Faculty Opinions recommendation of Fusobacterium nucleatum induces premature and term stillbirths in pregnant mice: implication of oral bacteria in preterm birth.

ABSTRACT Fusobacterium nucleatum is a gram-negative anaerobe ubiquitous to the oral cavity. It is associated with periodontal disease. It is also associated with preterm birth and has been isolated from the amniotic fluid, placenta, and chorioamnionic membranes of women delivering prematurely. Periodontal disease is a newly recognized risk factor for preterm birth. This study examined the possible mechanism underlying the link between these two diseases. F. nucleatum strains isolated from amniotic fluids and placentas along with those isolated from orally related sources invaded both epithelial and endothelial cells. The invasive ability may enable F. nucleatum to colonize and infect the pregnant uterus. Transient bacteremia caused by periodontal infection may facilitate bacterial transmission from the oral cavity to the uterus. To test this hypothesis, we intravenously injected F. nucleatum into pregnant CF-1 mice. The injection resulted in premature delivery, stillbirths, and nonsustained live births. The bacterial infection was restricted inside the uterus, without spreading systemically. F. nucleatum was first detected in the blood vessels in murine placentas. Invasion of the endothelial cells lining the blood vessels was observed. The bacteria then crossed the endothelium, proliferated in surrounding tissues, and finally spread to the amniotic fluid. The pattern of infection paralleled that in humans. This study represents the first evidence that F. nucleatum may be transmitted hematogenously to the placenta and cause adverse pregnancy outcomes. The results strengthen the link between periodontal disease and preterm birth. Our study also indicates that invasion may be an important virulence mechanism for F. nucleatum to infect the placenta.

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Repurposing N,N-Dimethylacetamide (DMA), a Pharmaceutical Excipient, as a Prototype Novel Anti-inflammatory Agent for the Prevention and/or Treatment of Preterm Birth

Current Pharmaceutical Design ◽

10.2174/1381612824666180130121706 ◽

2018 ◽

Vol 24 (9) ◽

pp. 989-992 ◽

Cited By ~ 4

Author(s):

Samir Gorasiya ◽

Juliet Mushi ◽

Ryan Pekson ◽

Sabesan Yoganathan ◽

Sandra E. Reznik

Keyword(s):

Preterm Birth ◽

Ex Vivo ◽

The United States ◽

Occurrence Rate ◽

Pharmaceutical Excipient ◽

Ongoing Work ◽

Exciting Line ◽

Pregnant Mice

Background: Preterm birth (PTB), or birth that occurs before 37 weeks of gestation, accounts for the majority of perinatal morbidity and mortality. As of 2016, PTB has an occurrence rate of 9.6% in the United States and accounts for up to 18 percent of births worldwide. Inflammation has been identified as the most common cause of PTB, but effective pharmacotherapy has yet to be developed to prevent inflammation driven PTB. Our group has discovered that N,N-dimethylacetamide (DMA), a readily available solvent commonly used as a pharmaceutical excipient, rescues lipopolysaccharide (LPS)-induced timed pregnant mice from PTB. Methods: We have used in vivo, ex vivo and in vitro approaches to investigate this compound further. Results: Interestingly, we found that DMA suppresses cytokine secretion by inhibiting nuclear factor-kappa B (NF-κB). In ongoing work in this exciting line of investigation, we are currently investigating structural analogs of DMA, some of them novel, to optimize this approach focused on the inflammation associated with PTB. Conclusion: Successful development of pharmacotherapy for the prevention of PTB rests upon the pursuit of multiple strategies to solve this important clinical challenge.

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Fretibacterium fastidiosum gen. nov., sp. nov., isolated from the human oral cavity

INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY ◽

10.1099/ijs.0.041038-0 ◽

2013 ◽

Vol 63 (Pt_2) ◽

pp. 458-463 ◽

Cited By ~ 45

Author(s):

Sonia R. Vartoukian ◽

Julia Downes ◽

Richard M. Palmer ◽

William G. Wade

Keyword(s):

New Genus ◽

Novel Species ◽

Fusobacterium Nucleatum ◽

Oral Bacteria ◽

Rrna Gene ◽

Good Growth ◽

Content Type ◽

Cellular Fatty Acids ◽

Link Type ◽

Peptone Yeast Extract Glucose

SGP1T, a strain belonging to a lineage of the phylum Synergistetes with no previously cultivated representatives was subjected to a comprehensive range of phenotypic and genotypic tests. For good growth the strain was dependent on co-culture with, or extracts from, selected other oral bacteria. Cells of strain SGP1T were asaccharolytic and major amounts of acetic acid and moderate amounts of propionic acid were produced as end products of metabolism in peptone-yeast extract-glucose broth supplemented with a filtered cell sonicate of Fusobacterium nucleatum subsp. nucleatum ATCC 25586T (25 %, v/v). Hydrogen sulphide was produced and gelatin was weakly hydrolysed. The major cellular fatty acids were C14 : 0, C18 : 0 and C16 : 0. The DNA G+C content of strain SGP1T was 63 mol%. Phylogenetic analysis of the full-length 16S rRNA gene showed that strain SGP1T represented a novel group within the phylum Synergistetes . A novel species in a new genus, Fretibacterium fastidiosum gen. nov., sp. nov., is proposed. The type strain of Fretibacterium fastidiosum is SGP1T ( = DSM 25557T = JCM 16858T).

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Effect of S-PRG Eluate on Biofilm Formation and Enzyme Activity of Oral Bacteria

International Journal of Dentistry ◽

10.1155/2012/814913 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 18

Author(s):

Masahiro Yoneda ◽

Nao Suzuki ◽

Yosuke Masuo ◽

Akie Fujimoto ◽

Kosaku Iha ◽

...

Keyword(s):

Biofilm Formation ◽

Composite Resin ◽

Fusobacterium Nucleatum ◽

Microtiter Plate ◽

Oral Bacteria ◽

Gelatin Film ◽

Glass Ionomer ◽

Microtiter Plate Assay ◽

Substrate Hydrolysis ◽

Adherence Ability

Recently, the antibacterial activity of a composite resin containing prereacted glass ionomer (S-PRG) filler was revealed. We examined the effect of an S-PRG eluate on various biologic activities ofStreptococcus mutansandPorphyromonas gingivalis. Adherence ability ofS. mutanswas evaluated by microtiter plate assay; protease and gelatinase activities ofP. gingivaliswere examined by synthetic substrate hydrolysis and gelatin film spot assay, respectively. Coaggregation ofP. gingivaliswithFusobacterium nucleatumwas also examined. S-PRG eluate was found to suppress streptococcal adherence. S-PRG eluate inhibited the protease and gelatinase activities ofP. gingivalisand the coaggregation betweenP. gingivalisandF. nucleatum. These results indicate that S-PRG eluate suppresses streptococcal adherence and inhibits the protease and coaggregation activities ofP. gingivalis. These findings may prompt research into novel strategies for preventing caries and periodontitis.

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Inhibition of gingipains prevents Porphyromonas gingivalis-induced preterm birth and fetal death in pregnant mice

European Journal of Pharmacology ◽

10.1016/j.ejphar.2018.01.028 ◽

2018 ◽

Vol 824 ◽

pp. 48-56 ◽

Cited By ~ 5

Author(s):

Ryosuke Takii ◽

Tomoko Kadowaki ◽

Takayuki Tsukuba ◽

Kenji Yamamoto

Keyword(s):

Preterm Birth ◽

Porphyromonas Gingivalis ◽

Fetal Death ◽

Pregnant Mice

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New Pyrimidinone-Fused 1,4-Naphthoquinone Derivatives Inhibit the Growth of Drug Resistant Oral Bacteria

Biomedicines ◽

10.3390/biomedicines8060160 ◽

2020 ◽

Vol 8 (6) ◽

pp. 160

Author(s):

Kyungmin Kim ◽

Daseul Kim ◽

Hyunjin Lee ◽

Tae Hoon Lee ◽

Ki-Young Kim ◽

...

Keyword(s):

Antimicrobial Agents ◽

Physiological Activity ◽

Phenyl Group ◽

Fusobacterium Nucleatum ◽

Antimicrobial Activities ◽

Oral Bacteria ◽

Drug Resistant ◽

Streptococcus Sobrinus ◽

Disk Diffusion Assay ◽

Drug Resistant Strains

Background: Dental caries is considered to be a preventable disease, and various antimicrobial agents have been developed for the prevention of dental disease. However, many bacteria show resistance to existing agents. Methods/Principal Findings: In this study, four known 1,4-naphthoquinones and newly synthesized 10 pyrimidinone-fused 1,4-naphthoquinones, i.e. KHQ 701, 702, 711, 712, 713, 714, 715, 716, 717 and 718, were evaluated for antimicrobial activity against Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus mutans, Streptococcus sobrinus, Porphyromonas gingivalis, Actinomyces viscosus and Fusobacterium nucleatum. Pyrimidinone-fused 1,4-naphthoquinones were synthesized in good yields through a series of chemical reactions from a commercially available 1,4-dihydroxynaphthoic acid. MIC values of KHQ 711, 712, 713, 714, 715, 716, 717 and 718 were 6.25–50 μg/mL against E. faecalis (CCARM 5511), 6.25–25 μg/mL against E. faecium (KACC11954) and S. aureus (CCARM 3506), 1.56–25 μg/mL against S. epidermidis (KACC 13234), 3.125–100 μg/mL against S. mutans (KACC16833), 1.56–100 μg/mL against S. sobrinus (KCTC5809) and P. gingivalis (KCTC 5352), 3.125–50 μg/mL against A. viscosus (KCTC 9146) and 3.125–12.5 μg/mL against F. nucleatum (KCTC 2640) with a broth microdilution assay. A disk diffusion assay with KHQ derivatives also exhibited strong susceptibility with inhibition zones of 0.96 to 1.2 cm in size against P. gingivalis. Among the 10 compounds evaluated, KHQ 711, 712, 713, 715, 716 and 717 demonstrated strong antimicrobial activities against the 9 types of pathogenic oral bacteria. A pyrimidin-4-one moiety comprising a phenyl group at the C2 position and a benzyl group at the N3 position appears to be essential for physiological activity. Conclusion/Significance: Pyrimidinone-fused 1,4-naphthoquinones synthesized from simple starting compounds and four known 1,4-naphthoquinones were synthesized and showed strong antibacterial activity to the 9 common oral bacteria. These results suggest that these derivatives should be prospective for the treatment of dental diseases caused by oral bacteria, including drug-resistant strains.

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Central Role of the Early Colonizer Veillonella sp. in Establishing Multispecies Biofilm Communities with Initial, Middle, and Late Colonizers of Enamel

Journal of Bacteriology ◽

10.1128/jb.01631-09 ◽

2010 ◽

Vol 192 (12) ◽

pp. 2965-2972 ◽

Cited By ~ 89

Author(s):

Saravanan Periasamy ◽

Paul E. Kolenbrander

Keyword(s):

Lactic Acid ◽

Fluorescent Antibody ◽

Fusobacterium Nucleatum ◽

Single Species ◽

Oral Bacteria ◽

Flow Cells ◽

Significant Growth ◽

Dental Biofilm ◽

Antibody Staining

ABSTRACT Human dental biofilm communities comprise several species, which can interact cooperatively or competitively. Bacterial interactions influence biofilm formation, metabolic changes, and physiological function of the community. Lactic acid, a common metabolite of oral bacteria, was measured in the flow cell effluent of one-, two- and three-species communities growing on saliva as the sole nutritional source. We investigated single-species and multispecies colonization by using known initial, early, middle, and late colonizers of enamel. Fluorescent-antibody staining and image analysis were used to quantify the biomass in saliva-fed flow cells. Of six species tested, only the initial colonizer Actinomyces oris exhibited significant growth. The initial colonizer Streptococcus oralis produced lactic acid but showed no significant growth. The early colonizer Veillonella sp. utilized lactic acid in two- and three-species biofilm communities. The biovolumes of all two-species biofilms increased when Veillonella sp. was present as one of the partners, indicating that this early colonizer promotes mutualistic community development. All three-species combinations exhibited enhanced growth except one, i.e., A. oris, Veillonella sp., and the middle colonizer Porphyromonas gingivalis, indicating specificity among three-species communities. Further specificity was seen when Fusobacterium nucleatum (a middle colonizer), Aggregatibacter actinomycetemcomitans (a late colonizer), and P. gingivalis did not grow with S. oralis in two-species biofilms, but inclusion of Veillonella sp. resulted in growth of all three-species combinations. We propose that commensal veillonellae use lactic acid for growth in saliva and that they communicate metabolically with initial, early, middle, and late colonizers to establish multispecies communities on enamel.

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Interactions between Periodontal Bacteria and Human Oral Epithelial Cells: Fusobacterium nucleatum Adheres to and Invades Epithelial Cells

Infection and Immunity ◽

10.1128/iai.68.6.3140-3146.2000 ◽

2000 ◽

Vol 68 (6) ◽

pp. 3140-3146 ◽

Cited By ~ 257

Author(s):

Yiping W. Han ◽

Wenyuan Shi ◽

George T.-J. Huang ◽

Susan Kinder Haake ◽

No-Hee Park ◽

...

Keyword(s):

Protein Synthesis ◽

Epithelial Cell ◽

Epithelial Cells ◽

Periodontal Diseases ◽

Fusobacterium Nucleatum ◽

Oral Bacteria ◽

Metabolic Inhibitors ◽

Kb Cells ◽

Gingival Epithelial Cells ◽

Oral Epithelial

ABSTRACT Bacteria are causative agents of periodontal diseases. Interactions between oral bacteria and gingival epithelial cells are essential aspects of periodontal infections. Using an in vitro tissue culture model, a selected group of gram-negative anaerobic bacteria frequently associated with periodontal diseases, includingBacteroides forsythus, Campylobacter curvus,Eikenella corrodens, Fusobacterium nucleatum,Porphyromonas gingivalis, and Prevotella intermedia, were examined for their ability to adhere to and invade primary cultures of human gingival epithelial cells (HGEC). The effects of these bacteria on the production of interleukin-8 (IL-8), a proinflammatory chemokine, were also measured. These studies provided an initial demonstration that F. nucleatum adhered to and invaded HGEC and that this was accompanied by high levels of IL-8 secretion from the epithelial cells. The attachment and invasion characteristics of F. nucleatumwere also tested using KB cells, an oral epithelial cell line. The invasion was verified by transmission electron microscopy and with metabolic inhibitors. Invasion appeared to occur via a “zipping” mechanism and required the involvement of actins, microtubules, signal transduction, protein synthesis, and energy metabolism of the epithelial cell, as well as protein synthesis by F. nucleatum. A spontaneous mutant, lam, of F. nucleatum, isolated as defective in autoagglutination, was unable to attach to or invade HGEC or KB cells, further indicating the requirement of bacterial components in these processes. Sugar inhibition assays indicated that lectin-like interactions were involved in the attachment of F. nucleatum to KB cells. Investigation of these new virulence phenotypes should improve our understanding of the role of F. nucleatum in periodontal infections.

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TGF-β1 Inhibits TLR-mediated Odontoblast Responses to Oral Bacteria

Journal of Dental Research ◽

10.1177/0022034509334846 ◽

2009 ◽

Vol 88 (4) ◽

pp. 333-338 ◽

Cited By ~ 37

Author(s):

O.V. Horst ◽

K.A. Tompkins ◽

S.R. Coats ◽

P.H. Braham ◽

R.P. Darveau ◽

...

Keyword(s):

Cell Surface ◽

Tissue Repair ◽

Lactobacillus Casei ◽

Tooth Development ◽

Fusobacterium Nucleatum ◽

Poor Response ◽

Oral Bacteria ◽

Cellular Processes ◽

Tgf Β1

TGF-β1 exerts diverse functions in tooth development and tissue repair, but its role in microbial defenses of the tooth is not well-understood. Odontoblasts extending their cellular processes into the dentin are the first cells to recognize signals from TGF-β1 and bacteria in carious dentin. This study aimed to determine the role of TGF-β1 in modulating odontoblast responses to oral bacteria. We show that these responses depend upon the expression levels of microbial recognition receptors TLR2 and TLR4 on the cell surface. Porphyromonas gingivalis, Prevotella intermedia, and Fusobacterium nucleatum activated both TLRs, but TLR4 played a greater role. Lack of cell-surface TLR2 was associated with poor response to Streptococcus mutans, Enterococcus faecalis, and Lactobacillus casei. TGF-β1 inhibited TLR2 and TLR4 expression and attenuated odontoblast responses. Our findings suggest that the balance between TLR-mediated inflammation and TGF-β1 anti-inflammatory activity plays an important role in pulpal inflammation.

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Preterm Birth Is Correlated With Increased Oral Originated Microbiome in the Gut

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.579766 ◽

2021 ◽

Vol 11 ◽

Author(s):

Chunhua Yin ◽

Jingrui Chen ◽

Xuena Wu ◽

Yeling Liu ◽

Quan He ◽

...

Keyword(s):

Preterm Birth ◽

Gut Microbiome ◽

Preterm Labor ◽

Amplicon Sequencing ◽

Oral Bacteria ◽

Gut Bacteria ◽

Oral Microbiome ◽

16S Rrna Amplicon Sequencing ◽

Threatened Preterm Labor ◽

Adverse Pregnancy

BackgroundPreterm birth is one of the leading causes of perinatal morbidity and mortality. Gut microbiome dysbiosis is closely related to adverse pregnancy outcomes. However, the role of the gut microbiome in the pathogenesis of preterm birth remains poorly studied.MethodWe collected fecal samples from 41 women (cases presenting with threatened preterm labor =19, 11 of which delivered preterm; gestational age-matched no-labor controls, all of which delivered at term = 22) were recruited for the study. We performed 16S rRNA amplicon sequencing to compare the composition of the gut microbiome in threatened preterm labor cases and controls and among women who delivered preterm and at term. By annotating taxonomic biomarkers with the Human Oral Microbiome Database, we observed an increased abundance of potential oral-to-gut bacteria in preterm patients.ResultsPatients with preterm birth showed a distinct gut microbiome dysbiosis compared with those who delivered at term. Opportunistic pathogens, particularly Porphyromonas, Streptococcus, Fusobacterium, and Veillonella, were enriched, whereas Coprococcus and Gemmiger were markedly depleted in the preterm group. Most of the enriched bacteria were annotated oral bacteria using the Human Oral Microbiome Database. These potential oral-to-gut bacteria were correlated with clinical parameters that reflected maternal and fetal status.ConclusionsThis study suggests that patients who deliver preterm demonstrate altered gut microbiome that may contain higher common oral bacteria.

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