scholarly journals Genetic and molecular determinants of polymicrobial interactions in Fusobacterium nucleatum

2021 ◽  
Vol 118 (23) ◽  
pp. e2006482118
Author(s):  
Chenggang Wu ◽  
Yi-Wei Chen ◽  
Matthew Scheible ◽  
Chungyu Chang ◽  
Manuel Wittchen ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Fusobacterium Nucleatum ◽  
Oral Microbiome ◽  
Metabolic Inhibitor ◽  
Interspecies Interactions ◽  
Native Culture ◽  
Metabolic Genes ◽  
Genome Wide ◽  
Oral Biofilms ◽  
Two Component Signal Transduction

A gram-negative colonizer of the oral cavity, Fusobacterium nucleatum not only interacts with many pathogens in the oral microbiome but also has the ability to spread to extraoral sites including placenta and amniotic fluid, promoting preterm birth. To date, however, the molecular mechanism of interspecies interactions—termed coaggregation—by F. nucleatum and how coaggregation affects bacterial virulence remain poorly defined. Here, we employed genome-wide transposon mutagenesis to uncover fusobacterial coaggregation factors, revealing the intertwined function of a two-component signal transduction system (TCS), named CarRS, and a lysine metabolic pathway in regulating the critical coaggregation factor RadD. Transcriptome analysis shows that CarR modulates a large regulon including radD and lysine metabolic genes, such as kamA and kamD, the expression of which are highly up-regulated in the ΔcarR mutant. Significantly, the native culture medium of ΔkamA or ΔkamD mutants builds up abundant amounts of free lysine, which blocks fusobacterial coaggregation with streptococci. Our demonstration that lysine-conjugated beads trap RadD from the membrane lysates suggests that lysine utilizes RadD as its receptor to act as a metabolic inhibitor of coaggregation. Lastly, using a mouse model of preterm birth, we show that fusobacterial virulence is significantly attenuated with the ΔkamA and ΔcarR mutants, in contrast to the enhanced virulence phenotype observed upon diminishing RadD (ΔradD or ΔcarS mutant). Evidently, F. nucleatum employs the TCS CarRS and environmental lysine to modulate RadD-mediated interspecies interaction, virulence, and nutrient acquisition to thrive in the adverse environment of oral biofilms and extraoral sites.

scholarly journals Exploring the Role of Fusobacterium nucleatum in Preterm Birth: A Narrative Review

2020 ◽  
Vol 8 (F) ◽  
pp. 253-259
Author(s):  
Biagio Rapone ◽  
Elisabetta Ferrara ◽  
Ilaria Converti ◽  
Matteo Loverro ◽  
Maria Teresa Loverro ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Intrauterine Infection ◽  
Fusobacterium Nucleatum ◽  
Current Data ◽  
Oral Microbiome ◽  
Obstetric Outcomes ◽  
Adverse Pregnancy ◽  
Negative Impacts ◽  
Poor Outcomes

In recent years, substantive attention has been drawn to the relationship between oral microbiome homeostatic equilibrium disruption and systemic health, demonstrating the negative impacts of this reciprocal biological interplay. Increasingly, there is a concern over the potential noxious effect of oral microbiome dysbiosis on obstetric poor outcomes, focusing on preterm birth. This epidemiological observation remains unexplained, although biologically plausible mechanism has been proposed. Intrauterine infection has long been associated with adverse pregnancy, when the elicitation of an immune response is determinant. There is evidence that Fusobacterium nucleatum (FN), a Gram-negative anaerobe ubiquitous in the oral cavity, infects the mouse placenta originating in the decidua basalis. Based on the current data in literature, we performed a review to provide resources for the explanation of the potential impact of microbiome dysbiosis on poor obstetric outcomes, focusing on the role of FN.

scholarly journals Oral microbial dysbiosis and its performance in predicting oral cancer

2020 ◽  
Author(s):  
Shih-Chi Su ◽  
Lun-Ching Chang ◽  
Hsien-Da Huang ◽  
Chih-Yu Peng ◽  
Chun-Yi Chuang ◽  
...  
Keyword(s):  
Oral Cancer ◽  
Fusobacterium Nucleatum ◽  
Risky Behaviors ◽  
Health Condition ◽  
Oral Microbiome ◽  
Oral Microbiota ◽  
Microbial Dysbiosis ◽  
Anti Cancer ◽  
Betel Quid Chewing ◽  
Male Patients

Abstract Dysbiosis of oral microbiome may dictate the progression of oral squamous cell carcinoma (OSCC). Yet, the composition of oral microbiome fluctuates by saliva and distinct sites of oral cavity and is affected by risky behaviors (smoking, drinking and betel quid chewing) and individuals’ oral health condition. To characterize the disturbances in the oral microbial population mainly due to oral tumorigenicity, we profiled the bacteria within the surface of OSCC lesion and its contralateral normal tissue from discovery (n = 74) and validation (n = 42) cohorts of male patients with cancers of the buccal mucosa. Significant alterations in the bacterial diversity and relative abundance of specific oral microbiota (most profoundly, an enrichment for genus Fusobacterium and the loss of genus Streptococcus in the tumor sites) were identified. Functional prediction of oral microbiome shown that microbial genes related to the metabolism of terpenoids and polyketides were differentially enriched between the control and tumor groups, indicating a functional role of oral microbiome in formulating a tumor microenvironment via attenuated biosynthesis of secondary metabolites with anti-cancer effects. Furthermore, the vast majority of microbial signatures detected in the discovery cohort was generalized well to the independent validation cohort, and the clinical validity of these OSCC-associated microbes was observed and successfully replicated. Overall, our analyses reveal signatures (a profusion of Fusobacterium nucleatum CTI-2 and a decrease in Streptococcus pneumoniae) and functions (decreased production of tumor-suppressive metabolites) of oral microbiota related to oral cancer.

scholarly journals Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue-specific circadian networks

2018 ◽  
Vol 115 (52) ◽  
pp. E12305-E12312 ◽  
Author(s):  
Meng Qu ◽  
Tomas Duffy ◽  
Tsuyoshi Hirota ◽  
Steve A. Kay
Keyword(s):  
Nuclear Receptor ◽  
Metabolic Pathways ◽  
Feedback Loop ◽  
Transcriptional Activity ◽  
Transcript Level ◽  
Colon Cells ◽  
Tissue Specific ◽  
Metabolic Genes ◽  
Genome Wide ◽  
Circadian Control

Either expression level or transcriptional activity of various nuclear receptors (NRs) have been demonstrated to be under circadian control. With a few exceptions, little is known about the roles of NRs as direct regulators of the circadian circuitry. Here we show that the nuclear receptor HNF4A strongly transrepresses the transcriptional activity of the CLOCK:BMAL1 heterodimer. We define a central role for HNF4A in maintaining cell-autonomous circadian oscillations in a tissue-specific manner in liver and colon cells. Not only transcript level but also genome-wide chromosome binding of HNF4A is rhythmically regulated in the mouse liver. ChIP-seq analyses revealed cooccupancy of HNF4A and CLOCK:BMAL1 at a wide array of metabolic genes involved in lipid, glucose, and amino acid homeostasis. Taken together, we establish that HNF4A defines a feedback loop in tissue-specific mammalian oscillators and demonstrate its recruitment in the circadian regulation of metabolic pathways.

scholarly journals Hypermethylation of the VTRNA2-1 promoter in maternal blood is associated with preterm birth

2020 ◽  
Author(s):  
Young-Ah You ◽  
Eun Jin Kwon ◽  
Han-Sung Hwang ◽  
Suk-Joo Choi ◽  
Sae Kyung Choi ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Large Population ◽  
Underlying Mechanism ◽  
Maternal Blood ◽  
Blood Cell Count ◽  
Genome Wide ◽  
Increased Risk ◽  
Health And Disease ◽  
Whole Blood Cells ◽  
Dna Methylation Analysis

Abstract Background: Preterm birth is associated with an increased risk of neonatal complications and death, as well as poor health and disease later in life. Epigenetics could contribute to the mechanism underlying preterm birth. Results: Genome-wide DNA methylation analysis of whole blood cells from ten women was performed using an Illumina Infinium HumanMethylation450 BeadChips array. We identified 1,581 differentially methylated CpG sites in promotor regions between term and preterm birth. Although the differences were not significant after correcting for multiple tests, seven CpGs on the genomically imprinted VTRNA2-1 showed the largest differences (range: 26–39%). Pyrosequencing verification was performed with blood samples from pregnant women recruited additionally (n = 82). In total, 28 (34.1%) cases showed hypomethylation of the VTRNA2-1 promoter (< 13% methylation), while 54 cases (65.9%) showed a methylation level of 30–60%. Hypermethylation of VTRNA2-1 was associated with an increased risk of preterm birth after adjusting for maternal age, season of delivery, parity and white blood cell count. The mRNA expression of VTRNA2-1 was 0.51-fold lower in women with preterm deliveries (n = 20) compared with women with term deliveries (n = 20). Conclusions: Our results suggest that changes in VTRNA2-1 methylation in maternal blood are related to preterm birth. Further studies are needed to confirm the association of VTRNA2-1 methylation with preterm birth in a large population, and to elucidate the underlying mechanism.

scholarly journals Epigenetic changes in preterm birth placenta suggest a role for ADAMTS genes in spontaneous preterm birth

2018 ◽  
Vol 28 (1) ◽  
pp. 84-95 ◽  
Author(s):  
Sneha Mani ◽  
Jayashri Ghosh ◽  
Yemin Lan ◽  
Suneeta Senapati ◽  
Teri Ord ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Critical Role ◽  
Spontaneous Preterm Birth ◽  
Gene Methylation ◽  
Vitro Fertilization ◽  
Genome Wide ◽  
Common Etiology ◽  
Adamts Gene ◽  
Extravillous Trophoblasts

Abstract Preterm birth (PTB) affects approximately 1 in 10 pregnancies and contributes to approximately 50% of neonatal mortality. However, despite decades of research, little is understood about the etiology of PTB, likely due to the multifactorial nature of the disease. In this study, we examined preterm and term placentas, from unassisted conceptions and those conceived using in vitro fertilization (IVF). IVF increases the risk of PTB and causes epigenetic change in the placenta and fetus; therefore, we utilized these patients as a unique population with a potential common etiology. We investigated genome-wide DNA methylation in placentas from term IVF, preterm IVF, term control (unassisted conception) and preterm control pregnancies and discovered epigenetic dysregulation of multiple genes involved in cell migration, including members of the ADAMTS family, ADAMTS12 and ADAMTS16. These genes function in extracellular matrix regulation and tumor cell invasion, processes replicated by invasive trophoblasts (extravillous trophoblasts (EVTs)) during early placentation. Though expression was similar between term and preterm placentas, we found that both genes demonstrate high expression in first- and second-trimester placenta, specifically in EVTs and syncytiotrophoblasts. When we knocked down ADAMTS12 or ADAMTS16in vitro, there was poor EVT invasion and reduced matrix metalloproteinase activity, reinforcing their critical role in placentation. In conclusion, utilizing a population at high risk for PTB, we have identified a role for ADAMTS gene methylation in regulating early placentation and susceptibility to PTB.

scholarly journals A prospective cohort for the investigation of alteration in temporal transcriptional and microbiome trajectories preceding preterm birth: a study protocol

BMJ Open ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. e023417 ◽  
Author(s):  
Tobias Brummaier ◽  
Basirudeen Syed Ahamed Kabeer ◽  
Stephen Lindow ◽  
Justin C Konje ◽  
Sasithon Pukrittayaamee ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Blood Serum ◽  
Postpartum Period ◽  
Transcript Abundance ◽  
Ethics Committee ◽  
Capillary Blood ◽  
Oral Microbiome ◽  
Control Analysis ◽  
Term Neonates ◽  
Non Coding Rna

IntroductionPreterm birth (PTB) results from heterogeneous influences and is a major contributor to neonatal mortality and morbidity that continues to have adverse effects on infants beyond the neonatal period. This protocol describes the procedures to determine molecular signatures predictive of PTB through high-frequency sampling during pregnancy, at delivery and the postpartum period.Methods and analysisFour hundred first trimester pregnant women from either Myanmar or Thailand of either Karen or Burman ethnicity, with a viable, singleton pregnancy will be enrolled in this non-interventional, prospective pregnancy birth cohort study and will be followed through to the postpartum period. Fortnightly finger prick capillary blood sampling will allow the monitoring of genome-wide transcript abundance in whole blood. Collection of stool samples and vaginal swabs each trimester, at delivery and postpartum will allow monitoring of intestinal and vaginal microbial composition. In a nested case–control analysis, perturbations of transcript abundance in capillary blood as well as longitudinal changes of the gut, vaginal and oral microbiome will be compared between mothers giving birth to preterm and matched cases giving birth to term neonates. Placenta tissue of preterm and term neonates will be used to determine bacterial colonisation as well as for the establishment of coding and non-coding RNA profiles. In addition, RNA profiles of circulating, non-coding RNA in cord blood serum will be compared with those of maternal peripheral blood serum at time of delivery.Ethics and disseminationThis research protocol that aims to detect perturbations in molecular trajectories preceding adverse pregnancy outcomes was approved by the ethics committee of the Faculty of Tropical Medicine, Mahidol University in Bangkok, Thailand (Ethics Reference: TMEC 15–062), the Oxford Tropical Research Ethics Committee (Ethics Reference: OxTREC: 33–15) and the local Tak Province Community Ethics Advisory Board. The results of this cooperative project will be disseminated in multiple publications staggered over time in international peer-reviewed scientific journals.Trial registration numberNCT02797327; Pre-results.

scholarly journals Streptococcal Antagonism in Oral Biofilms: Streptococcus sanguinis and Streptococcus gordonii Interference with Streptococcus mutans

2008 ◽  
Vol 190 (13) ◽  
pp. 4632-4640 ◽  
Author(s):  
Jens Kreth ◽  
Yongshu Zhang ◽  
Mark C. Herzberg
Keyword(s):  
Streptococcus Mutans ◽  
Bacterial Species ◽  
Ecological Factors ◽  
Oral Streptococci ◽  
Streptococcus Gordonii ◽  
Interspecies Interactions ◽  
Streptococcus Sanguinis ◽  
Production Of Hydrogen ◽  
Oral Biofilms ◽  
Competence System

ABSTRACT Biofilms are polymicrobial, with diverse bacterial species competing for limited space and nutrients. Under healthy conditions, the different species in biofilms maintain an ecological balance. This balance can be disturbed by environmental factors and interspecies interactions. These perturbations can enable dominant growth of certain species, leading to disease. To model clinically relevant interspecies antagonism, we studied three well-characterized and closely related oral species, Streptococcus gordonii, Streptococcus sanguinis, and cariogenic Streptococcus mutans. S. sanguinis and S. gordonii used oxygen availability and the differential production of hydrogen peroxide (H2O2) to compete effectively against S. mutans. Interspecies antagonism was influenced by glucose with reduced production of H2O2. Furthermore, aerobic conditions stimulated the competence system and the expression of the bacteriocin mutacin IV of S. mutans, as well as the H2O2-dependent release of heterologous DNA from mixed cultures of S. sanguinis and S. gordonii. These data provide new insights into ecological factors that determine the outcome of competition between pioneer colonizing oral streptococci and the survival mechanisms of S. mutans in the oral biofilm.

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