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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 -
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 Aug 2017Cas13a, a type VI-A CRISPR-Cas RNA-guided RNA ribonuclease, degrades invasive RNAs targeted by CRISPR RNA (crRNA) and has potential applications in RNA technology. To...
Cas13a, a type VI-A CRISPR-Cas RNA-guided RNA ribonuclease, degrades invasive RNAs targeted by CRISPR RNA (crRNA) and has potential applications in RNA technology. To understand how Cas13a is activated to cleave RNA, we have determined the crystal structure of Leptotrichia buccalis (Lbu) Cas13a bound to crRNA and its target RNA, as well as the cryo-EM structure of the LbuCas13a-crRNA complex. The crRNA-target RNA duplex binds in a positively charged central channel of the nuclease (NUC) lobe, and Cas13a protein and crRNA undergo a significant conformational change upon target RNA binding. The guide-target RNA duplex formation triggers HEPN1 domain to move toward HEPN2 domain, activating the HEPN catalytic site of Cas13a protein, which subsequently cleaves both single-stranded target and collateral RNAs in a non-specific manner. These findings reveal how Cas13a of type VI CRISPR-Cas systems defend against RNA phages and set the stage for its development as a tool for RNA manipulation.
Topics: Bacterial Proteins; Base Sequence; CRISPR-Associated Proteins; CRISPR-Cas Systems; Leptotrichia; Models, Molecular; RNA Processing, Post-Transcriptional; RNA, Bacterial; RNA, Guide, CRISPR-Cas Systems; RNA, Viral; X-Ray Diffraction
PubMed: 28757251
DOI: 10.1016/j.cell.2017.06.050 -
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 -
Nature Biomedical Engineering Sep 2019The microbiota in the human gut is strongly correlated with the progression of colorectal cancer (CRC) and with therapeutic responses to CRC. Here, by leveraging the...
The microbiota in the human gut is strongly correlated with the progression of colorectal cancer (CRC) and with therapeutic responses to CRC. Here, by leveraging the higher concentration of the pro-tumoural Fusobacterium nucleatum and the absence of antineoplastic butyrate-producing bacteria in the faecal microbiota of patients with CRC, we show that-in mice with orthotopic colorectal tumours or with spontaneously formed colorectal tumours-oral or intravenous administration of irinotecan-loaded dextran nanoparticles covalently linked to azide-modified phages that inhibit the growth of F. nucleatum significantly augments the efficiency of first-line chemotherapy treatments of CRC. We also show that oral administration of the phage-guided irinotecan-loaded nanoparticles in piglets led to negligible changes in haemocyte counts, immunoglobulin and histamine levels, and liver and renal functions. Phage-guided nanotechnology for the modulation of the gut microbiota might inspire new approaches for the treatment of CRC.
Topics: Animals; Antineoplastic Agents; Bacteria; Bacteriophages; Butyrates; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Colorectal Neoplasms; Dextrans; Disease Models, Animal; Drug Therapy; Fusobacterium nucleatum; Gastrointestinal Microbiome; Immunoglobulins; Irinotecan; Male; Mice; Mice, Inbred C57BL; Nanoparticles
PubMed: 31332342
DOI: 10.1038/s41551-019-0423-2 -
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 Advanced Research Feb 2024Metastasis is an important cause of high mortality and lethality of oral cancer. Fusobacterium nucleatum (Fn) can promote tumour metastasis. Outer membrane vesicles...
INTRODUCTION
Metastasis is an important cause of high mortality and lethality of oral cancer. Fusobacterium nucleatum (Fn) can promote tumour metastasis. Outer membrane vesicles (OMVs) are secreted by Fn. However, the effects of Fn-derived extracellular vesicles on oral cancer metastasis and the underlying mechanisms are unclear.
OBJECTIVES
We aimed to determine whether and how Fn OMVs mediate oral cancer metastasis.
METHODS
OMVs were isolated from brain heart infusion (BHI) broth supernatant of Fn by ultracentrifugation. Tumour-bearing mice were treated with Fn OMVs to evaluate the effect of OMVs on cancer metastasis. Transwell assays were performed to determine how Fn OMVs affect cancer cell migration and invasion. The differentially expressed genes in Fn OMV-treated/untreated cancer cells were identified by RNA-seq. Transmission electron microscopy, laser confocal microscopy, and lentiviral transduction were used to detect changes in autophagic flux in cancer cells stimulated with Fn OMVs. Western blotting assay was performed to determine changes in EMT-related marker protein levels in cancer cells. Fn OMVs' effects on migration after blocking autophagic flux by autophagy inhibitors were determined by in vitro and in vivo experiments.
RESULTS
Fn OMVs were structurally similar to vesicles. In the in vivo experiment, Fn OMVs promoted lung metastasis in tumour-bearing mice, while chloroquine (CHQ, an autophagy inhibitor) treatment reduced the number of pulmonary metastases resulting from the intratumoral Fn OMV injection. Fn OMVs promoted the migration and invasion of cancer cells in vivo, leading to altered expression levels of EMT-related proteins (E-cadherin downregulation; Vimentin/N-cadherin upregulation). RNA-seq showed that Fn OMVs activate intracellular autophagy pathways. Blocking autophagic flux with CHQ reduced in vitro and in vivo migration of cancer cells induced by Fn OMVs as well as reversed changes in EMT-related protein expression.
CONCLUSION
Fn OMVs not only induced cancer metastasis but also activated autophagic flux. Blocking autophagic flux weakened Fn OMV-stimulated cancer metastasis.
Topics: Animals; Mice; Fusobacterium nucleatum; Mouth Neoplasms; Autophagy
PubMed: 37059221
DOI: 10.1016/j.jare.2023.04.002 -
International Journal of Molecular... Aug 2023Atherosclerosis (AS) is an inflammatory vascular disease that constitutes a major underlying cause of cardiovascular diseases (CVD) and stroke. Infection is a... (Review)
Review
Atherosclerosis (AS) is an inflammatory vascular disease that constitutes a major underlying cause of cardiovascular diseases (CVD) and stroke. Infection is a contributing risk factor for AS. Epidemiological evidence has implicated individuals afflicted by periodontitis displaying an increased susceptibility to AS and CVD. This review concisely outlines several prevalent periodontal pathogens identified within atherosclerotic plaques, including , , and . We review the existing epidemiological evidence elucidating the association between these pathogens and AS-related diseases, and the diverse mechanisms for which these pathogens may engage in AS, such as endothelial barrier disruption, immune system activation, facilitation of monocyte adhesion and aggregation, and promotion of foam cell formation, all of which contribute to the progression and destabilization of atherosclerotic plaques. Notably, the intricate interplay among bacteria underscores the complex impact of periodontitis on AS. In conclusion, advancing our understanding of the relationship between periodontal pathogens and AS will undoubtedly offer invaluable insights and potential therapeutic avenues for the prevention and management of AS.
Topics: Humans; Plaque, Atherosclerotic; Atherosclerosis; Fusobacterium nucleatum; Cardiovascular Diseases; Porphyromonas gingivalis
PubMed: 37629042
DOI: 10.3390/ijms241612861 -
Advanced Materials (Deerfield Beach,... Nov 2023Clinical evidence indicates that tumor-colonizing bacteria can be closely related to the tumor development and therapeutic responses. Selectively eliminating bacteria...
Clinical evidence indicates that tumor-colonizing bacteria can be closely related to the tumor development and therapeutic responses. Selectively eliminating bacteria within tumors may be an attractive approach to enhance cancer treatment without additional side effects. Herein, it is found that, owing to the high affinity between the membrane protein Fap-2 on Fusobacterium nucleatum and d-galactose-β (1-3)-N-acetyl-d-galactosamine (Gal-GalNAc) overexpressed on colorectal tumor cells, F. nucleatum can colonize in colorectal tumors, as evidenced by both clinical samples and animal tumor models. Notably, F. nucleatum colonized in colorectal tumors can lead to an immunosuppressive tumor microenvironment, greatly reducing their responses to immune checkpoint blockade (ICB) therapy. Inspired by this finding, an F. nucleatum-mimetic nanomedicine is designed by fusing F. nucleatum cytoplasmic membrane (FM) with Colistin-loaded liposomes to achieve selective killing of tumor-colonizing F. nucleatum without affecting gut microbes. As a result, the therapeutic responses of F. nucleatum-colonized tumors to ICB therapies can be successfully restored, as demonstrated in an F. nucleatum-infected subcutaneous CT-26 tumor model, chemically induced spontaneous colorectal cancer models, and MC-38 tumor model. In summary, this work presents an F. nucleatum-mimicking nanomedicine that can selectively eliminate tumor-colonized bacteria, which is promising for enhancing the responses of cancer immunotherapy against F. nucleatum-colonized colorectal cancer.
Topics: Animals; Fusobacterium nucleatum; Nanomedicine; Colorectal Neoplasms; Anti-Bacterial Agents; Immunotherapy; Tumor Microenvironment
PubMed: 37722134
DOI: 10.1002/adma.202306281 -
Advanced Drug Delivery Reviews Jun 2024The microbiome has emerged as a significant biomarker and modulator in cancer development and treatment response. Recent research highlights the notable role of... (Review)
Review
The microbiome has emerged as a significant biomarker and modulator in cancer development and treatment response. Recent research highlights the notable role of Fusobacterium nucleatum (F. nucleatum) in various tumor types, including breast, colorectal, esophageal, gastric, pancreatic, and lung cancers. Accumulating evidence suggests that the local microbial community forms an integral component of the tumor microenvironment, with bacterial communities within tumors displaying specificity to tumor types. Mechanistic investigations indicate that tumor-associated microbiota can directly influence tumor initiation, progression, and responses to chemotherapy or immunotherapy. This article presents a comprehensive review of microbial communities especially F. nucleatum in tumor tissue, exploring their roles and underlying mechanisms in tumor development, treatment, and prevention. When the tumor-associated F. nucleatum is killed, the host immune response is activated to recognize tumor cells. Bacteria epitopes restricted by the host antigens, can be identified for future anti-bacteria/tumor vaccine development.
Topics: Humans; Fusobacterium nucleatum; Neoplasms; Drug Delivery Systems; Carcinogenesis; Tumor Microenvironment; Animals
PubMed: 38643839
DOI: 10.1016/j.addr.2024.115319