Fusobacterium nucleatum is a Gram-negative oncobacterium that is associated with colorectal cancer. The molecular mechanisms utilized by F. nucleatum to promote colorectal tumor development have largely focused on adhesin-mediated binding to the tumor tissue and on the pro-inflammatory capacity of F. nucleatum. However, the exact manner in which F. nucleatum promotes inflammation in the tumor microenvironment and subsequent tumor promotion remains underexplored. Here, we show that both living F. nucleatum and sterile F. nucleatum-conditioned medium promote CXCL8 release from the intestinal adenocarcinoma HT-29 cell line. We determined that the observed pro-inflammatory effect was ALPK1-dependent in both HEK293 and HT-29 cells and that the released F. nucleatum molecule had characteristics that match those of the pro-inflammatory ALPK1 ligand ADP-heptose or related heptose phosphates. In addition, we determined that not only F. nucleatum promoted an ALPK1-dependent pro-inflammatory environment but also other Fusobacterium species such as F. varium, F. necrophorum and F. gonidiaformans generated similar effects, indicating that ADP-heptose or related heptose phosphate secretion is a conserved feature of the Fusobacterium genus. By performing transcriptional analysis of ADP-heptose stimulated HT-29 cells, we found several inflammatory and cancer-related pathways to be differentially regulated, including DNA mismatch repair genes and the immune inhibitory receptor PD-L1. Finally, we show that stimulation of HT-29 cells with F. nucleatum resulted in an ALPK1-dependent upregulation of PD-L1. These results aid in our understanding of the mechanisms by which F. nucleatum can affect tumor development and therapy and pave the way for future therapeutic approaches.

Dysbiosis and pathobionts contribute to inflammation and the risk of colitis-associated carcinoma (CAC) in animal models, but their roles in humans with this uncommon disease are unknown. We identified microbiome differences in human CAC compared with longstanding inflammatory bowel disease (IBD) and sporadic colorectal carcinoma (CRC). Twenty-four CAC resections were matched with CRC and IBD controls. Methods included histopathology, 16S rDNA metagenomics, and pathobiont-specific qPCR. Beta diversity differed by diagnosis (PERMANOVA p = 0.007). The distinguishing taxa included Akkermansia enriched in CRC, and Bacteroides spp. enriched in IBD. The non-neoplastic mucosae presented distinct beta diversity (p = 0.005), but the CAC/CRC tumor microbiomes were similar (p = 0.7). Within metastases and margins, Enterobacteriaceae were enriched in CAC, and Bacteroidales in CRC. Pathobiont-specific qPCR confirmed a greater frequency of pks+ E. coli and enterotoxigenic Bacteroides fragilis in CAC than IBD. High alpha diversity was associated with active inflammation, advanced cancer stage, and shorter overall survival (log-rank p = 0.008). Mucosal microbiomes distinguish CAC from longstanding IBD, implicating pathobionts as markers for disease progression. Integrating our findings with prior animal model research, pathobionts promote carcinogenesis in IBD patients through genotoxicity and host cell signaling.

The gut microbiome, composed of bacteria, fungi, and viruses, plays a crucial role in maintaining the delicate balance of human health. Emerging evidence suggests that microbiome disruptions can have far-reaching implications, ranging from the development of inflammatory diseases and cancer to metabolic disorders. Bacteriophages, or "phages", are viruses that specifically infect bacterial cells, and their interactions with the gut microbiome are receiving increased attention. Despite the recently revived interest in the gut phageome, it is still considered the "dark matter" of the gut, with more than 80% of viral genomes remaining uncharacterized. Today, research is focused on understanding the mechanisms by which phages influence the gut microbiota and their potential applications. Bacteriophages may regulate the relative abundance of bacterial communities, affect bacterial functions in various ways, and modulate mammalian host immunity. This review explores how phages can regulate bacterial functionality, particularly in gut commensals and pathogens, emphasizing their role in gut health and disease.

Locally advanced rectal cancer (LARC) is treated with neoadjuvant chemo-radiotherapy (nCRT) followed by surgery. A minority of patients show complete response (CR) to nCRT and may avoid surgery and its functional consequences. Instead, most patients show non-complete response (non-CR) and may benefit from additional treatments to increase CR rates. Reliable predictive markers are lacking. Aim of this study was to identify novel signatures predicting nCRT responsiveness. We performed a combined analysis of tumor-associated microbiome and immune gene expression profiling of diagnostic biopsies from 70 patients undergoing nCRT followed by rectal resection, including 16 with CR and 54 with non-CR. Findings were validated by an independent cohort of 49 patients, including 7 with CR and 42 with non-CR. Intratumoral microbiota significantly differed between CR and non-CR groups at genus and species level. Colonization by bacterial species of Ruminococcus genera was consistently associated with CR, whereas abundance of Fusobacterium, Porhpyromonas, and Oscillibacter species predicted non-CR. Immune gene profiling revealed a panel of 59 differentially expressed genes and significant upregulation of IFN-gamma and -alpha response in patients with CR. Integrated microbiome and immune gene profiling analysis unraveled clustering of microbial taxa with each other and with immune cell-related genes and allowed the identification of a combined signature correctly identifying non-CRS in both cohorts. Thus, combined intratumoral microbiome-immune profiling improves the prediction of response to nCRT. Correct identification of unresponsive patients and of bacteria promoting responsiveness might lead to innovative therapeutic approaches based on gut microbiota pre-conditioning to increase nCRT effectiveness in LARC.

Liver cancer is usually diagnosed at an advanced stage and is the third most common cause of cancer-related death worldwide. In addition to the lack of effective treatment options, resistance to therapeutic drugs is a major clinical challenge. The gut microbiota has recently been recognized as one of the key factors regulating host health. The microbiota and its metabolites can directly or indirectly regulate gene expression in the liver, leading to gut-liver axis dysregulation, which is closely related to liver cancer occurrence and the treatment response. Gut microbiota disturbance may participate in tumor progression and drug resistance through metabolite production, gene transfer, immune regulation, and other mechanisms. However, systematic reviews on the role of the gut microbiota in drug resistance in liver cancer are lacking. Herein, we review the relationships between the gut microbiota and the occurrence and drug resistance of hepatocellular carcinoma, summarize the emerging mechanisms underlying gut microbiota-mediated drug resistance, and propose new personalized treatment options to overcome this resistance.

The focus of this study is to explore the impact of gut microbiota in different states on the blood components of couplet medications (dried toad skin and radix clematidis) and to identify drug metabolites associated with the gut microbiota. By constructing a pseudo-sterile rat model and combining non-targeted metabolomics with plasma pharmacology, we found that the plasma metabolites of couplet medications underwent significant changes in different gut microbiome environments. The GABA and PGE1 levels in the model group and the model+TCM (traditional chinese medicine) group were both significantly lower than those in the normal+TCM group. When the gut microbiota is imbalanced, drug interventions cannot significantly increase the levels of GABA and PGE1. It further confirmed the correlation between the levels of GABA and PGE1 and the gut microbiota. Based on the results of non-targeted metabolomics, we applied network pharmacology and molecular docking to explore the core targets for colorectal cancer treatment based on gut microbiota. In the end, we identified TNF and PPARG as the two core targets. These research findings provide a possibility for clarifying the molecular mechanisms of couplet medications in the treatment of colorectal cancer. It also laid the foundation for further clarifying the molecular mechanisms of Chanling Paste in the treatment of colorectal cancer.

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.

The evidence suggests that the microbiome plays a crucial role in cancer development. The oral cavity has many microorganisms that can influence oral cancer progression. Understanding the mechanisms and signaling pathways of the oral, gum, and teeth microbiome in tumor progression can lead to new treatment strategies. Probiotics, which are friendly microorganisms, have shown potential as anti-cancer agents. These positive characteristics of probiotic strains make them suitable for cancer prevention or treatment. The oral-gut microbiome axis supports health and homeostasis, and imbalances in the oral microbiome can disrupt immune signaling pathways, epithelial barriers, cell cycles, apoptosis, genomic stability, angiogenesis, and metabolic processes. Changes in the oral microbiome in oral cancer may suggest using probiotics-based treatments for their direct or indirect positive roles in cancer development, progression, and metastasis, specifically oral squamous cell carcinoma (OSCC). Here, reported relationships between probiotics, oral microbiota, and oral cancer are summarized.

The biology of cancer is characterized by an intricate interplay of cells originating not only from the tumor mass, but also its surrounding environment. Different microbial species have been suggested to be enriched in tumors and the impacts of these on tumor phenotypes is subject to intensive investigation. For these efforts, model systems that accurately reflect human-microbe interactions are rapidly gaining importance. Here we present a guide for selecting a suitable in vitro co-culture platform used to model different cancer-microbiome interactions. Our discussion spans a variety of in vitro models, including 2D cultures, tumor spheroids, organoids, and organ-on-a-chip platforms, where we delineate their respective advantages, limitations, and applicability in cancer microbiome research. Particular focus is placed on methodologies that facilitate the exposure of cancer cells to microbes, such as organoid microinjections and co-culture on microfluidic devices. We highlight studies offering critical insights into possible cancer-microbe interactions and underscore the importance of in vitro models in those discoveries. We anticipate the integration of more complex microbial communities and the inclusion of immune cells into co-culture systems to more accurately simulate the tumor microenvironment. The advent of ever more sophisticated co-culture models will aid in unraveling the mechanisms of cancer-microbiome interplay and contribute to exploiting their potential in novel diagnostic and therapeutic strategies.

An increasing body of research indicates that Fusobacterium nucleatum (F. nucleatum) significantly influences the onset and progression of colorectal cancer (CRC). Our previous study has shown that F. nucleatum exerts pro-tumorigenic effects through aryl hydrocarbon receptor (AhR) activation. However, the role of its microbial metabolites in regulating immune responses remains unclear. Here, we report for the first time that F. nucleatum-derived 3-Indolepropionic acid (IPA) activates AhR in macrophages, driving M2 polarization and tumor-promoting immunosuppression. We discovered that culture supernatant of F. nucleatum (CSF) robustly activates AhR in macrophages. In co-culture systems, CSF upregulated the expression of the M2 marker CD206 and elevated mRNA levels of CD163, TGF-β, IL-10, and VEGF. In a subcutaneous allograft model, CSF induced an elevated number of CD206+ macrophages and decreased presence of CD8+ T cells within the tumor microenvironment, thereby promoting tumor growth. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed IPA as a novel major AhR-activating metabolite in CSF. Strikingly, IPA recapitulated CSF's effects in promoting tumor cell migration and immunosuppression, both in vitro and in vivo. Critically, the AhR inhibitor CH223191 abolished both IPA-mediated M2 polarization and tumor growth. Our study revealed a novel mechanism by which F. nucleatum-derived IPA reprograms macrophages through AhR activation to fuel CRC progression, providing potential therapeutic targets for CRC treatment and prognosis improvement.

This review delves into the complex and multi-layered mechanisms that govern the interaction between gut microbiota and T cells in the context of colorectal cancer (CRC), revealing a novel "microbiota-immune regulatory landscape" within the tumor microenvironment. As CRC progresses, the gut microbiota experiences a significant transformation in both its composition and metabolic patterns. On one hand, specific microbial entities within the gut microbiota can directly engage with T cells, functioning as "immunological triggers" that shape T-cell behavior. Simultaneously, microbial metabolites, such as short-chain fatty acids and bile acids, serve as "molecular regulators" that intricately govern T-cell function and differentiation, fine-tuning the immune response. On the other hand, the quorum-sensing mechanism, a recently recognized communication network among bacteria, also plays a pivotal role in orchestrating T-cell immunity. Additionally, the gut microbiota forms an intriguing connection with the neuro-immune regulatory axis, a largely unexplored "territory" in CRC research. Regarding treatment strategies, a diverse array of intervention approaches-including dietary modifications, the utilization of probiotics, bacteriophages, and targeted antibiotic therapies-offer promising prospects for restoring the equilibrium of the gut microbiota, thereby acting as "ecosystem renovators" that impede tumor initiation and progression. Nevertheless, the current research landscape in this field is fraught with challenges. These include significant variations in microbial composition, dietary preferences, and tumor microenvironments among individuals, a lack of large-scale cohort studies, and insufficient research that integrates tumor mutation analysis, gut microbiota investigations, and immune microenvironment evaluations. This review emphasizes the necessity for future research efforts to seamlessly incorporate multiple factors and utilize bioinformatics analysis to construct a more comprehensive "interactive map" of the gut microbiota-T cell relationship in CRC. The aim is to establish a solid theoretical basis for the development of highly effective and personalized treatment regimens, ultimately transforming the therapeutic approach to CRC.

Lung cancer is a common malignant tumor worldwide with high incidence and mortality rates. Previous studies have claimed that the microbial community plays an integral role in the development and progression of lung cancer. Emerging evidence reveals that gut flora plays a key role in cancer formation and evolution by participating in mechanisms such as metabolism, regulation of inflammation and immune response. Not only the gut flora, but also the presence of intratumoral microbiota may influence lung cancer progression through multiple mechanisms. These research advances suggest that intestinal flora and intratumoral microbiota may not only serve as potential biomarkers for lung cancer, but may also be targets for therapy. However, current studies on both in lung cancer are still limited. Given this, this study aimed to systematically review the latest findings on the major bacterial species of the intestinal flora and their possible protective or harmful roles in the formation, progression, and metastasis of lung cancer. In addition, we analyzed the potential mechanisms by which the intratumoral microbiota affected lung cancer and elaborated on the potential roles of the gut flora and its metabolites, as well as the intratumoral microbiota, in modulating the efficacy of immunotherapy in lung cancer.

This narrative review explores the multifaceted links between periodontal diseases (gingivitis and periodontitis) and systemic health conditions, including cardiovascular disease, diabetes, adverse pregnancy outcomes, Alzheimer's disease, cancers, rheumatoid arthritis, and respiratory infections. It aims to synthesize evidence on how local oral infections exert systemic effects and evaluate the potential of diagnostic technologies to monitor these interactions.

This narrative review synthesizes current scientific literature on periodontal disease pathogenesis, focusing on key pathogens (e.g., Porphyromonas gingivalis, Fusobacterium nucleatum) and their roles in driving local and systemic inflammation via virulence factors and microbial dysbiosis. It examines biomarker-based diagnostic approaches (e.g., IL-1β, TNF-α, microbial DNA) in saliva, blood, and gingival crevicular fluid (GCF) and evaluates current and emerging diagnostic tools (e.g., ELISA, PCR, lateral flow assays, biosensors, microfluidics).

The review highlights that periodontal pathogens contribute to systemic disease through complex mechanisms including persistent inflammation (driven by cytokines like IL-1β, TNF-α), endotoxemia (via LPS, noting pathogen-specific structural variations impacting immune response), molecular mimicry, and immune modulation. Current diagnostic methods provide valuable information but often face limitations in speed, portability, and multiplexing capability needed for comprehensive point-of-care assessment. Emerging technologies, particularly multiplex platforms integrating biosensors or microfluidics, demonstrate significant potential for rapid, user-friendly analysis of multiple biomarkers, facilitating earlier detection and personalized risk stratification, especially in high-risk populations.

Periodontal diseases significantly impact systemic health via intricate microbial and inflammatory pathways. The complexity of these interactions necessitates moving beyond conventional diagnostics towards integrated, advanced technologies. Implementing rapid, multiplex biomarker detection platforms within a multidisciplinary healthcare framework holds the potential to revolutionize early detection of linked conditions, improve personalized management strategies, and ultimately reduce the systemic burden of periodontal disease.

Fusobacterium nucleatum (Fn) has been implicated in various diseases, including colorectal cancer (CRC). This study elucidates Fn's contribution to cholesterol synthesis and the underlying link with CRC, as well as butyrate's counteracting effects in this process. Cells and mouse models were treated with Fn followed/accompanied by butyrate treatments to investigate the interplay between butyrate and Fn's oncogenic properties. Transcriptomics analysis pinpointed Fn's profound impact on cholesterol biosynthesis genes and pathways. Fn treatment upregulated the expression of genes involved in cholesterol synthesis (FDPS, FDFT1, and SQLE) and increased SREBF2 activity in cells and mouse intestines, elevating cholesterol levels in cells, intestines, and sera. Fn upregulated miR-130a-3p, identified through transcriptomics and target prediction, through nuclear factor-κB activation. miR-130a-3p subsequently downregulated AMPKα/β1 expression to activate SREBF2 and upregulate cholesterol biosynthesis genes. These effects were predominantly mitigated by butyrate. Notably, analysis of TCGA data revealed that fusobacterial abundance correlated significantly with the expression of FDPS, FDFT1, SQLE, and AMPKα/β1 in CRC. Fn abundance and miRNA expression in human stools were quantified using qPCR and RT-qPCR. Fecal miR-130a-3p levels increased progressively from normal subjects through adenoma patients to CRC patients, correlating significantly with fecal Fn abundance. Additionally, heightened fecal Fn abundance was associated with an increased incidence of hypercholesterolemia in CRC patients. Fn promotes cholesterol biosynthesis by upregulating miR-130a-3p, which downregulates AMPK proteins and activates SREBF2. This study highlights the influence of gut bacteria on host cholesterol synthesis. Targeted modulation of gut microbiota to reduce cholesterol may represent a promising preventive strategy for CRC.

The Gram-negative anaerobe Fusobacterium nucleatum is an oral oncobacterium that promotes colorectal cancer (CRC) development with the amyloid-forming cell surface adhesin FadA integral to CRC tumorigenesis. We describe here molecular genetic studies uncovering a novel mode of metabolic regulation of FadA-mediated tumor formation by a highly conserved respiratory enzyme known as the Rnf complex. First, we show that genetic disruption of Rnf, via rnfC deletion, significantly reduces the level of fadA transcript, accompanied by a near-complete abolishment of the precursor form of FadA (pFadA), reduced assembly of FadA at the mature cell pole, and severe defects in the osmotic stress-induced formation of FadA amyloids. We show further that the Rnf complex regulates three response regulators (CarR, ArlR, and S1), which modulate the expression of pFadA, without affecting fadA transcript. Consistent with our hypothesis that these response regulators control factors that process FadA, deletion of rnfC, carR, arlR, or s1 each impairs expression of the signal peptidase gene lepB, and FadA production is nearly abolished by CRISPR-induced depletion of lepB. Importantly, while rnfC deletion does not affect the ability of the mutant cells to adhere to CRC cells, rnfC deficiency significantly diminishes the fusobacterial invasion of CRC cells and formation of spheroid tumors in vitro. Evidently, the Rnf complex modulates the expression of the FadA adhesin and tumorigenesis through a gene regulatory network consisting of multiple response regulators, each controlling a signal peptidase that is critical for the post-translational processing of FadA and surface assembly of FadA amyloids.IMPORTANCEThe Rhodobacter nitrogen-fixation (Rnf) complex of Fusobacterium nucleatum plays an important role in the pathophysiology of this oral pathobiont since genetic disruption of this conserved respiratory enzyme negatively impacts a wide range of metabolic pathways, as well as bacterial virulence in mice. Nonetheless, how Rnf deficiency weakens the virulence potential of F. nucleatum is not well understood. Here, we show that genetic disruption of the Rnf complex reduces surface assembly of adhesin FadA and FadA-mediated amyloid formation, via regulation of signal peptidase LepB by multiple response regulators. As FadA is critical in the carcinogenesis of colorectal cancer (CRC), the ability to invade CRC cells and promote spheroid tumor growth is strongly diminished in an Rnf-deficient mutant. Thus, this work uncovers a molecular linkage between the Rnf complex and LepB-regulated processing of FadA-likely via metabolic signaling-that maintains the virulence potential of this oncobacterium in various cellular niches.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, with varying clinical phenotypes and prognoses. Regulatory T cells (Tregs), particularly CD4+FOXP3+ T cell subpopulations, are crucial in modulating immune responses. This study investigates the distribution of two CD4+FOXP3+ T cell subpopulations in bronchoalveolar lavage fluid (BALF) from COPD patients and their association with disease phenotypes and prognosis. Patients were classified into Type A (lower frequencies of inflammatory FOXP3lo T cells) and Type B (higher frequencies of inflammatory FOXP3lo T cells). Type B COPD patients, who demonstrated more severe emphysema, heightened inflammatory responses, faster lung function decline, and more pronounced osteoporosis, showed a significant increase in FOXP3lo non-suppressive T cells. In contrast, Type A patients exhibited a higher proportion of FOXP3hi Treg cells, which correlated with milder disease phenotypes. The distinct distribution of CD4+FOXP3+ T cell subpopulations provides insights into the progression of COPD and suggests that these cells could serve as potential biomarkers for disease severity and prognosis. Further research may offer new therapeutic avenues by targeting these Treg subpopulations in COPD management.

Oral squamous cell carcinoma (OSCC) was the most common malignant type of head and neck squamous cell carcinoma (HNSCC) with a low survival rate. The microbiota in oral cavity or tumor tissues may play a critical role in the OSCC. In this study, we characterized the microbiota from oral cancer tissues, oral swabs and saliva of patients with OSCC using 16S rRNA sequencing. We found differential profiles and amounts of microbiota in oral cancer tissues compared with adjacent tissues, as well as in oral swabs and saliva from OSCC patients compared with healthy individuals. Fusobacterium nucleatum and Porphyromonas endodontalis were found increased in cancer tissues and saliva from OSCC patients. Prevotella melaninogenica was found increased in the saliva and oral swabs from OSCC patients. These data suggested that microbiota varied according to different samples. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated an important role of metabolic pathways in the interaction between microbiota and cancers. Then we analyzed the metabolites from cancer tissues and saliva of OSCC patients by liquid chromatograph-mass spectrometry/mass spectrometry (LC-MS/MS) and gas chromatograph-mass spectrometry (GC-MS). Differential profiles of metabolites were also observed in the cancer tissues compared with adjacent tissues and in the saliva from OSCC patients compared with healthy individuals. It showed that denticulaflavonol was significantly increased while D-mannose was significantly decreased in both cancer tissues and saliva of OSCC patients. Taken together, these results suggested an association between microbiota/metabolites (such as Fusobacterium and mannose) and OSCC, in which the molecular mechanism need further investigated.

Human-resident microbes typically cluster into biofilms - structurally organized communities embedded within a matrix of self-produced extracellular polymeric substance (EPS) that serves as a protective shield. These biofilms enhance microbial survival and functional adaptability, favoring a symbiotic relationship with the host under physiological conditions. However, biofilms exhibit a dual role in modulating the immune response. If their ability to promote tolerance is key to safeguarding homeostasis, by contrast, their persistence can overcome the cutting-edge balance resulting in immune evasion, chronic inflammation and development of numerous diseases such as cancer. Recent evidence highlights the significance of cancer-associated microbiota in shaping the tumor microenvironment (TME). These microbial inhabitants often exhibit biofilm-like structures, which may protect them from host immune responses and therapeutic interventions. The presence of biofilm-forming microbiota within the TME may promote chronic inflammation, and release of bioactive molecules that interfere with immune surveillance mechanisms, thereby enabling cancer cells to evade immune destruction. This review delves into the complex interplay between biofilms and cancer, with particular focus on the tumor-associated microbiota and the implications of biofilm involvement in modulating the immune landscape of the TME. Addressing this intricate relationship holds promises for innovative therapeutic approaches aimed at reprogramming the microbiota-cancer axis for better clinical outcomes.

The intratumoral microbiota, as an important component of the tumor microenvironment, is increasingly recognized as a key factor in regulating responses to cancer immunotherapy. Recent studies have revealed that the intratumoral microbiota is not uniformly distributed but instead exhibits significant spatial heterogeneity, with its distribution patterns influenced by factors such as tumor anatomy, local immune status, and therapeutic interventions. This spatial heterogeneity not only alters the interactions between microbes and the host immune system but may also reshape the immunogenic and immunosuppressive landscapes of tumors. The enrichment or depletion of microbiota in different tumor regions can influence immune cell infiltration patterns, metabolic pathway activities, and immune checkpoint molecule expression, thereby driving the development of resistance to immunotherapy. Moreover, certain bacterial metabolites form concentration gradients between the tumor core and margins, thereby regulating immune cell function. Therefore, understanding and manipulating the spatial distribution of intratumoral microbiota, particularly in resistant patients, holds promise for developing new strategies to overcome immunotherapy resistance. In the future, precise modulation strategies targeting microbial spatial heterogeneity, such as engineered bacterial vectors, probiotic combinations, and phage therapy, may open new avenues for immunotherapy.

The gut microbiota significantly impacts the development and progression of upper gastrointestinal (GI) cancers, including esophageal and gastric cancers. Microbial dysbiosis contributes to carcinogenesis through mechanisms such as inflammation, immune modulation, and direct DNA damage. Techniques for sampling oral, esophageal, and gastric microbiota vary, with standardization being essential for reliable results. Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) are associated with an enrichment of Gram-negative bacteria, promoting inflammation and cancer progression. Esophageal squamous cell carcinoma (ESCC) also shows distinct microbial patterns, with reduced diversity and increased harmful bacteria like Porphyromonas gingivalis and Fusobacterium nucleatum. In gastric cancer (GC), Helicobacter pylori (HP) and non-HP gastric microbiota play significant roles, with diverse microbial communities contributing to cancer development through nitrate reduction, immune modulation, and inflammation. Emerging evidence highlights the role of non-HP bacteria in promoting carcinogenesis, with specific taxa like Fusobacterium nucleatum and Lactobacillus influencing tumor growth and immune evasion. Further research is needed to elucidate the complex interactions between gut microbiota and upper GI cancers, paving the way for novel diagnostic and therapeutic approaches. Understanding these microbial dynamics offers potential for microbiota-based interventions, improving the early detection, prognosis, and treatment of upper GI cancers. This comprehensive review summarizes the available evidence on the role of microbiota in upper GI oncology and the need for continued exploration in this field.

There is a widely known relationship between certain microbes and cancer progression. For instance, Helicobacter pylori is associated with the occurrence of gastric cancer, while HPV is associated with cervical and head and neck cancers. Recent studies have uncovered novel and important associations between bacterial presence and tumor formation and treatment response. Apart from the influence of the intestinal microbiome on cancer, the local activity of bacteria affects disease properties as well. Bacteria can localize within tumors in less vascularized niches. Their presence mediates the activity of signaling pathways, which contribute to tumorigenesis. Furthermore, they affect the composition of the tumor microenvironment, a highly complex structure composed of immunoregulatory cells and secreted inflammatory mediators. Recently, researchers have analyzed the properties of bacteria to develop novel anticancer strategies. The aim of this review is to discuss the latest findings regarding the relationships between bacteria and cancer and the properties of bacteria that could be used to kill cancer cells.

The gut microbiota is a complex community of microorganisms that inhabit the human gastrointestinal tract, helping to maintain the ecological balance of the body's internal and external environments. Disruptions in the composition and diversity of gut microbiota, as well as changes in their metabolic functions, can link to the development and severity of conditions such as premature ovarian insufficiency, polycystic ovary syndrome, and ovarian tumors. This article thoroughly reviews recent research on the connection between gut microbiota and ovarian diseases, providing fresh perspectives on their prevention, pathogenesis, and treatment.

The gut microbiota constitutes a complex ecosystem essential for host health, offering metabolic support, modulating the immune system, and protecting against pathogens. However, this community faces constant destabilizing challenges, including dietary changes, antibiotics, and enteric infection. Prolonged microbiota imbalance or dysbiosis can exacerbate intestinal disease states, including inflammatory bowel disease and colorectal cancer. Understanding the mechanisms that sustain microbiota resilience in the face of these imbalances is crucial for maintaining host health and developing effective therapeutics. This review explores microbiota resilience through the lens of an ecological model, emphasizing the interplay between microbial communities and host-driven environmental controls. We highlight two critical factors shaping microbiota resilience: oxygen tension and iron availability-challenges encountered by ancient anaerobic organisms during early evolutionary history, from which the predominant members of the microbiota have descended. Disruptions in intestinal anaerobiosis during inflammation increase luminal oxygen levels, favoring pro-inflammatory facultative anaerobes and depleting obligately anaerobic commensals. Simultaneously, host nutritional immunity restricts iron availability, further challenging commensal survival. This dual environmental challenge of rising oxygen tension and reduced iron availability is a convergent outcome of a diverse array of perturbations, from pathogen invasion to antibiotic treatment. By highlighting these conserved downstream environmental challenges rather than the specific upstream perturbations, this ecological view offers a focused framework for understanding microbiota resilience. This perspective not only enhances our understanding of host-microbiota interactions but also informs therapeutic strategies to foster resilience and support host health.

Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality worldwide, highlighting the urgent need for novel preventive and therapeutic strategies. Emerging research highlights the crucial role of the gut microbiota, including bacteria, fungi, viruses, and their metabolites, in the pathogenesis of CRC. Dysbiosis, characterized by an imbalance in microbial composition, contributes to tumorigenesis through immune modulation, metabolic reprogramming, and genotoxicity. Specific bacterial species, such as Fusobacterium nucleatum and enterotoxigenic Bacteroides fragilis, along with fungal agents like Candida species, have been implicated in CRC progression. Moreover, viral factors, including Epstein-Barr virus and human cytomegalovirus, are increasingly recognized for their roles in promoting inflammation and immune evasion. This review synthesizes the latest evidence on host-microbiome interactions in CRC, emphasizing microbial metabolites, such as short-chain fatty acids and bile acids, which may act as both risk factors and therapeutic agents. We further discuss the latest advances in microbiota-targeted clinical applications, including biomarker-assisted diagnosis, next-generation probiotics, and microbiome-based interventions. A deeper understanding of the role of gut microbiome in CRC pathogenesis could pave the way for diagnostic, preventive, and personalized therapeutic strategies.

Intratumoral microbiota can affect the development and progression of many types of cancer, including gastric cancer. A better understanding of the precise mechanisms by which microbiota support gastric cancer could lead to improved therapeutic approaches. In this study, we investigated the effect of intratumoral microbiota on the tumor immune microenvironment during gastric cancer malignant progression. Analysis of human gastric cancer tissues with 16S rRNA amplicon sequencing revealed that Fusobacterium nucleatum was significantly enriched in gastric cancer tissues with lymph node metastasis and correlated with a poor prognosis. F. nucleatum infection spontaneously induced chronic gastritis and promoted gastric mucosa dysplasia in mice. Furthermore, gastric cancer cells infected with F. nucleatum showed accelerated growth in immunocompetent mice compared with immunodeficient mice. Single-cell RNA sequencing uncovered that F. nucleatum recruited tumor-associated neutrophils (TAN) to reshape the tumor immune microenvironment. Mechanistically, F. nucleatum invaded gastric cancer cells and activated IL17/NF-κB/RelB signaling, inducing TAN recruitment. F. nucleatum also stimulated TAN differentiation into the protumoral subtype and subsequent promotion of PD-L1 expression, further facilitating gastric cancer immune evasion while also enhancing the efficacy of anti-PD-L1 antibody therapy. Together, these data uncover mechanisms by which F. nucleatum affects gastric cancer immune evasion and immunotherapy efficacy, providing insights for developing effective treatment strategies. Significance: Intratumoral F. nucleatum activates NF-κB signaling to facilitate gastric cancer immune evasion by promoting tumor-associated neutrophil recruitment that sensitizes tumors to immune checkpoint blockade therapy.

Natural killer (NK) cells are a subset of innate lymphoid cells that possess cytotoxic properties, playing a pivotal role in immune surveillance against tumor cells. However, it remains unclear whether there are any alterations in the quantity and functional status of NK cells in colorectal cancer (CRC).

In this study, we collected peripheral blood samples from both CRC patients and age- and sex-matched healthy controls (HCs). The distribution characteristics, phenotypic changes, functional status, apoptosis susceptibility, and proliferative capacity of circulating NK cells were detected and analyzed by flow cytometry. An in vitro study was performed to investigate the blocking effect of KLRG1 antibody on peripheral blood NK cells in CRC patients.

The frequency and absolute number of circulating NK cells were significantly decreased in CRC patients compared to those in HCs. Meanwhile, the function of NK cells from CRC patients was compromised, as shown by the reduced production of IFN-γ, TNF-α, and CD107a, with this impairment becoming increasingly significant as neural invasion progressed and tumor invasion advanced. We further found that the expression of activating receptors NKp30 and NKp46 were reduced, while the expression of inhibitory receptor KLRG1 was remarkably increased. The increased proportion of KLRG1 on NK cells was associated with CRC progression, and KLRG1+ NK cells showed impaired production of IFN-γ, TNF-α, and CD107a and were more susceptible to apoptosis. Importantly, blockade of the KLRG1 pathway could restore the cytokine production and degranulation ability of NK cells from CRC patients.

The present study demonstrates that NK cells in CRC patients exhibit functional exhaustion, and KLRG1 blockade restores the effector function of NK cells, indicating that targeting KLRG1 represents a promising strategy for immunotherapy in patients with CRC.

Periodontitis is a chronic inflammatory disease that significantly impacts periodontal bone regeneration, yet the distinct biological features of osteoblasts in this condition remain poorly understood. This study aims to elucidate the cellular and molecular mechanisms underlying osteoblast dysfunction in periodontitis, with a focus on the role of Fusobacterium nucleatum (Fn) and its effector protein, D-galactose-binding periplasmic protein (Gbp).

Single-cell RNA sequencing (scRNA-seq) data from human gingival tissues of periodontitis patients (PD) and healthy controls (HC) were analyzed to identify cellular heterogeneity and molecular pathways. An experimental periodontitis model in mice and primary osteoblast cultures were used to investigate the effects of Fn and Gbp on osteogenic differentiation. Transcriptomic analysis, gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) networks were employed to explore the underlying mechanisms.

scRNA-seq revealed a reduction in mesenchymal stem cells (MSCs) and osteoblastic lineage cells in PD tissues, with significant downregulation of osteogenic pathways such as Wnt signaling. Fn infection induced alveolar bone destruction in vivo and inhibited osteoblast proliferation, differentiation, and mineralization in vitro. Gbp, an Fn adhesin, similarly impaired osteogenic differentiation by downregulating key osteogenic genes and pathways. Transcriptomic analysis identified shared inflammatory and osteogenic pathways affected by Fn and Gbp, with NF-κB signaling activated and Wnt/β-catenin signaling inhibited. Mechanistically, Gbp interacted with the host protein ANXA2, disrupting the ANXA2/GSK3β complex and inhibiting Wnt/β-catenin signaling, a pivotal route for osteoblast differentiation. ANXA2 knockdown mitigated the Fn/Gbp-induced suppression of osteogenic activity, emphasizing its role in Fn-induced bone loss.

This study demonstrates that Fn and its effector Gbp disrupt osteogenic differentiation by inactivating the Wnt/β-catenin pathway binding to ANXA2.

Intratumoral microbiota plays a crucial role in cancer progression. However, the relationship between host genetics and intratumoral microbiota, as well as their interaction in colorectal cancer (CRC) progression, remains unclear. With 748 Chinese CRC patients enrolled from three cohorts, we find that the single nucleotide polymorphism (SNP) rs2355016, located in the intron of ATP-sensitive inward rectifier potassium channel 11 (KCNJ11), is significantly associated with the abundance of Fusobacterium. Compared with the rs2355016 GG genotype, patients carrying the A allele exhibit downregulation of KCNJ11 and enrichment of Fusobacterium, which corresponds to accelerated proliferation and progression. Low expression of KCNJ11 can increase the level of galactose-N-acetyl-d-galactosamine (Gal-GalNAc) on the surface of CRC cells, thereby facilitating the binding of the Fap2 protein from F. nucleatum to Gal-GalNAc. This further enhances the adhesion and invasion of F. nucleatum and promotes CRC growth. Our study explores the interaction between intratumoral microbiota and SNPs in CRC patients, which will enhance our understanding of CRC proliferation.

The intratumoral microbe-host interaction plays crucial role in the development of cancer. The microbiome can influence cancer development by modulating inflammation, immune responses and metabolic pathways. Therefore, we aim to delineate the landscape and role of intratumoral microbiota in cervical cancer (CC).

The presence of bacterial community in CC tissues was confirmed by fluorescence in situ hybridization (FISH). Then 16s rRNA and RNA-Seq were used to characterize the composition of intratumoral microbiota. Combined with cervical squamous cell carcinoma (CESC) data from the Tumor Cancer Genome Atlas (TCGA), the clinical signatures of intratumoral microbiota and DEGs were further analyzed. Finally, the effect of the up-regulated Fibrinogen beta chain (FGB) expressed fragment peptide on the biological behavior of cancer was verified in vitro.

We found the composition heterogeneity of bacteria in CC tumors. Pseudomonas was most highly enriched in CC tissues and grouped according to the relative abundance level. The clinical characteristics of patients with relatively high abundance of Pseudomonas had the higher levels of fibrinogen and lower levels of white blood cell (WBC) and albumin (ALB) expression. Combining transcriptome data from the two our collective CC and TCGA-CESC cohorts, we found that Pseudomonas abundance was significantly associated with fibrinogen beta peptide expression and worse overall survival in CC patients. In vitro experiment revealed that Pseudomonas could promote the proliferation and migration of cervical cancer cells through overexpression of FGB.

We characterized the composition of the intratumoral microbiota in CC tissues and identified the most significantly differentially abundant bacteria between cancerous and non-cancerous tissues. Our findings provide novel insights into the relationship between intratumoral Pseudomonas and the tumorigenesis of CC. A deeper understanding of the tumor microenvironment and its associated microbiota may reveal new potential therapeutic targets and improve clinical outcomes.

Cancers of the oral cavity, lip, salivary gland, and oropharynx cause substantial global disease burden. While tobacco-use and alcohol use are highly associated with oral cancers, the rising incidence of disease in patients who do not use tobacco or alcohol points to additional carcinogenic risk factors. Chronic inflammation, disruption of the oral microbiome, and dysbiosis are becoming more widely implicated in the pathogenesis of oral cancer. Several studies have identified specific bacterial species enriched in patients with oral cancer, including Porphyromonas gingivalis and Fusobacterium nucleatum. In this narrative review, we describe potential carcinogenic mechanisms exhibited by these species and other microbes in the development of oral cancer.

Cancer has long been associated with genetic and environmental factors, but recent studies reveal the important role of gut microbiota in its initiation and progression. Around 13% of cancers are linked to infectious agents, highlighting the need to identify the specific microorganisms involved. Gut microbiota can either promote or inhibit cancer growth by influencing oncogenic signaling pathways and altering immune responses. Dysbiosis can lead to cancer, while certain probiotics and their metabolites may help reestablish micro-ecological balance and improve anti-tumor immune responses. Research into targeted approaches that enhance therapy with probiotics is promising. However, the effects of probiotics in humans are complex and not yet fully understood. Additionally, methods to counteract harmful bacteria are still in development. Early clinical trials also indicate that modifying gut microbiota may help manage side effects of cancer treatments. Ongoing research is crucial to understand better how gut microbiota can be used to improve cancer prevention and treatment outcomes.

The gut microbiome has a crucial role in cancer development and therapy through its interactions with the immune system and tumour microenvironment. Although evidence links gut microbiota composition to cancer progression, its precise role in modulating treatment responses remains unclear. In this Review, we summarize current knowledge on the gut microbiome's involvement in cancer, covering its role in tumour initiation and progression, interactions with chemotherapy, radiotherapy and targeted therapies, and its influence on cancer immunotherapy. We discuss the impact of microbial metabolites on immune responses, the relationship between specific bacterial species and treatment outcomes, and potential microbiota-based therapeutic strategies, including dietary interventions, probiotics and faecal microbiota transplantation. Understanding these complex microbiota-immune interactions is critical for optimizing cancer therapies. Future research should focus on defining microbial signatures associated with treatment success and developing targeted microbiome modulation strategies to enhance patient outcomes.

Evidence of changes in the composition and function of the gut microbiota (GM) in post-stroke depression (PSD) patients is gradually accumulating. This study aimed to systematically evaluate the relationship between PSD and GM.

We searched in PubMed, Web of Science, Embase, Cochrane databases, Wangfang, VIP, CBM, and CNKI from the establishment of the database to April 17, 2024, and systematic review and meta-analysis were performed to investigate the differences of GM between patients with PSD spectrum and healthy controls (HC) or stroke spectrum.

There were 14 studies consisting a total of 1,556 individuals included in the meta-analysis. The pooled results showed that PSD spectrum demonstrated significantly increased α diversity as indexed by Chao1 index, ACE indexes, Shannon index, and Simpson index as compared to HC. Additionally, stroke spectrum significantly increased α diversity as indexed by Simpson index compared to PSD. Furthermore, the pooled estimation of relative abundance showed that Bacteroidota, Fusobacteriota, and Pseudomonadota in PSD patients were significantly higher than those in the HC group, while the abundance of Bacillota was higher in the HC group. Moreover, significant differences in GM were observed between PSD patients and HC at the family and genus levels.

This study found that the α diversity of PSD patients was higher than that of HC. Moreover, there were also differences in the distribution of GM at the phylum, family, and genus levels, respectively. At the same time, the level of Lachnospira in PSD patients was lower than that in the stroke group.

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024582708.

The intestinal microbiome contributes to colorectal carcinogenesis, disease progression, and response to therapy. Pathologic complete response is the therapeutic goal of neoadjuvant chemoradiation in rectal carcinoma. Nonoperative management has become an accepted strategy, and markers of complete treatment response are needed. Intestinal commensal bacteria contribute to treatment response and radiation colitis, and microbiome-targeted therapies have shown promise in clinical trials. We investigated the relationship among mucosa-associated bacteria, neoadjuvant therapy response, and radiation colitis symptoms in 57 patients who received neoadjuvant regimens with no therapy, chemotherapy only, or chemoradiation. The design was a retrospective cohort study. Microbiome profiling was performed by 16S rDNA sequencing of formalin-fixed, paraffin-embedded tissue at the proximal margin of resection. Global β diversity differed according to neoadjuvant therapy modality and was associated with radiation colitis. Taxonomic differences were detectable at phylum and lower classification levels, and radiation-induced colitis was associated with enrichment of the Bacillaceae family. Taxonomic features, including reduced Streptococcus, Lachnospiraceae, and Bacillaceae, were enriched in complete histopathologic responders to neoadjuvant therapy. Taxon-based prediction of metabolic pathways identified enrichment of prokaryotic NAD+ biosynthesis and salvage pathways in complete responders. Mucosal microbiome responses to multimodal neoadjuvant therapy reflect symptomatic radiation colitis, histopathologic evidence of radiation injury, and pathologic treatment response. Posttreatment microbiome β diversity markers of complete pathologic response may be useful in decisions to manage rectal carcinoma nonoperatively.

Posttreatment markers of the complete response of rectal carcinoma to neoadjuvant chemoradiation are needed to guide decisions about surgical resection. We found that mucosal microbiome β diversity, bacterial metabolic capacities, and specific taxonomic groups distinguished between complete and incomplete responders. The mucosal microbiome provides markers for complete pathologic response.

The gut microbiota is a diverse ecosystem that significantly impacts human health and disease. This article focuses on how the gut microbiota interacts with inflammatory bowel diseases and colorectal tumors, especially through immune regulation. The gut microbiota plays a role in immune system development and regulation, while the body's immune status can also affect the composition of the microbiota. These microorganisms exert pathogenic effects or correct disease states in gastrointestinal diseases through the actions of toxins and secretions, inhibition of immune responses, DNA damage, regulation of gene expression, and protein synthesis. The microbiota and its metabolites are essential in the development and progression of inflammatory bowel diseases and colorectal tumors. The complexity and bidirectionality of this connection with tumors and inflammation might render it a new therapeutic target. Hence, we explore therapeutic strategies for the gut microbiota, highlighting the potential of probiotics and fecal microbiota transplantation to restore or adjust the microbial community. Additionally, we address the challenges and future research directions in this area concerning inflammatory bowel diseases and colorectal tumors.