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Nature Reviews. Microbiology Mar 2019Fusobacterium nucleatum has long been found to cause opportunistic infections and has recently been implicated in colorectal cancer; however, it is a common member of... (Review)
Review
Fusobacterium nucleatum has long been found to cause opportunistic infections and has recently been implicated in colorectal cancer; however, it is a common member of the oral microbiota and can have a symbiotic relationship with its hosts. To address this dissonance, we explore the diversity and niches of fusobacteria and reconsider historic fusobacterial taxonomy in the context of current technology. We also undertake a critical reappraisal of fusobacteria with a focus on F. nucleatum as a mutualist, infectious agent and oncogenic microorganism. In this Review, we delve into recent insights and future directions for fusobacterial research, including the current genetic toolkit, our evolving understanding of its mechanistic role in promoting colorectal cancer and the challenges of developing diagnostics and therapeutics for F. nucleatum.
Topics: Carcinogenesis; Colorectal Neoplasms; Fusobacterium Infections; Fusobacterium nucleatum; Host Microbial Interactions; Humans; Mouth; Symbiosis
PubMed: 30546113
DOI: 10.1038/s41579-018-0129-6 -
Periodontology 2000 Jun 2022Accumulating evidence demonstrates that the oral pathobiont Fusobacterium nucleatum is involved in the progression of an increasing number of tumors types. Thus far, the... (Review)
Review
Accumulating evidence demonstrates that the oral pathobiont Fusobacterium nucleatum is involved in the progression of an increasing number of tumors types. Thus far, the mechanisms underlying tumor exacerbation by F. nucleatum include the enhancement of proliferation, establishment of a tumor-promoting immune environment, induction of chemoresistance, and the activation of immune checkpoints. This review focuses on the mechanisms that mediate tumor-specific colonization by fusobacteria. Elucidating the mechanisms mediating fusobacterial tumor tropism and promotion might provide new insights for the development of novel approaches for tumor detection and treatment.
Topics: Fusobacterium Infections; Fusobacterium nucleatum; Humans; Neoplasms
PubMed: 35244982
DOI: 10.1111/prd.12426 -
Cell Host & Microbe May 2023Rheumatoid arthritis (RA) is an autoimmune disorder that has been associated with the gut microbiota. However, whether and how the gut microbiota plays a pathogenic role...
Rheumatoid arthritis (RA) is an autoimmune disorder that has been associated with the gut microbiota. However, whether and how the gut microbiota plays a pathogenic role in RA remains unexplored. Here, we observed that Fusobacterium nucleatum is enriched in RA patients and positively associated with RA severity. F. nucleatum similarly aggravates arthritis in a mouse model of collagen-induced arthritis (CIA). F. nucleatum outer membrane vesicles (OMVs) containing the virulence determinant FadA translocate into the joints, triggering local inflammatory responses. Specifically, FadA acts on synovial macrophages, resulting in the activation of the Rab5a GTPase involved in vesicle trafficking and inflammatory pathways and YB-1, a key regulator of inflammatory mediators. OMVs containing FadA and heightened Rab5a-YB-1 expression were observed in RA patients compared with controls. These findings suggest a causal role of F. nucleatum in aggravating RA and provide promising therapeutic targets for clinically ameliorating RA.
Topics: Animals; Mice; Fusobacterium nucleatum; Virulence Factors; Arthritis, Rheumatoid
PubMed: 37054714
DOI: 10.1016/j.chom.2023.03.018 -
Current Opinion in Microbiology Feb 2015Fusobacterium nucleatum is an anaerobic oral commensal and a periodontal pathogen associated with a wide spectrum of human diseases. This article reviews its implication... (Review)
Review
Fusobacterium nucleatum is an anaerobic oral commensal and a periodontal pathogen associated with a wide spectrum of human diseases. This article reviews its implication in adverse pregnancy outcomes (chorioamnionitis, preterm birth, stillbirth, neonatal sepsis, preeclampsia), GI disorders (colorectal cancer, inflammatory bowel disease, appendicitis), cardiovascular disease, rheumatoid arthritis, respiratory tract infections, Lemierre's syndrome and Alzheimer's disease. The virulence mechanisms involved in the diseases are discussed, with emphasis on its colonization, systemic dissemination, and induction of host inflammatory and tumorigenic responses. The FadA adhesin/invasin conserved in F. nucleatum is a key virulence factor and a potential diagnostic marker for F. nucleatum-associated diseases.
Topics: Bacteria, Anaerobic; Cell Transformation, Neoplastic; Female; Fusobacterium Infections; Fusobacterium nucleatum; Humans; Inflammation; Male; Pregnancy; Pregnancy Complications, Infectious; Virulence; Virulence Factors
PubMed: 25576662
DOI: 10.1016/j.mib.2014.11.013 -
BMC Cancer Nov 2021There is a growing level of interest in the potential role inflammation has on the initiation and progression of malignancy. Notable examples include Helicobacter... (Review)
Review
There is a growing level of interest in the potential role inflammation has on the initiation and progression of malignancy. Notable examples include Helicobacter pylori-mediated inflammation in gastric cancer and more recently Fusobacterium nucleatum-mediated inflammation in colorectal cancer. Fusobacterium nucleatum is a Gram-negative anaerobic bacterium that was first isolated from the oral cavity and identified as a periodontal pathogen. Biofilms on oral squamous cell carcinomas are enriched with anaerobic periodontal pathogens, including F. nucleatum, which has prompted hypotheses that this bacterium could contribute to oral cancer development. Recent studies have demonstrated that F. nucleatum can promote cancer by several mechanisms; activation of cell proliferation, promotion of cellular invasion, induction of chronic inflammation and immune evasion. This review provides an update on the association between F. nucleatum and oral carcinogenesis, and provides insights into the possible mechanisms underlying it.
Topics: Animals; Anti-Bacterial Agents; Bacterial Adhesion; Biofilms; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Fusobacterium Infections; Fusobacterium nucleatum; Humans; Immune Evasion; Immunity, Cellular; Inflammation; Metronidazole; Mice; Mouth Neoplasms; Neoplasm Invasiveness; Porphyromonas gingivalis; Squamous Cell Carcinoma of Head and Neck
PubMed: 34774023
DOI: 10.1186/s12885-021-08903-4 -
Journal of Bacteriology Oct 2010The human oral cavity contains a number of different habitats, including the teeth, gingival sulcus, tongue, cheeks, hard and soft palates, and tonsils, which are...
The human oral cavity contains a number of different habitats, including the teeth, gingival sulcus, tongue, cheeks, hard and soft palates, and tonsils, which are colonized by bacteria. The oral microbiome is comprised of over 600 prevalent taxa at the species level, with distinct subsets predominating at different habitats. The oral microbiome has been extensively characterized by cultivation and culture-independent molecular methods such as 16S rRNA cloning. Unfortunately, the vast majority of unnamed oral taxa are referenced by clone numbers or 16S rRNA GenBank accession numbers, often without taxonomic anchors. The first aim of this research was to collect 16S rRNA gene sequences into a curated phylogeny-based database, the Human Oral Microbiome Database (HOMD), and make it web accessible (www.homd.org). The HOMD includes 619 taxa in 13 phyla, as follows: Actinobacteria, Bacteroidetes, Chlamydiae, Chloroflexi, Euryarchaeota, Firmicutes, Fusobacteria, Proteobacteria, Spirochaetes, SR1, Synergistetes, Tenericutes, and TM7. The second aim was to analyze 36,043 16S rRNA gene clones isolated from studies of the oral microbiota to determine the relative abundance of taxa and identify novel candidate taxa. The analysis identified 1,179 taxa, of which 24% were named, 8% were cultivated but unnamed, and 68% were uncultivated phylotypes. Upon validation, 434 novel, nonsingleton taxa will be added to the HOMD. The number of taxa needed to account for 90%, 95%, or 99% of the clones examined is 259, 413, and 875, respectively. The HOMD is the first curated description of a human-associated microbiome and provides tools for use in understanding the role of the microbiome in health and disease.
Topics: Actinobacteria; Bacteria; Bacteroidetes; Chlamydia; Chloroflexi; Fusobacteria; Humans; Metagenome; Molecular Sequence Data; Mouth; Phylogeny; Proteobacteria; RNA, Ribosomal, 16S; Spirochaetales
PubMed: 20656903
DOI: 10.1128/JB.00542-10 -
Cell Host & Microbe Aug 2013Increasing evidence links the gut microbiota with colorectal cancer. Metagenomic analyses indicate that symbiotic Fusobacterium spp. are associated with human colorectal...
Increasing evidence links the gut microbiota with colorectal cancer. Metagenomic analyses indicate that symbiotic Fusobacterium spp. are associated with human colorectal carcinoma, but whether this is an indirect or causal link remains unclear. We find that Fusobacterium spp. are enriched in human colonic adenomas relative to surrounding tissues and in stool samples from colorectal adenoma and carcinoma patients compared to healthy subjects. Additionally, in the Apc(Min/+) mouse model of intestinal tumorigenesis, Fusobacterium nucleatum increases tumor multiplicity and selectively recruits tumor-infiltrating myeloid cells, which can promote tumor progression. Tumors from Apc(Min/+) mice exposed to F. nucleatum exhibit a proinflammatory expression signature that is shared with human fusobacteria-positive colorectal carcinomas. However, unlike other bacteria linked to colorectal carcinoma, F. nucleatum does not exacerbate colitis, enteritis, or inflammation-associated intestinal carcinogenesis. Collectively, these data suggest that, through recruitment of tumor-infiltrating immune cells, fusobacteria generate a proinflammatory microenvironment that is conducive for colorectal neoplasia progression.
Topics: Adenoma; Animals; Carcinogenesis; Colorectal Neoplasms; Cytokines; Disease Models, Animal; Fusobacterium nucleatum; Humans; Leukocytes; Mice
PubMed: 23954159
DOI: 10.1016/j.chom.2013.07.007 -
Clinical Oral Investigations Jan 2022The aim of this in vitro and in vivo study was to investigate the interaction of periodontitis and orthodontic tooth movement on interleukin (IL)-6 and C-X-C motif...
OBJECTIVES
The aim of this in vitro and in vivo study was to investigate the interaction of periodontitis and orthodontic tooth movement on interleukin (IL)-6 and C-X-C motif chemokine 2 (CXCL2).
MATERIALS AND METHODS
The effect of periodontitis and/or orthodontic tooth movement (OTM) on alveolar bone and gingival IL-6 and CXCL2 expressions was studied in rats by histology and RT-PCR, respectively. The animals were assigned to four groups (control, periodontitis, OTM, and combination of periodontitis and OTM). The IL-6 and CXCL2 levels were also studied in human gingival biopsies from periodontally healthy and periodontitis subjects by RT-PCR and immunohistochemistry. Additionally, the synthesis of IL-6 and CXCL2 in response to the periodontopathogen Fusobacterium nucleatum and/or mechanical strain was studied in periodontal fibroblasts by RT-PCR and ELISA.
RESULTS
Periodontitis caused an increase in gingival levels of IL-6 and CXCL2 in the animal model. Moreover, orthodontic tooth movement further enhanced the bacteria-induced periodontal destruction and gingival IL-6 gene expression. Elevated IL-6 and CXCL2 gingival levels were also found in human periodontitis. Furthermore, mechanical strain increased the stimulatory effect of F. nucleatum on IL-6 protein in vitro.
CONCLUSIONS
Our study suggests that orthodontic tooth movement can enhance bacteria-induced periodontal inflammation and thus destruction and that IL-6 may play a pivotal role in this process.
CLINICAL RELEVANCE
Orthodontic tooth movement should only be performed after periodontal therapy. In case of periodontitis relapse, orthodontic therapy should be suspended until the periodontal inflammation has been successfully treated and thus the periodontal disease is controlled again.
Topics: Animals; Fusobacterium nucleatum; Gingiva; Periodontal Ligament; Periodontitis; Rats; Tooth Movement Techniques
PubMed: 34024010
DOI: 10.1007/s00784-021-03988-4 -
Cell Communication and Signaling : CCS Dec 2022Z-DNA binding protein 1 (ZBP1) is a vital innate immune sensor that regulates inflammation during pathogen invasion. ZBP1 may contribute to pyroptosis, apoptosis and...
BACKGROUND
Z-DNA binding protein 1 (ZBP1) is a vital innate immune sensor that regulates inflammation during pathogen invasion. ZBP1 may contribute to pyroptosis, apoptosis and necroptosis in infectious diseases. In this study, Fusobacterium nucleatum (F. nucleatum) infection caused periapical inflammation through proinflammatory cell death and ZBP1 was involved in regulating the inflammatory activities caused by F. nucleatum infection in apical periodontitis (AP).
METHODS
Human periapical tissues were tested by fluorescent in situ hybridization, immunohistochemical staining, immunofluorescence staining, quantitative real-time PCR (qRT‒PCR) and western blotting. F. nucleatum-infected and F. nucleatum extracellular vesicles (F. nucleatum-EVs)-treated RAW264.7 cells were used to detect the expression of inflammatory cytokines and different cell death mechanisms by qRT‒PCR and western blotting. ZBP1 expression in F. nucleatum-infected tissues and RAW264.7 cells was detected by qRT‒PCR, western blotting, and immunohistochemical and immunofluorescence staining. Furthermore, the expression of ZBP1 was inhibited by siRNA and different cell death pathways, including pyroptosis, apoptosis, and necroptosis, and inflammatory cytokines were measured in F. nucleatum-infected RAW264.7 cells.
RESULTS
F. nucleatum was detected in AP tissues. F. nucleatum-infected RAW264.7 cells polarized to the M1 phenotype, and this was accompanied by inflammatory cytokine production. High levels of ZBP1 and GSDME (gasdermin E)-mediated pyroptosis, caspase-3-mediated apoptosis and MLKL-mediated necroptosis (PANoptosis) were identified in F. nucleatum-infected tissues and RAW264.7 cells. ZBP1 inhibition reduced inflammatory cytokine secretion and the occurrence of PANoptosis.
CONCLUSION
The present study identified a previously unknown role of ZBP1 in regulating F. nucleatum-induced proinflammatory cell death and inflammatory activation. Video abstract.
Topics: Humans; Fusobacterium nucleatum; In Situ Hybridization, Fluorescence; Cell Death; Inflammation; Cytokines; Periapical Periodontitis; DNA-Binding Proteins
PubMed: 36539813
DOI: 10.1186/s12964-022-01005-z -
Genome Research Feb 2012An estimated 15% or more of the cancer burden worldwide is attributable to known infectious agents. We screened colorectal carcinoma and matched normal tissue specimens...
An estimated 15% or more of the cancer burden worldwide is attributable to known infectious agents. We screened colorectal carcinoma and matched normal tissue specimens using RNA-seq followed by host sequence subtraction and found marked over-representation of Fusobacterium nucleatum sequences in tumors relative to control specimens. F. nucleatum is an invasive anaerobe that has been linked previously to periodontitis and appendicitis, but not to cancer. Fusobacteria are rare constituents of the fecal microbiota, but have been cultured previously from biopsies of inflamed gut mucosa. We obtained a Fusobacterium isolate from a frozen tumor specimen; this showed highest sequence similarity to a known gut mucosa isolate and was confirmed to be invasive. We verified overabundance of Fusobacterium sequences in tumor versus matched normal control tissue by quantitative PCR analysis from a total of 99 subjects (p = 2.5 × 10(-6)), and we observed a positive association with lymph node metastasis.
Topics: Cell Line, Tumor; Cluster Analysis; Colorectal Neoplasms; Fusobacterium Infections; Fusobacterium nucleatum; Genome, Bacterial; Humans; Intestine, Large; Metagenome; Phylogeny
PubMed: 22009989
DOI: 10.1101/gr.126516.111