Pancreatic cancers have high mortality and rising incidence rates which may be related to unhealthy western-type dietary and lifestyle patterns as well as increasing body weights and obesity rates. Recent data also suggest a role for the gut microbiome in the development of pancreatic cancer. Here, we review the experimental and observational evidence for the roles of the oral, gut and intratumoural microbiomes, impaired gut barrier function and exposure to inflammatory compounds as well as metabolic dysfunction as contributors to pancreatic disease with a focus on pancreatic ductal adenocarcinoma (PDAC) initiation and progression. We also highlight some emerging gut microbiome editing techniques currently being investigated in the context of pancreatic disease. Notably, while the gut microbiome is significantly altered in PDAC and its precursor diseases, its utility as a diagnostic and prognostic tool is hindered by a lack of reproducibility and the potential for reverse causality in case-control cohorts. Future research should emphasise longitudinal and mechanistic studies as well as integrating lifestyle exposure and multi-omics data to unravel complex host-microbiome interactions. This will allow for deeper aetiologic and mechanistic insights that can inform treatments and guide public health recommendations.

Emerging evidence suggests that harnessing the microbiome holds promise for innovative diagnostic and therapeutic strategies in the management of pancreatic cancer (PC). This study aims to systematically summarize the microbial markers associated with PC and assess their potential application in clinical outcome. Forty-one studies were included to assess the associations between microbial markers and PC. Among these, 13 were developed prediction models related to the microbiome in which the highest diagnostic and prognostic model belong to blood and intratumor markers, respectively. Notably, findings that utilize microbiotas from various body sites were elucidated, demonstrating their importance as unique signatures in biomarker discovery for diverse clinical applications. This review provides unique perspectives on overcoming challenges in PC by highlighting potential microbial-related markers as non-invasive approaches. Further clinical studies should evaluate the utility and accuracy of key indicators in the microbiome as a personalized tool for managing PC.

Pancreatic cancer (PC), particularly pancreatic ductal adenocarcinoma (PDAC), is a significant global health issue with high mortality rates. PDAC, though only 3 % of cancer diagnoses, causes 7 % of cancer deaths due to its severity and asymptomatic early stages. Risk factors include lifestyle choices, environmental exposures, and genetic predispositions. Conditions like new-onset type 2 diabetes and chronic pancreatitis also contribute significantly. Modifiable risk factors include smoking, alcohol consumption, non-alcoholic fatty pancreatic disease (NAFPD), and obesity. Smoking and heavy alcohol consumption increase PC risk, while NAFPD and obesity, particularly central adiposity, contribute through chronic inflammation and insulin resistance. Refined sugar and sugar-sweetened beverages (SSBs) are also linked to increased PC risk, especially among younger individuals. Hormonal treatments and medications like statins, aspirin, and metformin have mixed results on PC risk, with some showing protective effects. The gut microbiome influences PC through the gut-pancreas axis, with disruptions leading to inflammation and carcinogenesis. Exposure to toxic substances, including heavy metals and chemicals, is associated with increased PC risk. Glycome changes, such as abnormal glycosylation patterns, are significant in PDAC development and offer potential for early diagnosis. Interactions between environmental and genetic factors are crucial in PDAC susceptibility. Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) linked to PDAC, but gene-environment interactions remain largely unexplored. Future research should focus on polygenic risk scores (PRS) and large-scale studies to better understand these interactions and their impact on PDAC risk.

This review provides an overview of research evidence focused on the microbial components essential to clinical cancer care, called the oncobiota (the interaction of human microbiota and cancer cells). It specifically examines the oncobiota in central nervous system cancer,breast cancer, pancreatic cancer, liver cancer, lung cancer, and cervical cancer. The literature review reveals insufficient knowledge about the oncobiota of organs once considered sterile. Many studies on oncobiota focus on small, geographically specific patient groups, and the absence of a reference (control) group complicates the development of microbial profiles for selected cancers. Consequently, this review aims to analyze the literature data and reports on the role of oncobiota in selected "sterile" organs and the resulting therapeutic or preventive implications. All relevant publications on oncobiota in patients with the selected cancers were considered to provide the most thorough analysis possible. Understanding the significance and role of oncobiota in the pathomechanisms of carcinogenesis may pave the way for targeted cancer prevention methods. Furthermore, therapeutic strategies based on oncobiota could represent a novel area of ​​personalized cancer treatment. Additionally, oncobiota may serve as an additional diagnostic tool in oncology.

Lung cancer is a significant health concern that poses a considerable threat to human health and quality of life. In order to enhance the prognosis of patients with lung cancer, we conducted a combined analysis of 16S rDNA gene sequencing of alveolar lavage fluid and LC-MS metabolomics research, with the objective of identifying biomarkers in patients with early-stage lung cancer presenting as SPN. A comparison of the benign nodule group and the early-stage lung cancer patients revealed that the phylum-level Bacteroidetes and the genus-level Chryseobacterium and Delftia were more abundant in the latter group. Additionally, the Fusobacteriales might serve as a predictive marker for the diagnosis of early-stage lung cancer. In the context of metabolomics, the early-stage lung cancer was found to be characterised by elevated levels of specific metabolites, including Alternariol, dTMP, Oxymatrine, Gedunin, PC 36:4. Conversely, reductions in other metabolites, such as LPC O-24:0, PC 18:2_18:3, PC 19:2_19:2, Cholecalciferol and T-2 Triol, were also observed. Correlation analyses demonstrated that alveolar lavage microorganisms were closely associated with differential metabolites. Specifically, reductions in Cholecalciferol were associated with a variety of high-abundance flora and involved in vitamin digestion and absorption pathways. Furthermore, reductions in cholecalciferol may serve as a robust predictor of early-stage lung cancer. These findings provide new predictive biomarkers for early-stage lung cancer manifested by SPN, which is clinically important and requires further study of the potential mechanisms of action and function of the targets.

Digestive system tumours (DSTs) often diagnosed late due to nonspecific symptoms. Non-invasive biomarkers are crucial for early detection and improved outcomes.

We collected tongue coating samples from 710 patients diagnosed with DST and 489 healthy controls (HC) from April 2023, to December 2023. Microbial composition was analyzed using 16S rRNA sequencing, and five machine learning algorithms were applied to assess the diagnostic potential of tongue coating microbiota.

Alpha diversity analysis showed that the microbial diversity in the tongue coating was significantly increased in DST patients. LEfSe analysis identified DST-enriched genera Alloprevotella and Prevotella, contrasting with HC-dominant taxa Neisseria, Haemophilus, and Porphyromonas (LDA >4). Notably, when comparing each of the four DST subtypes with the HC group, the proportion of Haemophilus in the HC group was significantly higher, and it was identified as an important feature for distinguishing the HC group. Machine learning validation demonstrated superior diagnostic performance of the Extreme Gradient Boosting (XGBoost) model, achieving an AUC of 0.926 (95% CI: 0.893-0.958) in internal validation, outperforming the other four machine learning models.

Tongue coating microbiota shows promise as a non-invasive biomarker for DST diagnosis, supported by robust machine learning models.

Standard clinical parameters like tumor size, age, lymph node status, and molecular markers are used to predict progression risk and treatment response. However, exploring additional markers that reflect underlying biology could offer a more comprehensive understanding of the tumor microenvironment (TME). The TME influences tumor development, progression, disease severity, and survival, with tumor-associated bacteria posited to play significant roles. Studies on tumor-associated microbiota have focused on high bacterial-load sites such as the gut, oral cavity, and stomach, but interest is growing in non-gastrointestinal (GI) solid tumors, such as breast, lung, and pancreas. Microbe-based biomarkers, including Helicobacter pylori, human papillomavirus (HPV), and hepatitis B and C viruses, have proven valuable in predicting gastric, cervical, and renal cancers.

Potential of prognostic and predictive bacterial biomarkers in non-GI solid tumors and the methodologies used.

Advances in techniques like 16S rRNA gene sequencing, qPCR, immunostaining, and in situ hybridization have enabled detailed analysis of difficult-to-culture microbes in solid tumors. However, to ensure reliable results, it is critical to standardize protocols, accurately align reads, address contamination, and maintain proper sample handling. This will pave the way for developing reliable bacterial markers that enhance prognosis, prediction, and personalized treatment planning.

Only a minority of patients with head and neck squamous cell carcinoma (HNSCC) respond favourably to immunotherapy. The oral oncogenic bacterium Fusobacterium nucleatum (F.nucleatum) was recently observed to suppress the anti-tumour immune response, although the mechanisms remain unclear. In this study, we found that outer membrane vesicles (OMVs) derived from F.nucleatum (F.n-OMVs) promoted HNSCC progression by inducing immunosuppressive phenotypes of tumour-associated macrophages (TAMs), resulting in decreased cytotoxic T lymphocyte infiltration in vivo. Mechanistically, TAMs internalized tryptophanase presented in F.n-OMVs, which activated the tryptophan-2,3-dioxygenase 2/aryl hydrocarbon receptor (TDO2/AHR) pathway and upregulated the transcription of immunosuppressive cytokines and immune checkpoints. TDO2 inhibitor enhanced the therapeutic effect of anti-programmed death-1 in a tumour-bearing mouse model. Both TDO2 and F.nucleatum demonstrated excellent performance in predicting the immunotherapy outcomes in patients with HNSCC. These results indicate that F.n-OMVs induce immunotherapy resistance in HNSCC, providing novel insights into the microbiota-tumour immunity crosstalk.

Pancreatic cancer ranks among the most lethal digestive malignancies, exhibiting a steadily increasing incidence and mortality worldwide. Despite significant advances in cancer research, the 5-year survival rate remains below 10%, predominantly due to delayed diagnosis and limited therapeutic options. Concurrently, the gut microbiota-an integral component of host physiology-has emerged as a crucial player in the pathogenesis of pancreatic cancer. Mounting evidence indicates that alterations in gut microbial composition and function may influence tumor initiation, progression, and response to therapy. This review provides an in-depth examination of the intricate interplay between the gut microbiome and pancreatic cancer, highlighting potential diagnostic biomarkers and exploring microbiome-targeted therapeutic strategies to improve patient outcomes.

Pancreatic ductal adenocarcinoma is a clinically challenging malignancy largely because of its chemoresistance. Bacteria within the pancreatic ductal adenocarcinoma microbiome may mediate chemoresistance, suggesting that alteration of the microbiome with antibiotics could improve chemotherapy response.

We utilized the Surveillance, Epidemiology, and End Results Program-Medicare database to select patients with resected, early-stage pancreatic ductal adenocarcinoma diagnosed between 2007 and 2017. The primary outcome of this study was overall survival. Receipt of antibiotic treatment within 1 month after adjuvant chemotherapy initiation was determined from Medicare claims data. Propensity scores were used to match patients who received antibiotics with patients who did not receive antibiotics. The Kaplan-Meier method was used to calculate 5-year overall survival rates, and Cox regression analysis was used to assess the association between receiving antibiotics and overall survival. All hypotheses were 2 sided.

Of the 712 patients with resected, early-stage pancreatic ductal adenocarcinoma, 629 (88.3%) were treated with adjuvant gemcitabine and 177 (24.9%) received antibiotics in the 1 month following chemotherapy initiation. The mean (SD) age at diagnosis was 73.7 (5.1) years, and patients were mostly women, White, and from metropolitan areas in the northeastern or western United States. A total of 143 propensity score-matched pairs were evaluated. Among patients treated with gemcitabine, antibiotic treatment was associated with a 37% improvement in overall survival and a 30% improvement in cancer-specific survival.

Antibiotic treatment in the 1 month following adjuvant gemcitabine initiation was associated with improved survival. These findings provide additional support for the hypothesis that antibiotic treatment may alter the pancreatic microbiome in a manner that reduces chemoresistance, potentially improving pancreatic ductal adenocarcinoma outcomes.

Garlic is a popular ingredient used in cuisines and traditional medicines worldwide. It contains numerous bioactive organosulfur-containing compounds, such as allicin, with reported potential for anticancer and antimicrobial therapy. The biological activity and potential use of garlic and its products have been extensively investigated. Aged garlic extract (AGE) is a product manufactured by aging garlic, and has been shown to have numerous health benefits. It has been previously revealed that several garlic-derived compounds, including AGE, have tumor-suppressive effects in various cancer models. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, and carries a dismal prognosis. Recently, numerous tumors, including PDAC, were shown to harbor intracellular bacteria, some of which are oral pathogens. Tumor-associated bacteria have been linked to cancer progression. Garlic may inhibit tumor development, in part, by targeting these bacteria. Although it requires further investigation, pharmacological and antibacterial effects of garlic and its products could offer significant therapeutic benefits for the prevention and treatment of PDAC. In the present review, the therapeutic potential of garlic on PDAC is summarized and discussed.

Tumour-associated microbiota are integral components of the tumour microenvironment (TME). However, previous studies on intratumoral microbiota primarily rely on bulk tissue analysis, which may obscure their spatial distribution and localized effects. In this study, we applied in situ spatial-profiling technology to investigate the spatial distribution of intratumoral microbiota in breast cancer and their interactions with the local TME. Using 5R 16S rRNA gene sequencing and RNAscope FISH/CISH on patients' tissue, we identified significant spatial heterogeneity in intratumoral microbiota, with Fusobacterium nucleatum (F. nucleatum) predominantly localized in tumour cell-rich areas. GeoMx digital spatial profiling (DSP) revealed that regions colonized by F. nucleatum exhibit significant influence on the expression of RNAs and proteins involved in proliferation, migration and invasion. In vitro studies indicated that co-culture with F. nucleatum significantly stimulates the proliferation and migration of breast cancer cells. Integrative spatial multi-omics and co-culture transcriptomic analyses highlighted the MAPK signalling pathways as key altered pathways. By intersecting these datasets, VEGFD and PAK1 emerged as critical upregulated proteins in F. nucleatum-positive regions, showing strong positive correlations with MAPK pathway proteins. Moreover, the upregulation of VEGFD and PAK1 by F. nucleatum was confirmed in co-culture experiments, and their knockdown significantly reduced F. nucleatum-induced proliferation and migration. In conclusion, intratumoral microbiota in breast cancer exhibit significant spatial heterogeneity, with F. nucleatum colonization markedly altering tumour cell protein expression to promote progression and migration. These findings provide novel perspectives on the role of microbiota in breast cancer, identify potential therapeutic targets, and lay the foundation for future cancer treatments. KEY POINTS: Intratumoral Fusobacterium nucleatum exhibits significant spatial heterogeneity within breast cancer tissues. F. nucleatum colonization alters the expression of key proteins involved in tumour progression and migration. The MAPK signalling pathway is a critical mediator of F. nucleatum-induced breast cancer cell proliferation and migration. VEGFD and PAK1 are potential therapeutic targets to mitigate F. nucleatum-induced tumour progression.

Body mass index (BMI) is considered an important factor in tumor prognosis, but its role in gastric cancer (GC) remains controversial. There is a lack of studies exploring the effect of BMI on gastric cancer from the perspective of intratumoral microbiota. This study aimed to compare and analyze the differences in and functions of intratumoral microbiota among GC patients with varying BMIs, aiming to ascertain whether specific microbial features are associated with prognosis in low-BMI (LBMI) gastric cancer patients.

A retrospective analysis of the clinicopathological features and prognosis of 5567 patients with different BMIs was performed between January 2010 and December 2019. Tumor tissues from 189 GC patients were collected for 16S rRNA sequencing, 64 samples were selected for transcriptome sequencing, and 57 samples were selected for untargeted metabolomic analysis.

Clinical cohort analysis revealed that GC patients with a low BMI presented poorer clinical and pathological characteristics than those with a non-low-BMI (NLBMI). LBMI was identified as a significant independent risk factor for adverse prognosis, potentially exerting immunosuppressive effects on postoperative adjuvant chemotherapy. 16S rRNA sequencing revealed no significant differences in the alpha and beta diversity of the intratumoral microbiota between the two groups of GC patients. However, LEfSe analysis revealed 32 differential intratumoral microbiota between the LBMI and NLBMI groups. Notably, the genus Abiotrophia was significantly enriched in the LBMI group. Further in-depth analysis indicated that the genus Abiotrophia was inversely associated with eosinophils, P2RY12, and SCN4B genes, and positively linked with LGR6 in LBMI gastric cancer patients. Metabolomic assessments revealed that LBMI was positively associated with purine metabolites, specifically guanine and inosine diphosphate (IDP).

In conclusion, LBMI is an independent risk factor for poor prognosis in gastric cancer patients and may have an inhibitory effect on postoperative adjuvant chemotherapy. Intratumor flora of gastric cancer patients with different BMI levels differed, with different immune cell infiltration and metabolic characteristics. The genus Abiotrophia may promote gastric cancer development and progression by regulating eosinophils and the purine metabolism pathway, which provides a new idea for the precise treatment of gastric cancer.

Our study examined the composition of the intestinal microflora in a hospitalized patient with AP symptoms treated several months earlier for diverticulitis. The therapeutic intervention necessitated Hartmann's procedure, culminating in colostomy creation.

Employing a thorough microbiological analysis we attempted to demonstrate whether the microflora isolated from the peripancreatic fluid exhibited a stronger correlation with the contents of the stoma or with the rectal swab. Additionally, we sought to determine the association between later onset of AP and diverticulitis.

Following clinical materials from the patient in the initial phase of AP were collected: rectal swab, colostomy bag contents (in the publication referred to as stoma content/stool) and peripancreatic fluid. Microbiological analysis was performed, including classic culture methodology, NGS techniques, and genotyping methodologies. Furthermore, the effect of bile on the shift in the population of selected bacterial species was examined.

The NGS technique confirmed greater consistency in bacteria percentage (phyla/family) between stoma content and peripancreatic fluid. In both samples, a clear dominance of the Proteobacteria phyla (over 75%) and the Enterobacteriaceae family was demonstrated. Moreover, NGS verified the presence of the Fusobacteriota phylum and Fusobacteriaceae family only in rectal swabs, which may indicate a link between this type of bacteria and the etiology of diverticulitis. We observed that Escherichia coli 33 isolated from stool exhibited active gaseous metabolite production (mainly hydrogen).

The abundant production of hydrogen may substantially impact enzymatic processes, inducing specific alterations in disulfide bonds and trypsin inactivation. Our investigation alludes to the conceivable active involvement of bile in effecting qualitative and quantitative modifications in the peripancreatic microbiota composition, establishing a correlation between released bile and bacterial generation of gaseous metabolites.

Resistance to anti-PD-1 therapy in melanoma remains a major obstacle in achieving effective and durable treatment outcomes, highlighting the need to understand and address the underlying mechanisms. The first key factor is innate anti-PD-1 resistance signature (IPRES), an expression of a group of genes associated with tumor plasticity and immune evasion. IPRES promotes epithelial-to-mesenchymal transition (EMT), increasing melanoma cells' invasiveness and survival. Overexpressed AXL, TWIST2, and WNT5a induce phenotypic changes. The upregulation of pro-inflammatory cytokines frequently coincides with EMT-related changes, further promoting a resistant and aggressive tumor phenotype. Inflamed tumor microenvironment may also drive the expression of resistance. The complexity of immune resistance development suggests that combination therapies are necessary to overcome it. Furthermore, targeting epigenetic regulation and exploring novel approaches such as miR-146a modulation may provide new strategies to counter resistance in melanoma.

Periodontitis is an immuno-inflammatory disease of the soft tissues surrounding the teeth. Periodontitis is linked to many communicable and non-communicable diseases such as diabetes, cardiovascular disease, rheumatoid arthritis, and cancers. The oral-systemic link between periodontal disease and systemic diseases is attributed to the spread of inflammation, microbial products and microbes to distant organ systems. Oral bacteria reach the gut via swallowed saliva, whereby they induce gut dysbiosis and gastrointestinal dysfunctions. Some periodontal pathogens like Porphyromonas. gingivalis, Klebsiella, Helicobacter. Pylori, Streptococcus, Veillonella, Parvimonas micra, Fusobacterium nucleatum, Peptostreptococcus, Haemophilus, Aggregatibacter actinomycetomcommitans and Streptococcus mutans can withstand the unfavorable acidic, survive in the gut and result in gut dysbiosis. Gut dysbiosis increases gut inflammation, and induce dysplastic changes that lead to gut dysfunction. Various studies have linked oral bacteria, and oral-gut axis to various GIT disorders like inflammatory bowel disease, liver diseases, hepatocellular and pancreatic ductal carcinoma, ulcerative colitis, and Crohn's disease. Although the correlation between periodontitis and GIT disorders is well established, the intricate molecular mechanisms by which oral microflora induce these changes have not been discussed extensively. This review comprehensively discusses the intricate and unique molecular and immunological mechanisms by which periodontal pathogens can induce gut dysbiosis and dysfunction.

Fusobacterium species are anaerobic Gram-negative bacilli which are uncommon causes of bloodstream infection (BSI). This genus commonly colonises the gastrointestinal tract and can result in significant morbidity.

All blood cultures with growth of Fusobacterium species among residents of Queensland, Australia (population ≈ 5 million) were retrospectively identified over a 20-year period. Clinical, microbiological and outcome information was obtained from state-wide databases.

377 incident Fusobacterium species BSI among 375 individuals for an age and sex-standardised incidence of 4.4 per million residents per year. Median age was 47 years (IQR, 24.9-65.8) and 156 (42%) incident episodes were in females. There was a bimodal frequency distribution with respect to age with peaks occurring around 20 and 65 years, respectively. The most identified source of infection was the abdominal (17%), followed by head and neck (12%). 8% of patients had a septic thrombus present, and 4% had an abscess associated with their BSI. Most isolates were F. nucleatum (142, 38%) and F. necrophorum (140, 37%). 9% of isolates were resistant to penicillin. Older age (aHR 1.02, 95% CI 1.01-1.05), healthcare-associated hospital onset (aHR 3.16, 95% CI 1.35-7.40), and Charlson Comorbidity index (aHR 1.20, 95% CI 1.06-1.35) were all associated with 30-day all cause case-fatality. Oropharyngeal source appeared to be a protective factor (P = 0.02).

Fusobacterium species BSI results in significant morbidity and can cause death in vulnerable patient groups such as the elderly and those with malignancy. An identifiable oropharyngeal source identifies a favourable host.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis, primarily due to its immunosuppressive tumor microenvironment (TME), which contributes to treatment resistance. Recent research shows that the microbiome, including microbial communities in the oral cavity, gut, bile duct, and intratumoral environments, plays a key role in PDAC development, with microbial imbalances (dysbiosis) promoting inflammation, cancer progression, therapy resistance, and treatment side effects. Microbial metabolites can also affect immune cells, especially natural killer (NK) cells, which are vital for tumor surveillance, therapy response and treatment-related side effects. Dysbiosis can affect NK cell function, leading to resistance and side effects. We propose that a combined biomarker approach, integrating microbiome composition and NK cell profiles, can help predict treatment resistance and side effects, enabling more personalized therapies. This review examines how dysbiosis contributes to NK cell dysfunction in PDAC and discusses strategies (e.g., antibiotics, probiotics, vaccines) to modulate the microbiome and enhance NK cell function. Targeting dysbiosis could modulate NK cell activity, improve the effectiveness of PDAC treatments, and reduce side effects. However, further research is needed to develop unified NK cell-microbiome interaction-based biomarkers for more precise and effective patient outcomes.

There is growing evidence suggesting a strong association between members of the oral microbiota and various types of cancer, including oral cancer, colorectal cancer, esophageal squamous cell carcinoma, and pancreatic cancer. Periodontal diseases closely associated with pathogenic bacteria in the oral cavity have been shown to be correlated with the occurrence and development of cancers. Among the periodontal disease-associated bacteria in the oral cavity, two prominent oral pathogens, Porphyromonas gingivalis and Fusobacterium nucleatum, have been found to promote tumor cell proliferation, invasion, and migration, as well as to inhibit immune cell function, thereby facilitating tumor progression. The presence of other oral pathogenic bacteria, such as Treponema denticola, Tannerella forsythia, Parvimonas micra, and Aggregatibacter actinomycetemcomitans, has also been found to be associated with cancer worsening. Oral commensal bacteria play a crucial role in maintaining the normal oral homeostasis. However, the relationship between oral commensal bacteria and the occurrence and development of cancers remains controversial. Some studies suggest an increase in oral commensal bacteria during tumor development, while others suggest an association of certain commensal bacteria with lower tumor risk. The microbiota can significantly alter responses and toxicity to various forms of cancer treatment through interactions with the human body, thereby influencing disease progression. In this chapter, we provide a concise overview of current understanding of the role of the oral microbiota in cancer.

Fusobacterium nucleatum, an anaerobic Gram-negative bacterium primarily residing in the oral cavity, has garnered significant attention for its emerging role in cancer progression and prognosis. While extensive research has revealed mechanistic links between Fusobacterium nucleatum and colorectal cancer, a comprehensive review spanning its presence and metastatic implications in cancers beyond colorectal origin is conspicuously absent. This paper broadens our perspective from colorectal cancer to various malignancies associated with Fusobacterium nucleatum, including oral, pancreatic, esophageal, breast, and gastric cancers. Our central focus is to unravel the mechanisms governing Fusobacterium nucleatum colonization, initiation, and promotion of metastasis across diverse cancer types. Additionally, we explore Fusobacterium nucleatum's adverse impacts on cancer therapies, particularly within the domains of immunotherapy and chemotherapy. Furthermore, this paper underscores the clinical research significance of Fusobacterium nucleatum as a potential tumor biomarker and therapeutic target, offering a novel outlook on its applicability in cancer detection and prognostic assessment.

The intratumoral microbiome plays a significant role in many cancers, such as lung, pancreatic, and colorectal cancer. Pancreatic cancer (PC) is one of the most lethal malignancies and is often diagnosed at advanced stages. Fusobacterium nucleatum (Fn), an anaerobic Gram-negative bacterium primarily residing in the oral cavity, has garnered significant attention for its emerging role in several extra-oral human diseases and, lately, in pancreatic cancer progression and prognosis. It is now recognized as oncobacterium. Fn engages in pancreatic tumorigenesis and metastasis through multifaceted mechanisms, including immune response modulation, virulence factors, control of cell proliferation, intestinal metabolite interactions, DNA damage, and epithelial-mesenchymal transition. Additionally, compelling research suggests that Fn may exert detrimental effects on cancer treatment outcomes. This paper extends the perspective to pancreatic cancer associated with Fn. The central focus is to unravel the oncogenomic changes driven by Fn in colonization, initiation, and promotion of pancreatic cancer development. The presence of Fusobacterium species can be considered a prognostic marker of PC, and it is also correlated to chemoresistance. Furthermore, this review underscores the clinical research significance of Fn as a potential tumor biomarker and therapeutic target, offering a novel outlook on its applicability in cancer detection and prognostic assessment. It is thought that given the role of Fn in tumor formation and metastasis processes via its FadA, FapA, Fap2, and RadD, new therapies for tumor treatment targeting Fn will be developed.

Pancreatic cancer is one of the most lethal cancers, with a 5-year overall survival rate of less than 10%. Despite the development of novel therapies in recent decades, current chemotherapeutic strategies offer limited clinical benefits due to the high heterogeneity and desmoplastic tumor microenvironment (TME) of pancreatic cancer as well as inefficient drug penetration. Antibody- and nucleic acid-based targeting therapies have emerged as strong contenders in pancreatic cancer drug discovery. Numerous studies have shown that these strategies can significantly enhance drug accumulation in tumors while reducing systemic toxicity. Additionally, electron microscopy (EM) has been a critical tool for high-resolution analysis of the TME, providing insights into the ultrastructural changes associated with pancreatic cancer progression and treatment responses. This review traces the current and technological advances in EM, particularly the development of ultramicrotomy and improvements in sample preparation that have facilitated the detailed visualization of cellular and extracellular components of the TME. This review highlights the contribution of EM in assessing the efficacy of therapeutic agents, from revealing apoptotic changes to characterizing the effects of novel compounds like ionophore antibiotic gramicidin A on cellular ultrastructures. Moreover, the review delves into the potential of EM in studying the interactions between the tumor microbiome and cancer cell migration, as well as in aiding the development of targeted therapies like antibody-drug conjugates (ADCs) and aptamer-drug conjugates (ApDCs).

Despite advances in multimodality therapy, including surgery, chemotherapy, radiation therapy and chemoradiation, the fatality rate for esophageal cancer remains high. Specifically, Fusobacterium nucleatum, due to its aggregation capacity, has shown a tendency to form biofilms. The biofilm-forming capabilities of microbial communities are of utmost importance in the context of cancer treatment, as they have been shown to drive significant losses in the efficaciousness of various cancer treatments. Therefore, elucidating the dynamics of F. nucleatum will be important for the development of effective treatments for esophageal cancer. Therefore, this review summarizes the current knowledge of F. nucleatum, its involvement in cancer and its impact on chemotherapy and radiation therapy. In conclusion, further research on the role of F. nucleatum is essential for the continued advancement of the treatment of esophageal cancer and patient care.

The Fusobacterium genus comprises Gram-negative, obligate anaerobic bacteria that typically reside in the periodontium of the oral cavity, gastrointestinal tract, and female genital tract. The association of Fusobacterial spp. with colorectal tumours is widely accepted, with further evidence that this pathogen may also be implicated in the development of other malignancies. Fusobacterial spp. influence malignant cell behaviours and the tumour microenvironment in various ways, which can be related to the multiple surface adhesins expressed. These adhesins include Fap2 (fibroblast-activated protein 2), CpbF (CEACAM binding protein of Fusobacteria), FadA (Fusobacterium adhesin A) and FomA (Fusobacterial outer membrane protein A). This review outlines the influence of Fusobacteria in promoting cancer initiation and progression, impacts of therapeutic outcomes and discusses potential therapeutic interventions where appropriate.

Progress in immunotherapy for pancreatic ductal adenocarcinoma (PDAC) has been slow, yet the relationship between microorganisms and metabolites is crucial to PDAC development. This study compares the biliary microbiota and metabolomic profiles of PDAC patients with those of benign pancreatic disease patients to investigate PDAC pathogenesis and its relationship with immunotherapy.

A total of 27 patients were recruited, including 15 diagnosed with PDAC and 12 with benign pancreaticobiliary conditions, all of whom underwent surgical treatment. Intraoperative bile samples were collected and analyzed using 16S rRNA sequencing in conjunction with liquid chromatography-mass spectrometry (LC-MS). Multivariate statistical methods and correlation analyzes were employed to assess differences in microbial composition, structure, and function between malignant and benign pancreatic diseases. Additionally, a retrospective analysis was conducted on PDAC patients post-surgery regarding immunotherapy and its correlation with metabolic components.

PDAC patients exhibited a significantly higher abundance of bile microbiota compared to controls, with notable differences in microbiota structure between the two groups (P < 0.05). At the genus level, Muribaculum was markedly enriched in the bile of PDAC patients and was strongly correlated with phosphatidic acid (PA) (10:0/a-17:0). Both of these components, along with the tumor marker CA199, formulated a predictor of PDAC. Furthermore, PA (10:0/a-17:0) demonstrated a strong correlation with PDAC immunotherapy outcomes (Rho: 0.758; P=0.011).

These findings suggest that the biliary microbiota and associated metabolites play a crucial role in the development of PDAC and may serve as potential predictive biomarkers and therapeutic targets for disease management.

The incidence of pancreatic cancer is on the rise, and its prognosis remains poor. Recent reports have established a link between the gut and oral microbiome and pancreatic cancer. However, the intricacies of this association within the Japanese population remain unclear. In this study, we investigated the gut and oral microbiomes of Japanese patients with pancreatic cancer, comparing them with those of healthy individuals.

We recruited 30 patients with untreated pancreatic cancer and 18 healthy controls at Kyoto University Hospital (2018-2022). We performed a comprehensive 16S rRNA gene sequencing to analyze their gut and oral microbiomes.

Analysis revealed that the diversity of the gut and oral microbiomes of patients with pancreatic cancer was reduced compared to that of the healthy controls. Specifically, we observed an increase in the genus Streptococcus in both the gut and oral microbiomes and a significant decrease in several butyrate-producing bacteria in fecal samples. Moreover, bacteria such as Streptococcus mitis and Holdemanella biformis were present in pancreatic cancer tissues, suggesting that they might influence the carcinogenesis and progression of pancreatic cancer.

The gut and oral microbiome differed between patients with pancreatic cancer and healthy controls, with a notable decrease in butyrate-producing bacteria in the gut microbiome of the patients. This suggests that there may be a distinct microbial signature associated with pancreatic cancer in the Japanese population. Further studies are required to elucidate the microbiome's causal role in this cancer and help develop prognostic markers or targeted therapies.

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.

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 β-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.

The human microbiota represents a heterogeneous microbial community composed of several commensal, symbiotic, and even pathogenic microorganisms colonizing both the external and internal body surfaces. Despite the term "microbiota" being commonly used to identify microorganisms inhabiting the gut, several pieces of evidence suggest the presence of different microbiota physiologically colonizing other organs. In this context, several studies have also confirmed that microbes are integral components of tumor tissue in different types of cancer, constituting the so-called "intratumoral microbiota". The intratumoral microbiota is closely related to the occurrence and development of cancer as well as to the efficacy of anticancer treatments. Indeed, intratumoral microbiota can contribute to carcinogenesis and metastasis formation as some microbes can directly cause DNA damage, while others can induce the activation of proinflammatory responses or oncogenic pathways and alter the tumor microenvironment (TME). All these characteristics make the intratumoral microbiota an interesting topic to investigate for both diagnostic and prognostic purposes in order to improve the management of cancer patients. This review aims to gather the most recent data on the role of the intratumoral microbiota in cancer development, progression, and response to treatment, as well as its potential diagnostic and prognostic value.

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.

Fusobacterium nucleatum, a Gram-negative obligate anaerobe, is common to the oral microbiota, but the species is known to infect other sites of the body where it is associated with a range of pathologies. At present, little is known about the mechanisms by which F. nucleatum mitigates against oxidative and nitrosative stress. Inspection of the F. nucleatum subsp. polymorphum ATCC 10953 genome reveals that it encodes a flavodiiron protein (FDP; FNP2073) that is known in other organisms to reduce NO to N2O and/or O2 to H2O. FNP2073 is dicistronic with a gene encoding a multicomponent enzyme termed BCR for butyryl-CoA reductase. BCR is composed of a butyryl-CoA dehydrogenase domain (BCD), the C-terminal domain of the α-subunit of the electron-transfer flavoprotein (Etfα), and a rubredoxin domain. We show that BCR and the FDP form an α4β4 heterotetramic complex and use butyryl-CoA to selectively reduce O2 to H2O. The FAD associated with the Etfα domain (α-FAD) forms red anionic semiquinone (FAD•-), whereas the FAD present in the BCD domain (δ-FAD) forms the blue-neutral semiquinone (FADH•), indicating that both cofactors participate in one-electron transfers. This was confirmed in stopped-flow studies where the reduction of oxidized BCR with an excess of butyryl-CoA resulted in rapid (<1.6 ms) interflavin electron transfer evidenced by the formation of the FAD•-. Analysis of bacterial genomes revealed that the dicistron is present in obligate anaerobic gut bacteria considered to be beneficial by virtue of their ability to produce butyrate. Thus, BCR-FDP may help to maintain anaerobiosis in the colon.

Both periodontal disease and cancer are prevalent conditions with significant impacts on individuals and society. Extensive research has suggested a potential link between these two diseases. This study conducted a bibliometric analysis using the Thomson Reuters Web of Science Core Collection database, focusing on publications from 2014 to 2023. The analysis included data extraction and examination of authors, affiliations, publication dates, journals, countries, citation counts, keywords, and the H-index. A total of 253 relevant articles were identified, showing an increasing trend in both publications and citations over the years. The analysis highlighted the most productive authors, institutions, and countries/regions, with Michaud DS and Abnet CC leading in the number of publications. Highly cited articles emphasized the role of specific oral microbiota, particularly F. nucleatum and P. gingivalis, in various cancers, suggesting their potential as diagnostic markers and therapeutic targets. Four key thematic clusters emerged from the keyword analysis: the broader health implications of periodontal disease, the microbiome's role in carcinogenesis, inflammation, and specific bacteria in cancer, and epidemiological methods in studying the disease-cancer association. This bibliometric analysis underscores the growing interest in the connection between periodontal disease and cancer. Future research should adopt interdisciplinary approaches, focus on large-scale microbiome studies and longitudinal research to understand the systemic effects of periodontal disease, identify cancer-associated bacterial profiles, and investigate the molecular mechanisms of bacterial carcinogenesis. Additionally, public health interventions aimed at improving oral hygiene and reducing cancer risk factors are recommended.

Nano-mupirocin is a PEGylated nano-liposomal formulation of the antibiotic mupirocin, undergoing evaluation for treating infectious diseases and intratumor bacteria. Intratumoral microbiota play an important role in the regulation of tumor progression and therapeutic efficacy. However, antibiotic use to target intratumoral bacteria should be performed in a way that will not affect the gut microbiota, found to enable the efficacy of cancer treatments. Nano-mupirocin may offer such a selective treatment. Herein, we demonstrate the ability of Nano-mupirocin to successfully target tumor-residing Fusobacterium nucleatum without an immediate effect on the gut microbiome. In-depth characterization of this novel formulation was performed, and the main findings include: (i). the pharmacokinetic analysis of mupirocin administered as Nano-mupirocin vs mupirocin lithium (free drug) demonstrated that most of the Nano-mupirocin in plasma is liposome associated; (ii). microbiome analysis of rat feces showed no significant short-term difference between Nano-mupirocin, mupirocin lithium and controls; (iii). Nano-mupirocin was active against intratumoral F. nucleatum, a tumor promoting bacteria that accumulates in tumors of the AT3 mice model of breast cancer. These data suggest the ability of Nano-mupirocin to target tumor residing and promoting bacteria.

Several studies have reported the effects of Fusobacterium nucleatum stimulation on oral cancer cells. However, given that these studies typically span a stimulation period of three days to eight days, the in vitro studies conducted to date may not fully mimic the oral cancer environment, which involves constant exposure to oral commensal bacteria. This study aimed to elucidate the effects of prolonged and persistent Fusobacterium nucleatum infection on oral cancer cells.

Human tongue squamous cell carcinoma (SCC) cells were continuously stimulated with Fusobacterium nucleatum for two or four weeks, then experimentally evaluated.

Prolonged, persistent Fusobacterium nucleatum stimulation increased the cells' proliferative, invasive, and migratory capacities, decreased their expression of epithelial markers, and increased their expression of mesenchymal markers progressively with time. The cells also adopted a spindle-shaped morphology and cell-to-cell contact dependence was progressively lost, suggesting time-dependent occurrence of epithelial-mesenchymal transition. Furthermore, mRNA levels of CD44, a cancer stem cell marker, were time-dependently upregulated. When SCC cells were stimulated with Fusobacterium nucleatum for four weeks in the presence of dexamethasone, Fusobacterium nucleatum induced epithelial-mesenchymal transition was inhibited.

Epithelial-mesenchymal transition in human tongue SCC cells was time-dependently induced by prolonged, persistent Fusobacterium nucleatum stimulation and inhibited by dexamethasone. Routine decontamination of the oral cavity may be crucial for controlling tumor invasion and metastasis.

The incidence of tumors in the human digestive system is relatively high, including esophageal cancer, liver cancer, pancreatic cancer, gastric cancer and colorectal cancer. These malignancies arise from a complex interplay of environmental and genetic factors. Among them, long non‑coding RNAs (lncRNAs), which cannot be translated into proteins, serve an important role in the development, progression, migration and prognosis of tumors. Small nucleolar RNA host gene 16 (SNHG16) is a typical lncRNA, and its relationship with digestive system tumors has been widely explored. The prevailing hypothesis suggests that the principal molecular mechanism of SNHG16 in digestive system tumors involves it functioning as a competitive endogenous RNA that interacts with other proteins, regulates various genes and influences a downstream target molecule. The present review summarizes recent research on the relationship between SNHG16 and numerous types of digestive system cancer, encompassing its biological functions, underlying mechanisms and potential clinical implications. Furthermore, it outlines the association between SNHG16 expression and pertinent risk factors, such as smoking, infection and diet. The present review indicated the promise of SNHG16 as a potential biomarker and therapeutic target in human digestive system cancer.

Unraveling the intricate network of associations among microRNAs (miRNAs), genes, and diseases is pivotal for deciphering molecular mechanisms, refining disease diagnosis, and crafting targeted therapies. Computational strategies, leveraging link prediction within biological graphs, present a cost-efficient alternative to high-cost empirical assays. However, while plenty of methods excel at predicting specific associations, such as miRNA-disease associations (MDAs), miRNA-target interactions (MTIs), and disease-gene associations (DGAs), a holistic approach harnessing diverse data sources for multifaceted association prediction remains largely unexplored. The limited availability of high-quality data, as vitro experiments to comprehensively confirm associations are often expensive and time-consuming, results in a sparse and noisy heterogeneous graph, hindering an accurate prediction of these complex associations. To address this challenge, we propose a novel framework called Global-local aware Heterogeneous Graph Contrastive Learning (GlaHGCL). GlaHGCL combines global and local contrastive learning to improve node embeddings in the heterogeneous graph. In particular, global contrastive learning enhances the robustness of node embeddings against noise by aligning global representations of the original graph and its augmented counterpart. Local contrastive learning enforces representation consistency between functionally similar or connected nodes across diverse data sources, effectively leveraging data heterogeneity and mitigating the issue of data scarcity. The refined node representations are applied to downstream tasks, such as MDA, MTI, and DGA prediction. Experiments show GlaHGCL outperforming state-of-the-art methods, and case studies further demonstrate its ability to accurately uncover new associations among miRNAs, genes, and diseases. We have made the datasets and source code publicly available at https://github.com/Sue-syx/GlaHGCL.

Fusobacterium nucleatum is an oral commensal bacterium that can colonize extraoral tumor entities, such as colorectal cancer and breast cancer. Recent studies revealed its ability to modulate the immune response in the tumor microenvironment (TME), promoting cancer progression and metastasis. Importantly, F. nucleatum subsp. animalis was shown to bind to Siglec-7 via lipopolysaccharides, leading to a pro-inflammatory profile in human monocyte-derived dendritic cells. In this study, we show that F. nucleatum subsp. nucleatum RadD binds to Siglec-7 on NK cells, thereby inhibiting NK cell-mediated cancer cell killing. We demonstrate that this binding is dependent on arginine residue R124 in Siglec-7. Finally, we determine that this binding is independent of the known interaction of RadD with IgA. Taken together, our findings elucidate the targeting of Siglec-7 by F. nucleatum subsp. nucleatum RadD as a means to modulate the NK cell response and potentially promoting immune evasion and tumor progression.

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.