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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 -
Current Opinion in Oncology Mar 2023There is growing evidence that suggests a possible role for bacteria in the progression of cancer. Fusobacteria have been detected in different types of cancers,... (Review)
Review
PURPOSE OF REVIEW
There is growing evidence that suggests a possible role for bacteria in the progression of cancer. Fusobacteria have been detected in different types of cancers, including colorectal and oral cancers. Fusobacteria are common opportunistic oral bacteria known to cause various infections. In this review, we focus on the association between Fusobacteria and cancer, specifically oral cancer, and provide insight into the role of Fusobacteria in carcinogenesis and immune evasion.
RECENT FINDINGS
Recently, it has been suggested that Fusobacteria are among the bacteria that contribute to the progression of cancer and might affect disease prognosis and treatment outcome. Moreover, Fusobacteria might alter tumor microenvironment and have an impact on tumor immune response. Thus, understanding the effect of Fusobacteria on cancer cells and tumor microenvironment is crucial to improve treatment outcome.
SUMMERY
Recent evidences suggest that Fusobacteria not only have an impact on tumor progression, but might also affect tumor immune response. Moreover, Fusobacteria presence in the tumor microenvironment might have an impact on treatment outcome and might be used as a prognostic factor.
Topics: Humans; Fusobacterium; Fusobacteria; Immune Evasion; Mouth Neoplasms; Carcinogenesis; Tumor Microenvironment
PubMed: 36633319
DOI: 10.1097/CCO.0000000000000927 -
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 -
Anaerobe Aug 2014The members of the phylum Fusobacteria and its two families, Fusobacteriaceae and Leptotrichiaceae, are distinguished at present mainly on the basis of their branching...
The members of the phylum Fusobacteria and its two families, Fusobacteriaceae and Leptotrichiaceae, are distinguished at present mainly on the basis of their branching in the 16S rRNA gene trees and analysis of the internal transcribed spacer sequences in the 16S-23S rDNA. However, no biochemical or molecular characteristics are known that are uniquely shared by all of most members of these groups of bacteria. We report here detailed phylogenetic and comparative analyses on 45 sequenced Fusobacteria genomes to examine their evolutionary relationships and to identify molecular markers that are specific for the members of this phylum. In phylogenetic trees based on 16S rRNA gene sequences or concatenated sequences for 17 conserved proteins, members of the families Fusobacteriaceae and Leptotrichiaceae formed strongly supported clades and were clearly distinguished. In these trees, the species from the genus Fusobacterium also formed a number of well-supported clades. In parallel, comparative analyses on Fusobacteria genomes have identified 44 conserved signature indels (CSIs) in proteins involved in a broad range of functions that are either specific for the phylum Fusobacteria or a number of distinct subclades within this phylum. Seven of these CSIs in important proteins are uniquely present in the protein homologs of all sequenced Fusobacteria and they provide potential molecular markers for this phylum. Six and three other CSIs in other protein sequences are specific for members of the families Fusobacteriaceae and Leptotrichiaceae, respectively, and they provide novel molecular means for distinguishing members of these two families. Fourteen additional CSIs in different proteins, which are specific for either members of the genera Fusobacterium or Leptotrichia, or a number of other well-supported clades of Fusobacteria at multiple phylogenetic levels, provide molecular markers for these groups and information regarding the evolutionary relationships among the members of this phylum. Lastly, the present work has also identified 14 CSIs in divergent proteins that are specific for three specific subclades of Fusobacterium species, which are also indicated to be distinct by phylogenetic analyses. The members of these three Fusobacterium subclades also differ significantly from each other in their whole genome average nucleotide identities values, suggesting that they are possible candidates for recognition as different genera. The molecular markers reported here provide novel means for the identification of members of the phylum Fusobacteria and for their classification.
Topics: Bacterial Proteins; Cluster Analysis; DNA, Bacterial; Fusobacteria; Genetic Markers; Genetic Variation; Molecular Sequence Data; Multilocus Sequence Typing; Phylogeny; RNA, Ribosomal, 16S
PubMed: 24969840
DOI: 10.1016/j.anaerobe.2014.06.007 -
Current Protein & Peptide Science 2017There is growing recognition that composition and metabolic activity of the gut microbiota can be modulated by the dietary proteins which in turn impact health. The... (Review)
Review
There is growing recognition that composition and metabolic activity of the gut microbiota can be modulated by the dietary proteins which in turn impact health. The amino acid composition and digestibility of proteins, which are influenced by its source and amount of intake, play a pivotal role in determining the microbiota. Reciprocally, it appears that the gut microbiota is also able to affect protein metabolism which gives rise to the view that function between the microbiota and protein can proceed in both directions. In response to the alterations in dietary protein components, there are significant changes in the microbial metabolites including short chain fatty acids (SCFAs), ammonia, amines, gases such as hydrogen, sulfide and methane which are cytotoxins, genotoxins and carcinogens associated with development of colon cancer and inflammatory bowel diseases. A suitable ratio between protein and carbohydrate or even a low protein diet is recommended based on the evidence that excessive protein intake adversely affects health. Supplying high and undigested proteins will encourage pathogens and protein-fermenting bacteria to increase the risk of diseases. These changes of microbiota can affect the gut barrier and the immune system by regulating gene expression in relevant signaling pathways and by regulating the secretion of metabolites. The objective of this review is to assess the impact of dietary proteins on microbiota composition and activity in the gastrointestinal tract. Attention should be given to the dietary strategies with judicious selection of source and supplementation of dietary protein to benefit gut health.
Topics: Actinobacteria; Amines; Ammonia; Bacteroidetes; Dietary Carbohydrates; Dietary Proteins; Fatty Acids, Volatile; Fermentation; Firmicutes; Fusobacteria; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Proteobacteria; Proteolysis; Verrucomicrobia
PubMed: 28215168
DOI: 10.2174/1389203718666170216153505 -
Gut Jan 2018A history of periodontal disease and the presence of circulating antibodies to selected oral pathogens have been associated with increased risk of pancreatic cancer;...
OBJECTIVE
A history of periodontal disease and the presence of circulating antibodies to selected oral pathogens have been associated with increased risk of pancreatic cancer; however, direct relationships of oral microbes with pancreatic cancer have not been evaluated in prospective studies. We examine the relationship of oral microbiota with subsequent risk of pancreatic cancer in a large nested case-control study.
DESIGN
We selected 361 incident adenocarcinoma of pancreas and 371 matched controls from two prospective cohort studies, the American Cancer Society Cancer Prevention Study II and the National Cancer Institute Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. From pre-diagnostic oral wash samples, we characterised the composition of the oral microbiota using bacterial 16S ribosomal RNA (16S rRNA) gene sequencing. The associations between oral microbiota and risk of pancreatic cancer, controlling for the random effect of cohorts and other covariates, were examined using traditional and L1-penalised least absolute shrinkage and selection operator logistic regression.
RESULTS
Carriage of oral pathogens, and , were associated with higher risk of pancreatic cancer (adjusted OR for presence vs absence=1.60 and 95% CI 1.15 to 2.22; OR=2.20 and 95% CI 1.16 to 4.18, respectively). Phylum and its genus were associated with decreased pancreatic cancer risk (OR per per cent increase of relative abundance=0.94 and 95% CI 0.89 to 0.99; OR=0.87 and 95% CI 0.79 to 0.95, respectively). Risks related to these phylotypes remained after exclusion of cases that developed within 2 years of sample collection, reducing the likelihood of reverse causation in this prospective study.
CONCLUSIONS
This study provides supportive evidence that oral microbiota may play a role in the aetiology of pancreatic cancer.
Topics: Adenocarcinoma; Aged; Aggregatibacter actinomycetemcomitans; Carrier State; Case-Control Studies; Female; Fusobacteria; High-Throughput Nucleotide Sequencing; Humans; Male; Microbiota; Middle Aged; Mouth; Pancreatic Neoplasms; Periodontium; Porphyromonas gingivalis; Prospective Studies; Risk Factors
PubMed: 27742762
DOI: 10.1136/gutjnl-2016-312580 -
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 -
Nature Apr 2024Fusobacterium nucleatum (Fn), a bacterium present in the human oral cavity and rarely found in the lower gastrointestinal tract of healthy individuals, is enriched in...
Fusobacterium nucleatum (Fn), a bacterium present in the human oral cavity and rarely found in the lower gastrointestinal tract of healthy individuals, is enriched in human colorectal cancer (CRC) tumours. High intratumoural Fn loads are associated with recurrence, metastases and poorer patient prognosis. Here, to delineate Fn genetic factors facilitating tumour colonization, we generated closed genomes for 135 Fn strains; 80 oral strains from individuals without cancer and 55 unique cancer strains cultured from tumours from 51 patients with CRC. Pangenomic analyses identified 483 CRC-enriched genetic factors. Tumour-isolated strains predominantly belong to Fn subspecies animalis (Fna). However, genomic analyses reveal that Fna, considered a single subspecies, is instead composed of two distinct clades (Fna C1 and Fna C2). Of these, only Fna C2 dominates the CRC tumour niche. Inter-Fna analyses identified 195 Fna C2-associated genetic factors consistent with increased metabolic potential and colonization of the gastrointestinal tract. In support of this, Fna C2-treated mice had an increased number of intestinal adenomas and altered metabolites. Microbiome analysis of human tumour tissue from 116 patients with CRC demonstrated Fna C2 enrichment. Comparison of 62 paired specimens showed that only Fna C2 is tumour enriched compared to normal adjacent tissue. This was further supported by metagenomic analysis of stool samples from 627 patients with CRC and 619 healthy individuals. Collectively, our results identify the Fna clade bifurcation, show that specifically Fna C2 drives the reported Fn enrichment in human CRC and reveal the genetic underpinnings of pathoadaptation of Fna C2 to the CRC niche.
Topics: Animals; Humans; Mice; Adenoma; Case-Control Studies; Colorectal Neoplasms; Feces; Fusobacterium nucleatum; Gastrointestinal Tract; Genome, Bacterial; Mouth; Female
PubMed: 38509359
DOI: 10.1038/s41586-024-07182-w -
Genome Research Feb 2012The tumor microenvironment of colorectal carcinoma is a complex community of genomically altered cancer cells, nonneoplastic cells, and a diverse collection of...
The tumor microenvironment of colorectal carcinoma is a complex community of genomically altered cancer cells, nonneoplastic cells, and a diverse collection of microorganisms. Each of these components may contribute to carcinogenesis; however, the role of the microbiota is the least well understood. We have characterized the composition of the microbiota in colorectal carcinoma using whole genome sequences from nine tumor/normal pairs. Fusobacterium sequences were enriched in carcinomas, confirmed by quantitative PCR and 16S rDNA sequence analysis of 95 carcinoma/normal DNA pairs, while the Bacteroidetes and Firmicutes phyla were depleted in tumors. Fusobacteria were also visualized within colorectal tumors using FISH. These findings reveal alterations in the colorectal cancer microbiota; however, the precise role of Fusobacteria in colorectal carcinoma pathogenesis requires further investigation.
Topics: Colorectal Neoplasms; Fusobacterium; Genome, Bacterial; Humans; Intestine, Large; Metagenome; Phylogeny; RNA, Ribosomal, 16S; Sequence Analysis, DNA
PubMed: 22009990
DOI: 10.1101/gr.126573.111