Leucine restriction ameliorates Fusobacteriumnucleatum-driven malignant progression and radioresistance in nasopharyngeal carcinoma.

Radiotherapy resistance is the main cause of treatment failure among patients with nasopharyngeal carcinoma (NPC). Recently, increasing evidence has linked the presence of intratumoral Fusobacterium nucleatum (Fn) with the malignant progression and therapeutic resistance of multiple tumor types, but its influence on NPC has remained largely unknown. We found that Fn is prevalent in the tumor tissue of patients with NPC and is associated with radioresistance. Fn invaded and proliferated inside NPC cells and aggravated tumor progression. Mechanistically, Fn slowed mitochondrial dysfunction by promoting mitochondrial fusion and decreasing ROS generation, preventing radiation-induced oxidative damage. Fn inhibited PANoptosis by the SLC7A5/leucine-mTORC1 axis during irradiation stress, thus promoting radioresistance. Treatment with the mitochondria-targeted antibiotics or dietary restriction of leucine reduced intratumoral Fn load, resensitizing tumors to radiotherapy in vivo. These findings demonstrate that Fn has the potential to be a predictive marker for radioresistance and to help guide individualized treatment for patients with NPC.

Fusobacterium nucleatum: Unraveling its potential role in gastric carcinogenesis.

Fusobacterium nucleatum (F. nucleatum) is a Gram-negative anaerobic bacterium that plays a key role in the development of oral inflammation, such as periodontitis and gingivitis. In the last 10 years, F. nucleatum has been identified as a prevalent bacterium associated with colorectal adenocarcinoma and has also been linked to cancer progression, metastasis and poor disease outcome. While the role of F. nucleatum in colon carcinogenesis has been intensively studied, its role in gastric carcinogenesis is still poorly understood. Although Helicobacter pylori infection has historically been recognized as the strongest risk factor for the development of gastric cancer (GC), with recent advances in DNA sequencing technology, other members of the gastric microbial community, and F. nucleatum in particular, have received increasing attention. In this review, we summarize the existing knowledge on the involvement of F. nucleatum in gastric carcinogenesis and address the potential translational and clinical significance of F. nucleatum in GC.

Reexamining the role of Fusobacterium nucleatum subspecies in clinical and experimental studies.

The Gram-negative anaerobic species Fusobacterium nucleatum was originally described as a commensal organism from the human oral microbiome. However, it is now widely recognized as a key inflammophilic pathobiont associated with a wide variety of oral and extraoral diseases. Historically, F. nucleatum has been classified into four subspecies that have been generally considered as functionally interchangeable in their pathogenic potential. Recent studies have challenged this notion, as clinical data reveal a highly biased distribution of F. nucleatum subspecies within disease sites of both inflammatory oral diseases and various malignancies. This review details the historical basis for the F. nucleatum subspecies designations and summarizes our current understanding of the similarities and distinctions between these organisms to provide important context for future clinical and laboratory studies of F. nucleatum.

Single-cell RNA sequencing analysis reveals the distinct features of colorectal cancer with or without Fusobacterium nucleatum infection in PD-L1 blockade therapy.

MSS/pMMR patients are unresponsive to PD-1/PD-L1 blockade in colorectal cancer (CRC), but the mechanisms are unclear. A better understanding of immunotherapy resistance in CRC may lead to more precise treatment and expand the benefit of immunotherapy to patients. In this study, we constructed mouse model of subcutaneous CRC tumor received anti-PD-L1 treatment with or without fusobacterium nucleatum (F. nucleatum) infection. Then we used single-cell RNA sequencing (scRNA-seq) to explore the comprehensive landscape of the tumor microenvironment (TME). Our data delineated the composition, subclonal diversity and putative function of distinct cells, tracked the developmental trajectory of tumor cells and highlighted cell-cell interactions. We found different compositions and functions of both tumor cells and immune cells. Single anti-PD-L1 monoclonal antibody (mAb) treated tumor exhibited two specific clusters which might be resistant to PD-L1 blockade. The accumulation of immune cells, including T cell, NK cell and pro-inflammatory macrophage subset in tumors infected with F. nucleatum may be one of the reasons for the increased sensitivity to PD-L1 blockade. Thus, targeting F. nucleatum to change the composition of tumor cell subclusters and enliven the immune response might help to overcome immune checkpoint blockade (ICB) resistance.

Fusobacterium nucleatum induces invasive growth and angiogenic responses in malignant oral keratinocytes that are cell line- and bacterial strain-specific.

Fusobacterium nucleatum is an anaerobic commensal of the oral cavity recently reported to be associated with cancers of the gastrointestinal tract and oral squamous cell carcinoma (OSCC). In this study, we investigate the impact on oral keratinocytes of infection with a genetically diverse set of strains of F. nucleatum subsp. polymorphum recovered from patients with oral dysplasia (n=6). We employed H357 oral keratinocytes derived from a stage 1 OSCC and H376 cells derived from a stage 3 OSCC. Adhesion phenotypes were strain specific, with 3/6 clinical isolates examined exhibiting higher adherence to the stage 3 H376 cell line. Conversely, intracellular invasion was greatest in the H357 cells and was associated with specific transcriptional responses including autophagy and keratinization. Infection of both H357 and H376 cell lines induced transcriptional and cytokine responses linked to cancer cell migration and angiogenesis. F. nucleatum infection induced greater levels of MMP9 secretion in the H376 cell line which was associated with enhanced motility and invasion phenotypes. Additionally, the degree of F. nucleatum induced invasive growth by H376 cells varied between different clinical isolates of F. nucleatum subsp. polymorphum. Blockage of CCL5 signalling using the inhibitor metCCL5 resulted in reduced keratinocyte invasion. F. nucleatum infection also induced expression of the pro-angiogenic chemokine MCP-1 and the angiogenic growth factor VEGF-A resulting in increased capillary-like tube formation in HUVEC cells, most significantly in H376 cells. Treatment of HUVEC cells with resveratrol, a VEGF-A signalling inhibitor, significantly attenuated F. nucleatum induced tube formation. Our data indicate that the outcomes of F. nucleatum-oral cell interactions can vary greatly depending on the bacterial genotype and the malignant phenotype of the host cell.

Fusobacterium nucleatum facilitates anti-PD-1 therapy in microsatellite stable colorectal cancer.

Microsatellite stable (MSS) colorectal cancers (CRCs) are often resistant to anti-programmed death-1 (PD-1) therapy. Here, we show that a CRC pathogen, Fusobacterium nucleatum (Fn), paradoxically sensitizes MSS CRC to anti-PD-1. Fecal microbiota transplantation (FMT) from patients with Fn-high MSS CRC to germ-free mice bearing MSS CRC confers sensitivity to anti-PD-1 compared to FMT from Fn-low counterparts. Single Fn administration also potentiates anti-PD-1 efficacy in murine allografts and CD34+-humanized mice bearing MSS CRC. Mechanistically, we demonstrate that intratumoral Fn generates abundant butyric acid, which inhibits histone deacetylase (HDAC) 3/8 in CD8+ T cells, inducing Tbx21 promoter H3K27 acetylation and expression. TBX21 transcriptionally represses PD-1, alleviating CD8+ T cell exhaustion and promoting effector function. Supporting this notion, knockout of a butyric acid-producing gene in Fn abolishes its anti-PD-1 boosting effect. In patients with MSS CRC, high intratumoral Fn predicts favorable response to anti-PD-1 therapy, indicating Fn as a potential biomarker of immunotherapy response in MSS CRC.

Fusobacterium Nucleatum Promotes Microsatellite Instability in Colorectal Carcinoma Through Up-regulation of miRNA-155-5p-Targeted Inhibition of MSH6 via the TLR4/NF-κB Signaling Pathway.

Fusobacterium nucleatum (Fn) is significantly associated with poor prognosis in colorectal carcinoma (CRC), however, mechanisms of Fn in DNA mismatch repair (MMR) and microsatellite instability (MSI) in CRC have not been fully elucidated. Clinical samples are collected to analyze the relationship between Fn abundance and microsatellite stability. Tumor cells are treated with Fn to detect the expression of proteins related to toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88), mutS homolog 6 (MSH6), and nuclear factor-κB (NF-κB) signaling pathways, respectively. Combined with the prediction results from TargetScan, the regulatory role of microRNA upstream of MSH6 is demonstrated. The effect of this regulatory axis on CRC development is demonstrated using a nude mouse tumor model. Compared with microsatellite stability (MSS)-type CRC patients, MSI-type showed higher Fn abundance. Fn treatment of CRC cells activated TLR4/Myd88/NF-κB signaling pathway, transcriptionally activating miRNA-155-5p expression, thereby negatively regulating MSH6. Fn treatment accelerated the malignant progression of CRC in mice, and this process is inhibited by miRNA-155-5p antagomir. Fn in CRC upregulated miRNA-155-5p by activating TLR4/NF-κB signaling to inhibit MSH6, and this regulatory pathway may affect MSS of cancer cells.

Fusobacterium nucleatum: a novel regulator of antitumor immune checkpoint blockade therapy in colorectal cancer.

Neoadjuvant immune checkpoint blockade (ICB) has achieved significant success in treating various cancers, leading to improved therapeutic responses and survival rates among patients. However, in colorectal cancer (CRC), ICB has yielded poor results in tumors that are mismatch repair proficient, microsatellite-stable, or have low levels of microsatellite instability (MSI-L), which account for up to 95% of CRC cases. The underlying mechanisms behind the lack of immune response in MSI-negative CRC to immune checkpoint inhibitors remain an open conundrum. Consequently, there is an urgent need to explore the intrinsic mechanisms and related biomarkers to enhance the intratumoral immune response and render the tumor "immune-reactive". Intestinal microbes, such as the oral microbiome member Fusobacterium nucleatum (F. nucleatum), have recently been thought to play a crucial role in regulating effective immunotherapeutic responses. Herein, we advocate the idea that a complex interplay involving F. nucleatum, the local immune system, and the tumor microenvironment (TME) significantly influences ICB responses. Several mechanisms have been proposed, including the regulation of immune cell proliferation, inhibition of T lymphocyte, natural killer (NK) cell function, and invariant natural killer T (iNKT) cell function, as well as modification of the TME. This review aims to summarize the latest potential roles and mechanisms of F. nucleatum in antitumor immunotherapies for CRC. Additionally, it discusses the clinical application value of F. nucleatum as a biomarker for CRC and explores novel strategies, such as nano-delivery systems, for modulating F. nucleatum to enhance the efficacy of ICB therapy.

The role of Fusobacterium nucleatum in the pathogenesis of colon cancer.

Previously, many studies have reported changes in the gut microbiota of patients with colorectal cancer (CRC). While CRC is a well-described disease, the relationship between its development and features of the intestinal microbiome is still being understood. Evidence linking Fusobacterium nucleatum enrichment in colorectal tumor tissue has prompted the elucidation of various molecular mechanisms and tumor-promoting attributes. In this review we highlight various aspects of our understanding of the relationship between the development of CRC and the alteration of intestinal microbiome, focusing specifically on the role of F. nucleatum. As the amount of F. nucleatum DNA in CRC tissue is associated with shorter survival, it may potentially serve as a prognostic biomarker, and most importantly may open the door for a role in CRC treatment.

A Rare Case of Cerebral Abscess due to Fusobacterium nucleatum with Native Aortic Valve Infective Endocarditis and Pyogenic Liver Abscess.

Fusobacterium nucleatum is a commensal pathogen typically found in the oral cavity, digestive tract, and urogenital system which has been associated with Lemierre's syndrome, periodontal diseases, sinusitis, endocarditis, and intra-abdominal and brain abscesses. Our case is of a 62-year-old male who presented with headaches, nausea, and vision loss. Brain imaging identified a right occipito-parietal brain abscess. Following surgery and abscess drainage, Fusobacterium nucleatum was isolated from intraoperative cultures, and the infectious disease service was consulted for antibiotic recommendations. Additional history uncovered that he had also been experiencing night sweats, generalized weakness and 40-pound weight loss for 2 months, and had a prior history of colon polyps and diverticulitis. Furthermore, the patient disclosed having substandard oral hygiene practices, particularly in relation to the care of his dental appliances. Despite negative blood cultures, suspicion for hematogenous seeding was high. Imaging ruled out periodontal disease, but identified a colovesical fistula and liver abscesses, indicating potential translocation of bacteria via portal circulation to his liver. Echocardiogram workup revealed a 1-cm mobile vegetation on the aortic valve. His course was complicated by breakthrough seizures, renal failure, and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, and he ultimately completed 16 weeks of antibiotics. This case illustrates an uncommon presentation of brain abscess in an immunocompetent adult, with a prior episode of diverticulitis as the probable primary infection source, leading to development of a colovesical fistula and bacterial dissemination to the liver, heart, and brain. It highlights the importance of a comprehensive diagnostic approach, including consideration of atypical pathogens in immunocompetent adults.

Circulating Bacterial DNA in Colorectal Cancer Patients: The Potential Role of Fusobacterium nucleatum.

Intestinal dysbiosis is a major contributor to colorectal cancer (CRC) development, leading to bacterial translocation into the bloodstream. This study aimed to evaluate the presence of circulated bacterial DNA (cbDNA) in CRC patients (n = 75) and healthy individuals (n = 25). DNA extracted from peripheral blood was analyzed using PCR, with specific primers targeting 16S rRNA, Escherichia coli (E. coli), and Fusobacterium nucleatum (F. nucleatum). High 16S rRNA and E. coli detections were observed in all patients and controls. Only the detection of F. nucleatum was significantly higher in metastatic non-excised CRC, compared to controls (p < 0.001), non-metastatic excised CRC (p = 0.023), and metastatic excised CRC (p = 0.023). This effect was mainly attributed to the presence of the primary tumor (p = 0.006) but not the presence of distant metastases (p = 0.217). The association of cbDNA with other clinical parameters or co-morbidities was also evaluated, revealing a higher detection of E. coli in CRC patients with diabetes (p = 0.004). These results highlighted the importance of bacterial translocation in CRC patients and the potential role of F. nucleatum as an intratumoral oncomicrobe in CRC.

Fusobacterium nucleatum, immune responses, and metastatic organ diversity in colorectal cancer liver metastasis.

The presence of Fusobacterium nucleatum is associated with an immunosuppressive tumor immune microenvironment (TIM) in primary colorectal cancer (CRC), contributing to tumor progression. Its persistence in CRC liver metastasis tissues raises questions about its role in modulating local and systemic immune responses and influencing recurrence patterns. This retrospective cohort study of 218 patients with CRC liver metastasis investigated the association of F. nucleatum in CRC liver metastasis tissues with systemic inflammation, TIM alterations, and the number of metastatic organs involved in recurrence. Two-step polymerase chain reaction (PCR), including digital PCR, detected F. nucleatum in 42% (92/218) of fresh-frozen specimens of CRC liver metastases. Compared with the F. nucleatum-none group, the F. nucleatum-high group showed higher C-reactive protein levels (0.82 vs. 0.22 mg/dL; Ptrend = 0.02), lower numbers of CD8+ cells (33.2 vs. 65.3 cells/mm2; Ptrend = 0.04) and FOXP3+ cells (11.3 vs. 21.7 cells/mm2; Ptrend = 0.01) in the TIM, and a greater number of metastatic organs involved in recurrence (1.6 vs. 1.1; p < 0.001). The presence of F. nucleatum in CRC liver metastasis tissues was associated with increased systemic inflammation, TIM alterations, and a greater number of metastatic organs involved in recurrence. These findings suggest a potential contribution of F. nucleatum to the metastatic propensity of CRC cells and could inform future research to enhance understanding of the interaction between tumor, host, and microbes in the metastatic process.

Less is more! Low amount of Fusobacterium nucleatum supports macrophage-mediated trophoblast functions in vitro.

F. nucleatum, involved in carcinogenesis of colon carcinomas, has been described as part of the commensal flora of the female upper reproductive tract. Although its contribution to destructive inflammatory processes is well described, its role as commensal uterine bacteria has not been thoroughly investigated. Since carcinogenesis shares similar mechanisms with early pregnancy development (including proliferation, invasion, blood supply and the induction of tolerance), these mechanisms induced by F. nucleatum could play a role in early pregnancy. Additionally, implantation and placentation require a well-balanced immune activation, which might be suitably managed by the presence of a limited amount of bacteria or bacterial residues. We assessed the effect of inactivated F. nucleatum on macrophage-trophoblast interactions. Monocytic cells (THP-1) were polarized into M1, M2a or M2c macrophages by IFN-γ, IL-4 or TGF-ß, respectively, and subsequently treated with inactivated fusobacteria (bacteria:macrophage ratio of 0.1 and 1). Direct effects on macrophages were assessed by viability assay, flow cytometry (antigen presentation molecules and cytokines), qPCR (cytokine expression), in-cell Western (HIF and P-NF-κB) and ELISA (VEGF secretion). The function of first trimester extravillous trophoblast cells (HTR-8/SVneo) in response to macrophage-conditioned medium was microscopically assessed by migration (scratch assay), invasion (sprouting assay) and tube formation. Underlying molecular changes were investigated by ELISA (VEGF secretion) and qPCR (matrix-degrading factors and regulators). Inflammation-primed macrophages (M1) as well as high bacterial amounts increased pro-inflammatory NF-κB expression and inflammatory responses. Subsequently, trophoblast functions were impaired. In contrast, low bacterial stimulation caused an increased HIF activation and subsequent VEGF-A secretion in M2c macrophages. Accordingly, there was an increase of trophoblast tube formation. Our results suggest that a low-mass endometrial/decidual microbiome can be tolerated and while it supports implantation and further pregnancy processes.

Unveiling the Hidden Links: Periodontal Disease, Fusobacterium Nucleatum, and Cancers.

PURPOSE OF REVIEW: Fusobacterium nucleatum (F. nucleatum), an anaerobic, gram-negative microbe, commonly found in human dental biofilm and the gut flora. It has long been known to have a higher concentration in periodontal disease and has recently been implicated in both oral and distant cancers such as colorectal, gastrointestinal, esophageal, breast, pancreatic hepatocellular, and genitourinary cancers. However, the mechanism of its involvement in the development of cancer has not been fully discussed. This review aims to cover biological molecular and clinical aspects of F. nucleatum and cancers. RECENT FINDINGS: Studies indicate F. nucleatum promotes tumor development through chronic inflammation, immune evasion, cell proliferation activation, and direct cell interactions, as in oral squamous cell carcinoma (OSCC). In colorectal cancer (CRC), F. nucleatum contributes to tumorigenesis through ß-catenin signaling and NF-κB activation. It also induces autophagy, leading to chemoresistance in CRC and esophageal cancers, and enhances tumor growth and metastasis in breast cancer by reducing T-cell infiltration. F. nucleatum is linked to carcinogenesis and increased bacterial diversity in OSCC, with improved oral hygiene potentially preventing OSCC. F. nucleatum triggers cancer by causing mutations and epigenetic changes through cytokines and reactive oxygen species. It also promotes chemoresistance in CRC. F. nucleatum may potentially serve as a diagnostic tool in various cancers, with non-invasive detection methods available. Further investigation is needed to discover its potential in the diagnosis and treatment of OSCC and other cancers.

Lavandula angustifolia Essential Oil Inhibits the Ability of Fusobacterium nucleatum to Produce Volatile Sulfide Compounds, a Key Components in Oral Malodor.

Oral malodor still constitutes a major challenge worldwide. A strong effort is invested in eliminating volatile sulfur compound-producing oral bacteria through organic natural products such as essential oils. Fusobacterium nucleatum is a known volatile sulfur compound-producing bacteria that inspires oral malodor. The aim of the present study was to test the effect of lavender essential oil on the bacterium's ability to produce volatile sulfide compounds, the principal components of oral malodor. Lavender (Lavandula angustifolia) essential oil was extracted by hydrodistillation and analyzed using GC-MS. The minimal inhibitory concentration (MIC) of lavender essential oil on Fusobacterium nucleatum was determined in a previous trial. Fusobacterium nucleatum was incubated anaerobically in the presence of sub-MIC, MIC, and above MIC concentrations of lavender essential oil, as well as saline and chlorhexidine as negative and positive controls, respectively. Following incubation, volatile sulfur compound levels were measured using GC (Oralchroma), and bacterial cell membrane damage was studied using fluorescence microscopy. Chemical analysis of lavender essential oil yielded five main components, with camphor being the most abundant, accounting for nearly one-third of the total lavender essential oil volume. The MIC (4 µL/mL) of lavender essential oil reduced volatile sulfur compound secretion at a statistically significant level compared to the control (saline). Furthermore, the level of volatile sulfur compound production attributed to 1 MIC of lavender essential oil was in the range of the positive control chlorhexidine with no significant difference. When examining bacterial membrane damage, 2 MIC of lavender essential oil (i.e., 8 µL/mL) demonstrated the same, showing antibacterial membrane damage values comparative to chlorhexidine. Since lavender essential oil was found to be highly effective in hindering volatile sulfur compound production by Fusobacterium nucleatum through the induction of bacterial cell membrane damage, the results suggest that lavender essential oil may be a suitable alternative to conventional chemical-based anti-malodor agents.

Application of Fusobacterium nucleatum as a biomarker in gastrointestinal malignancies.

The morbidity and mortality of gastrointestinal (GI) malignancies are among the highest in the world, posing a serious threat to human health. Because of the insidious onset of the cancer, it is difficult for patients to be diagnosed at an early stage, and it rapidly progresses to an advanced stage, resulting in poor treatment and prognosis. Fusobacterium nucleatum (F. nucleatum) is a gram-negative, spore-free anaerobic bacterium that primarily colonizes the oral cavity and is implicated in the development of colorectal, esophageal, gastric, and pancreatic cancers via various intricate mechanisms. Recent development in novel research suggests that F. nucleatum may function as a biomarker in GI malignancies. Detecting the abundance of F. nucleatum in stool, saliva, and serum samples of patients may aid in the diagnosis, risk assessment, and prognosis monitoring of GI malignancies. This editorial systematically describes the biological roles and mechanisms of F. nucleatum in GI malignancies focusing on the application of F. nucleatum as a biomarker in the diagnosis and prognosis of GI malignancies to promote the clinical translation of F. nucleatum and GI tumors-related research.

The role of Fusobacterium nucleatum in cancer and its implications for clinical applications.

Fusobacterium nucleatum, a gram-negative anaerobic bacterium abundantly found in the human oral cavity, is widely recognized as a key pathobiont responsible for the initiation and progression of periodontal diseases due to its remarkable aggregative capabilities. Numerous clinical studies have linked F. nucleatum with unfavorable prognostic outcomes in various malignancies. In further research, scholars have partially elucidated the mechanisms underlying F. nucleatum's impact on various types of cancer, thus gaining a certain comprehension of the role played by F. nucleatum in cancer. In this comprehensive review, we present an in-depth synthesis of the interplay between F. nucleatum and different cancers, focusing on aspects such as tumor initiation, metastasis, chemoresistance, and modulation of the tumor immune microenvironment and immunotherapy. The implications for cancer diagnosis and treatment are also summarized. The objective of this review is to enhance our comprehension of the intricate relationship between F. nucleatum and oncogenic pathogenesis, while emphasizing potential therapeutic strategies.

Investigating the effect of Fusobacterium nucleatum on the aggressive behavior of cancer-associated fibroblasts in colorectal cancer.

Fusobacterium nucleatum, (F. nucleatum) as a known factor in inducing oncogenic, invasive, and inflammatory responses, can lead to an increase in the incidence and progression of colorectal cancer (CRC). Cancer-associated fibroblasts (CAF) are also one of the key components of the tumor microenvironment (TME), which lead to resistance to treatment, metastasis, and disease recurrence with their markers, secretions, and functions. This study aimed to investigate the effect of F. nucleatum on the invasive phenotype and function of fibroblast cells isolated from normal and cancerous colorectal tissue. F. nucleatum bacteria were isolated from deep periodontal pockets and confirmed by various tests. CAF cells from tumor tissue and normal fibroblasts (NF) from a distance of 10 cm of tumor tissue were isolated from 5 patients by the explant method and were exposed to secretions and ghosts of F. nucleatum. The expression level of two markers, fibroblast activation protein (FAP), and α-smooth muscle actin (α-SMA), and the amount of production of two cytokines TGF-ß and IL-6 from fibroblast cells were measured by flow cytometry and ELISA test, respectively before and after exposure to different bacterial components. The expression of the FAP marker was significantly higher in CAF cells compared to NF cells (P < 0.05). Also, the expression of IL-6 in CAF cells was higher than that of NF cells. In investigating the effect of bacterial components on the function of fibroblastic cells, after comparing the amount of IL-6 produced between the normal tissue of each patient and his tumoral tissue under 4 treated conditions, it was found that the amount of IL-6 production from the CAF cells of patients in the control group, treated with heat-killed ghosts and treated with paraformaldehyde-fixed ghosts had a significant increase compared to NF cells (P < 0.05). Due to the significant increase in FAP marker expression in fibroblast cells of tumor tissue compared to normal tissue, it seems that FAP can be used as a very good therapeutic marker, especially in patients with high levels of CAF cells. Various components of F. nucleatum could affect fibroblast cells differentially and at least part of the effect of this bacterium in the TME is mediated by CAF cells.

Antibacterial tellurium-containing polycarbonate drug carriers to eliminate intratumor bacteria for synergetic chemotherapy against colorectal cancer.

Intratumor microbes have attracted great attention in cancer research due to its influence on the tumorigenesis, progression and metastasis of cancer. However, the therapeutic strategies targeting intratumoral microbes are still in their infancy. Specific microorganisms, such as Fusobacterium nucleatum (F. nucleatum), are abundant in various cancer and always result in the CRC progression and chemotherapy resistance. Here, a combined anticancer and antibacterial therapeutic strategy is proposed to deliver antitumor drug to the tumors containing intratumor microbiota by the antibacerial polymeric drug carriers. We construct oral tellurium-containing drug carriers using a complex of tellurium-containing polycarbonate with cisplatin (PTE@CDDP). The results show that the particle size of the prepared nanoparticles could be maintained at about 105 nm in the digestive system environment, which is in line with the optimal particle size of oral nanomedicine. In vitro mechanism study indicates that the tellurium-containing polymers are highly effective in killing F.nucleatum through a membrane disruption mechanism. The pharmacokinetic experiments confirmed that PTE@CDDP has the potential function of enhancing the oral bioavailability of cisplatin. Both in vitro and in vivo studies show that PTE@CDDP could inhibit intratumor F.nucleatum and lead to a reduction in cell proliferation and inflammation in the tumor site. Together, the study identifies that the CDDP-loaded tellurium-containing nanoparticles have great potential for treating the F.nucleatum-promoted colorectal cancer (CRC) by combining intratumor microbiota modulation and chemotherapy. The synergistic therapeutic strategy provide new insight into treating various cancers combined with bacterial infection. STATEMENT OF SIGNIFICANCE: The synthesized antibacterial polymer was first employed to remodel the intratumor microbes in tumor microenvironment (TME). Moreover, it was the first report of tellurium-containing polymers against F.nucleatum and employed for treatment of the CRC. A convenient oral dosage form of cisplatin (CDDP)-loaded tellurium-containing nanoparticles (PTE@CDDP) was adopted here, and the synergistic antibacterial/chemotherapy effect occurred. The PTE@CDDP could quickly and completely eliminate F.nucleatum in a safe dose. In the CRC model, PTE@CDDP effectively reversed the inflammation level and even restored the intestinal barrier damaged by F.nucleatum. The ultrasensitive ROS-responsiveness of PTE@CDDP triggered the fast oxidation and efficient drug release of CDDP and thus a highly efficient apoptosis of the tumors. Therefore, the tellurium-containing polymers are expected to serve as novel antibacterial agents in vivo and have great potential in the F.nucleatum-associated cancers. The achievements provided new insight into treating CRC and other cancers combined with bacterial infection.

Effect of three oral pathogens on the TMA-TMAO metabolic pathway.

Background: Trimethylamine-N-oxide (TMAO) is produced by hepatic flavin-containing monooxygenase 3 (FMO3) from trimethylamine (TMA). High TMAO level is a biomarker of cardiovascular diseases and metabolic disorders, and it also affects periodontitis through interactions with the gastrointestinal microbiome. While recent findings indicate that periodontitis may alter systemic TMAO levels, the specific mechanisms linking these changes and particular oral pathogens require further clarification. Methods: In this study, we established a C57BL/6J male mouse model by orally administering Porphyromonas gingivalis (P. gingivalis, Pg), Fusobacterium nucleatum (F. nucleatum, Fn), Streptococcus mutans (S. mutans, Sm) and PBS was used as a control. We conducted LC-MS/MS analysis to quantify the concentrations of TMAO and its precursors in the plasma and cecal contents of mice. The diversity and composition of the gut microbiome were analyzed using 16S rRNA sequencing. TMAO-related lipid metabolism and enzymes in the intestines and liver were assessed by qPCR and ELISA methods. We further explored the effect of Pg on FMO3 expression and lipid molecules in HepG2 cells by stimulating the cells with Pg-LPS in vitro. Results: The three oral pathogenic bacteria were orally administered to the mice for 5 weeks. The Pg group showed a marked increase in plasma TMAO, betaine, and creatinine levels, whereas no significant differences were observed in the gut TMAO level among the four groups. Further analysis showed similar diversity and composition in the gut microbiomes of both the Pg and Fn groups, which were different from the Sm and control groups. The profiles of TMA-TMAO pathway-related genera and gut enzymes were not significantly different among all groups. The Pg group showed significantly higher liver FMO3 levels and elevated lipid factors (IL-6, TG, TC, and NEFA) in contrast to the other groups. In vitro experiments confirmed that stimulation of HepG2 cells with Pg-LPS upregulated the expression of FMO3 and increased the lipid factors TC, TG, and IL-6. Conclusion: This study conclusively demonstrates that Pg, compared to Fn and Sm, plays a critical role in elevating plasma TMAO levels and significantly influences the TMA-TMAO pathway, primarily by modulating the expression of hepatic FMO3 and directly impacting hepatic lipid metabolism.