-
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 Jul 2017Gut microbiota are linked to chronic inflammation and carcinogenesis. Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer...
Gut microbiota are linked to chronic inflammation and carcinogenesis. Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer patients. Here, we investigated the contribution of gut microbiota to chemoresistance in patients with colorectal cancer. We found that Fusobacterium (F.) nucleatum was abundant in colorectal cancer tissues in patients with recurrence post chemotherapy, and was associated with patient clinicopathological characterisitcs. Furthermore, our bioinformatic and functional studies demonstrated that F. nucleatum promoted colorectal cancer resistance to chemotherapy. Mechanistically, F. nucleatum targeted TLR4 and MYD88 innate immune signaling and specific microRNAs to activate the autophagy pathway and alter colorectal cancer chemotherapeutic response. Thus, F. nucleatum orchestrates a molecular network of the Toll-like receptor, microRNAs, and autophagy to clinically, biologically, and mechanistically control colorectal cancer chemoresistance. Measuring and targeting F. nucleatum and its associated pathway will yield valuable insight into clinical management and may ameliorate colorectal cancer patient outcomes.
Topics: Animals; Antineoplastic Agents; Autophagy; Capecitabine; Colorectal Neoplasms; Drug Resistance, Neoplasm; Fusobacterium nucleatum; Gastrointestinal Microbiome; Heterografts; Mice; MicroRNAs; Neoplasm Transplantation; Platinum Compounds; Recurrence; Toll-Like Receptors; Tumor Microenvironment
PubMed: 28753429
DOI: 10.1016/j.cell.2017.07.008 -
Cell Host & Microbe May 2023Immune checkpoint blockade therapy with anti-PD-1 monoclonal antibody (mAb) is a treatment for colorectal cancer (CRC). However, some patients remain unresponsive to...
Immune checkpoint blockade therapy with anti-PD-1 monoclonal antibody (mAb) is a treatment for colorectal cancer (CRC). However, some patients remain unresponsive to PD-1 blockade. The gut microbiota has been linked to immunotherapy resistance through unclear mechanisms. We found that patients with metastatic CRC who fail to respond to immunotherapy had a greater abundance of Fusobacterium nucleatum and increased succinic acid. Fecal microbiota transfer from responders with low F. nucleatum, but not F. nucleatum-high non-responders, conferred sensitivity to anti-PD-1 mAb in mice. Mechanistically, F. nucleatum-derived succinic acid suppressed the cGAS-interferon-β pathway, consequently dampening the antitumor response by limiting CD8 T cell trafficking to the tumor microenvironment (TME) in vivo. Treatment with the antibiotic metronidazole reduced intestinal F. nucleatum abundance, thereby decreasing serum succinic acid levels and resensitizing tumors to immunotherapy in vivo. These findings indicate that F. nucleatum and succinic acid induce tumor resistance to immunotherapy, offering insights into microbiota-metabolite-immune crosstalk in CRC.
Topics: Animals; Mice; Fusobacterium nucleatum; Colorectal Neoplasms; Succinic Acid; Fusobacterium Infections; Immunotherapy; Tumor Microenvironment
PubMed: 37130518
DOI: 10.1016/j.chom.2023.04.010 -
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 -
Nature Communications Jun 2020Fusobacterium nucleatum is an oral anaerobe recently found to be prevalent in human colorectal cancer (CRC) where it is associated with poor treatment outcome. In mice,...
Fusobacterium nucleatum is an oral anaerobe recently found to be prevalent in human colorectal cancer (CRC) where it is associated with poor treatment outcome. In mice, hematogenous F. nucleatum can colonize CRC tissue using its lectin Fap2, which attaches to tumor-displayed Gal-GalNAc. Here, we show that Gal-GalNAc levels increase as human breast cancer progresses, and that occurrence of F. nucleatum gDNA in breast cancer samples correlates with high Gal-GalNAc levels. We demonstrate Fap2-dependent binding of the bacterium to breast cancer samples, which is inhibited by GalNAc. Intravascularly inoculated Fap2-expressing F. nucleatum ATCC 23726 specifically colonize mice mammary tumors, whereas Fap2-deficient bacteria are impaired in tumor colonization. Inoculation with F. nucleatum suppresses accumulation of tumor infiltrating T cells and promotes tumor growth and metastatic progression, the latter two of which can be counteracted by antibiotic treatment. Thus, targeting F. nucleatum or Fap2 might be beneficial during treatment of breast cancer.
Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Colony Count, Microbial; DNA, Bacterial; Disease Models, Animal; Disease Progression; Female; Fusobacterium nucleatum; Galactosamine; Galactose; Genome, Bacterial; Humans; Immunity; Lung Neoplasms; Mice, Inbred BALB C; Neoplasm Metastasis
PubMed: 32591509
DOI: 10.1038/s41467-020-16967-2 -
MBio Mar 2021Multiple studies have implicated microbes in the development of inflammation, but the mechanisms remain unknown. Bacteria in the genus have been identified in the...
Multiple studies have implicated microbes in the development of inflammation, but the mechanisms remain unknown. Bacteria in the genus have been identified in the intestinal mucosa of patients with digestive diseases; thus, we hypothesized that promotes intestinal inflammation. The addition of >50 kDa conditioned media, which contain outer membrane vesicles (OMVs), to colonic epithelial cells stimulated secretion of the proinflammatory cytokines interleukin-8 (IL-8) and tumor necrosis factor (TNF). In addition, purified OMVs, but not compounds <50 kDa, stimulated IL-8 and TNF production; which was decreased by pharmacological inhibition of Toll-like receptor 4 (TLR4). These effects were linked to downstream effectors p-ERK, p-CREB, and NF-κB. >50-kDa compounds also stimulated TNF secretion, p-ERK, p-CREB, and NF-κB activation in human colonoid monolayers. In mice harboring a human microbiota, pretreatment with antibiotics and a single oral gavage of resulted in inflammation. Compared to mice receiving vehicle control, mice treated with showed disruption of the colonic architecture, with increased immune cell infiltration and depleted mucus layers. Analysis of mucosal gene expression revealed increased levels of proinflammatory cytokines (KC, TNF, IL-6, IFN-γ, and MCP-1) at day 3 and day 5 in -treated mice compared to controls. These proinflammatory effects were absent in mice who received without pretreatment with antibiotics, suggesting that an intact microbiome is protective against -mediated immune responses. These data provide evidence that promotes proinflammatory signaling cascade in the context of a depleted intestinal microbiome. Several studies have identified an increased abundance of in the intestinal tracts of patients with colon cancer, liver cirrhosis, primary sclerosing cholangitis, gastroesophageal reflux disease, HIV infection, and alcoholism. However, the direct mechanism(s) of action of on pathophysiological within the gastrointestinal tract is unclear. These studies have identified that subsp. releases outer membrane vesicles which activate TLR4 and NF-κB to stimulate proinflammatory signals Using mice harboring a human microbiome, we demonstrate that can promote inflammation, an effect which required antibiotic-mediated alterations in the gut microbiome. Collectively, these results suggest a mechanism by which may contribute to intestinal inflammation.
Topics: Animals; Bacterial Outer Membrane; Cells, Cultured; Colon; Culture Media; Cytokines; Epithelial Cells; Extracellular Vesicles; Female; Fusobacterium nucleatum; Gastrointestinal Microbiome; HT29 Cells; Humans; Inflammation; Intestines; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Signal Transduction; Toll-Like Receptor 4
PubMed: 33653893
DOI: 10.1128/mBio.02706-20 -
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