermore, exploratory correlations among intestinal bacteria abundance, cognition, and BMI underscored the putative influence of surgical menopause and E2 administration on gut-brain interactions. Collectively, this study showed that surgical menopause is associated with physiological and behavioral changes, and that E2-linked compositional changes in the intestinal microbiota might contribute to some of its related negative health consequences. Overall, this study provides novel insights into interactions among endocrine and gastrointestinal systems in the post-menopausal life stage that collectively alter the risk for the development and progression of cardiovascular, metabolic, and dementia-related diseases.
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Microbioma Gastrointestinal , Animales , Estrógenos , Femenino , Menopausia , Obesidad , Ratas , Memoria EspacialRESUMEN
The female reproductive tract (FRT), similar to other mucosal sites, harbours a site-specific microbiome, which has an essential role in maintaining health and homeostasis. In the majority of women of reproductive age, the microbiota of the lower FRT (vagina and cervix) microenvironment is dominated by Lactobacillus species, which benefit the host through symbiotic relationships. By contrast, the upper FRT (uterus, Fallopian tubes and ovaries) might be sterile in healthy individuals or contain a low-biomass microbiome with a diverse mixture of microorganisms. When dysbiosis occurs, altered immune and metabolic signalling can affect hallmarks of cancer, including chronic inflammation, epithelial barrier breach, changes in cellular proliferation and apoptosis, genome instability, angiogenesis and metabolic dysregulation. These pathophysiological changes might lead to gynaecological cancer. Emerging evidence shows that genital dysbiosis and/or specific bacteria might have an active role in the development and/or progression and metastasis of gynaecological malignancies, such as cervical, endometrial and ovarian cancers, through direct and indirect mechanisms, including modulation of oestrogen metabolism. Cancer therapies might also alter microbiota at sites throughout the body. Reciprocally, microbiota composition can influence the efficacy and toxic effects of cancer therapies, as well as quality of life following cancer treatment. Modulation of the microbiome via probiotics or microbiota transplant might prove useful in improving responsiveness to cancer treatment and quality of life. Elucidating these complex host-microbiome interactions, including the crosstalk between distal and local sites, will translate into interventions for prevention, therapeutic efficacy and toxic effects to enhance health outcomes for women with gynaecological cancers.
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Carcinogénesis , Disbiosis/microbiología , Neoplasias de los Genitales Femeninos/microbiología , Genitales Femeninos/microbiología , Microbiota/fisiología , Antiinfecciosos/uso terapéutico , Bacterias Anaerobias , Cuello del Útero/microbiología , Disbiosis/metabolismo , Estrógenos/metabolismo , Trompas Uterinas/microbiología , Femenino , Microbioma Gastrointestinal , Neoplasias de los Genitales Femeninos/metabolismo , Neoplasias de los Genitales Femeninos/prevención & control , Neoplasias de los Genitales Femeninos/terapia , Genitales Femeninos/metabolismo , Humanos , Lactobacillus , Ovario/microbiología , Probióticos/uso terapéutico , Útero/microbiología , Vagina/microbiologíaRESUMEN
The literature is replete with clinical studies that characterize the structure, diversity, and function of the gut microbiome and correlate the results to different disease states, including obesity. Whether the microbiome has a direct impact on obesity has not been established. To address this gap, we asked whether the gut microbiome and its bioenergetics quantitatively change host energy balance. This paper describes the design of a randomized crossover clinical trial that combines outpatient feeding with precisely controlled metabolic phenotyping in an inpatient metabolic ward. The target population was healthy, weight-stable individuals, age 18-45 and with a body mass index ≤30 kg/m2. Our primary objective was to determine within-participant differences in energy balance after consuming a control Western Diet versus a Microbiome Enhancer Diet intervention specifically designed to optimize the gut microbiome for positive impacts on host energy balance. We assessed the complete energy-balance equation via whole-room calorimetry, quantified energy intake, fecal energy losses, and methane production. We implemented conditions of tight weight stability and balance between metabolizable energy intake and predicted energy expenditure. We explored key factors that modulate the balance between host and microbial nutrient accessibility by measuring enteroendocrine hormone profiles, appetite/satiety, gut transit and gastric emptying. By integrating these clinical measurements with future bioreactor experiments, gut microbial ecology analysis, and mathematical modeling, our goal is to describe initial cause-and-effect mechanisms of gut microbiome metabolism on host energy balance. Our innovative methods will enable subsequent studies on the interacting roles of diet, the gut microbiome, and human physiology. CLINICALTRIALSGOV IDENTIFIER: NCT02939703. The present study reference can be found here: https://clinicaltrials.gov/ct2/show/NCT02939703.
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Although the etiology of obesity is not well-understood, genetic, environmental, and microbiome elements are recognized as contributors to this rising pandemic. It is well documented that Roux-en-Y gastric bypass (RYGB) surgery drastically alters the fecal microbiome, but data are sparse on temporal and spatial microbiome and metabolome changes, especially in human populations. We characterized the structure and function (through metabolites) of the microbial communities in the gut lumen and structure of microbial communities on mucosal surfaces in nine morbidly obese individuals before, 6 months, and 12 months after RYGB surgery. Moreover, using a comprehensive multi-omic approach, we compared this longitudinal cohort to a previously studied cross-sectional cohort (n = 24). In addition to the expected weight reduction and improvement in obesity-related comorbidities after RYGB surgery, we observed that the impact of surgery was much greater on fecal communities in comparison to mucosal ones. The changes in the fecal microbiome were linked to increased concentrations of branched-chain fatty acids and an overall decrease in secondary bile acid concentrations. The microbiome and metabolome data sets for this longitudinal cohort strengthen our understanding of the persistent impact of RYGB on the gut microbiome and its metabolism. Our findings highlight the importance of changes in mucosal and fecal microbiomes after RYGB surgery. The spatial modifications in the microbiome after RYGB surgery corresponded to persistent changes in fecal fermentation and bile acid metabolism, both of which are associated with improved metabolic outcomes.
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Bacterias/clasificación , Derivación Gástrica/efectos adversos , Metabolómica/métodos , Obesidad/cirugía , Análisis de Secuencia de ADN/métodos , Adulto , Bacterias/genética , Bacterias/metabolismo , Ácidos y Sales Biliares/análisis , ADN Bacteriano/genética , ADN Ribosómico/genética , Ácidos Grasos/análisis , Heces/microbiología , Femenino , Microbioma Gastrointestinal , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Obesidad/microbiología , Filogenia , ARN Ribosómico 16S/genética , Análisis Espacio-TemporalRESUMEN
BACKGROUND: Dysbiotic vaginal microbiota have been implicated as contributors to persistent HPV-mediated cervical carcinogenesis and genital inflammation with mechanisms unknown. Given that cancer is a metabolic disease, metabolic profiling of the cervicovaginal microenvironment has the potential to reveal the functional interplay between the host and microbes in HPV persistence and progression to cancer. METHODS: Our study design included HPV-negative/positive controls, women with low-grade and high-grade cervical dysplasia, or cervical cancer (nâ¯=â¯78). Metabolic fingerprints were profiled using liquid chromatography-mass spectrometry. Vaginal microbiota and genital inflammation were analysed using 16S rRNA gene sequencing and immunoassays, respectively. We used an integrative bioinformatic pipeline to reveal host and microbe contributions to the metabolome and to comprehensively assess the link between HPV, microbiota, inflammation and cervical disease. FINDINGS: Metabolic analysis yielded 475 metabolites with known identities. Unique metabolic fingerprints discriminated patient groups from healthy controls. Three-hydroxybutyrate, eicosenoate, and oleate/vaccenate discriminated (with excellent capacity) between cancer patients versus the healthy participants. Sphingolipids, plasmalogens, and linoleate positively correlated with genital inflammation. Non-Lactobacillus dominant communities, particularly in high-grade dysplasia, perturbed amino acid and nucleotide metabolisms. Adenosine and cytosine correlated positively with Lactobacillus abundance and negatively with genital inflammation. Glycochenodeoxycholate and carnitine metabolisms connected non-Lactobacillus dominance to genital inflammation. INTERPRETATION: Cervicovaginal metabolic profiles were driven by cancer followed by genital inflammation, HPV infection, and vaginal microbiota. This study provides evidence for metabolite-driven complex host-microbe interactions as hallmarks of cervical cancer with future translational potential. FUND: Flinn Foundation (#1974), Banner Foundation Obstetrics/Gynecology, and NIH NCI (P30-CA023074).
Asunto(s)
Metaboloma , Microbiota , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/virología , Neoplasias del Cuello Uterino/etiología , Neoplasias del Cuello Uterino/metabolismo , Vaginitis/etiología , Vaginitis/metabolismo , Adulto , Aminoácidos/metabolismo , Biología Computacional/métodos , Susceptibilidad a Enfermedades , Femenino , Humanos , Metabolismo de los Lípidos , Metabolómica/métodos , ARN Ribosómico 16S/genética , Curva ROC , Neoplasias del Cuello Uterino/patología , Vagina/metabolismo , Vagina/microbiología , Vagina/patología , Vagina/virología , Xenobióticos/metabolismoRESUMEN
Complete biodegradation and mineralization of pentachlorophenol (PCP), a priority pollutant in water, is challenging for water treatment. In this study, a hydrogen (H2)-based membrane biofilm reactor (MBfR) was applied to treat PCP, along with nitrate and sulfate, which often coexist in contaminated groundwater. Throughout 120-days of continuous operation, almost 100% of up to 10â¯mg/L PCP was removed with minimal intermediate accumulation and in parallel with complete denitrification of 20â¯mg-N/L nitrate. PCP initially was reductively dechlorinated to phenol, which was then mineralized to CO2 through pathways that began with aerobic activation via monooxygenation by Xanthobacter and anaerobic activation via carboxylation by Azospira and Thauera. Sulfur cycling induced by SO42- reduction affected the microbial community: The dominant bacteria became sulfate-reducers Desulfomicrobium, sulfur-oxidizers Sulfuritalea and Flavobacterium. This study provides insights and a promising technology for bioremediation of water contaminated with PCP, nitrate, and sulfate.
Asunto(s)
Reactores Biológicos , Pentaclorofenol/química , Purificación del Agua/instrumentación , Biopelículas , Reactores Biológicos/microbiología , Desnitrificación , Diseño de Equipo , Halogenación , Hidrógeno/química , Hidrógeno/metabolismo , Membranas Artificiales , Nitratos/química , Nitratos/metabolismo , Pentaclorofenol/metabolismo , Fenol/química , Fenol/metabolismo , Sulfatos/química , Sulfatos/metabolismo , Contaminantes Químicos del Agua/química , Contaminantes Químicos del Agua/metabolismo , Purificación del Agua/métodosRESUMEN
The microbiome not only represents a vital modifier of health and disease, but is a clinically important drug target. Therefore, study of the impact of the human microbiome on drug metabolism, toxicity and efficacy is urgently needed. This review focuses on gut and vaginal microbiomes, and the effect of those microbiomes or components thereof on the pharmacokinetics of specific chemotherapeutic agents, immunotherapies, anti-inflammatory and antimicrobial drugs. In some cases, the presence of specific bacterial species within the microbiome can alter the metabolism of certain drugs, such as chemotherapeutic agents and antiviral drugs. These microbiota-drug interactions are identified mostly through studies using germ-free or microbiome-depleted animal models, or by the administration of specific bacterial isolates. The biotransformation of drugs can cause drug-related toxicities; however, biotransformation also provides a mechanism by which drug developers could exploit host microbiota to create more site-specific drugs. Within this review we consider the importance of the route of drug administration and interactions with microbiota at various mucosal sites. Notably, we discuss the potential utility of bacterial therapeutics in altering the microbiome to enhance therapeutic efficacy and clinical outcomes in a personalized fashion. Based on the data to date, there is a clinically important relationship between microbiota and drug metabolism throughout the lifespan; therefore, profiling of the human microbiome will be essential in order to understand the mechanisms by which these microbiota-drug interactions occur and the degree to which this complex interplay affects drug efficacy.