The intracellular bacterium Fusobacterium nucleatum (Fn) mediates tumorigenesis and progression in colorectal cancer (CRC). However, the origin of intratumoral Fn and the role of Fn-infected immunocytes in the tumor microenvironment remain unclear. Here, we observed that Fn-infected neutrophils/macrophages (PMNs/MΦs), especially PMNs, accumulate in tumor tissues and fecal Fn abundance correlates positively with an abundance of blood PD-L1+ PMNs in CRC patients. Moreover, Fn accumulates in tumor tissues of tumor-bearing mice via intragingival infection and intravenous injection. Mechanistically, Fn can survive inside PMNs by reducing intracellular ROS levels and producing H2S. Specifically, the lysozyme inhibitor Fn1792 as a novel virulence factor of Fn suppressed apoptosis of phagocytes by inducing CX3CR1 expression. Furthermore, Fn-driven CX3CR1+PD-L1+ phagocytes transfer intracellular Fn to tumor cells, which recruit PMNs/MΦs through the CXCL2/8-CXCR2 and CCL5/CCR5 axes. Consequently, CX3CR1+PD-L1+ PMNs infiltration promotes CRC metastasis and weakens the efficacy of immunotherapy. Treatment with the doxycycline eradicated intracellular Fn, thereby reducing the CX3CR1+PD-L1+ PMNs populations and slowing Fn-promoted tumor growth and metastasis in mice. These results suggest phagocytes as Fn-presenting cells use mutualistic strategies to home to tumor tissues and induce immunosuppression, and treatment with ROS-enhanced antibiotics can inhibit Fn-positive tumor progression.

The gut microbiota undergoes continuous variations among individuals and across their lifespan, shaped by diverse factors encompassing diet, age, lifestyle choices, medication intake, and disease states. These microbial inhabitants play a pivotal role in orchestrating physiological metabolic pathways through the production of metabolites like bile acids, choline, short-chain fatty acids, and neurotransmitters, thereby establishing a dynamic "gut-organ axis" with the host. The intricate interplay between the gut microbiota and the host is indispensable for gut health, and RNA N6-methyladenosine modification, a pivotal epigenetic mark on RNA, emerges as a key player in this process. M6A modification, the most prevalent internal modification of eukaryotic RNA, has garnered significant attention in the realm of RNA epigenetics. Recent findings underscore its potential to influence gut microbiota diversity and intestinal barrier function by modulating host gene expression patterns. Conversely, the gut microbiota, through its impact on the epigenetic landscape of host cells, may indirectly regulate the recruitment and activity of RNA m6A-modifying enzymes. This review endeavors to delve into the biological functions of m6A modification and its consequences on intestinal injury and disease pathogenesis, elucidating the partial possible mechanisms by which the gut microbiota and its metabolites maintain host intestinal health and homeostasis. Furthermore, it also explores the intricate crosstalk between them in intestinal injury, offering a novel perspective that deepens our understanding of the mechanisms underlying intestinal diseases.

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.

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.

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.

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.

The composition of the microbiota in patients has been shown to correlate with cancer progression and response to therapy, highlighting unique opportunities to improve patient outcomes. In this review, we discuss the challenges and advancements in understanding the chemical mechanisms of specific microbiota species, pathways, and molecules involved in cancer progression and treatment. We also describe the modulation of cancer and immunotherapy by the microbiota, along with approaches for investigating microbiota enzymes and metabolites. Elucidating these specific microbiota mechanisms and molecules should offer new opportunities for developing enhanced diagnostics and therapeutics to improve outcomes for cancer patients. Nonetheless, many microbiota mechanisms remain to be determined and require innovative chemical genetic approaches.

The number of colorectal cancer (CRC) patients is steadily growing worldwide, particularly in developing nations. Nonetheless, recent advances in early detection studies and therapy alternatives have reduced CRC mortality in affluent countries, despite rising incidence. Gut microbiota and their metabolites may contribute to tumor growth and reduced therapeutic efficacy. This preliminary study sought to uncover metabolic fingerprints in colorectal cancer patients. It also emphasizes the correlation between the gut microbiome, microbial metabolism, and altered metabolites in CRC. In this study, stool samples from 20 CRC patients and matched healthy controls were enrolled. Untargeted metabolomics approach based on an ultra-high-performance liquid chromatography high-resolution mass spectrometry (UHPLC-MS/MS) were applied. Statistical approaches, pathway enrichment analysis, and network analysis were employed to unleash CRC perturbed metabolic pathways and putative biomarkers. The study identified a distinct manually curated metabolite profile that is substantially linked to CRC. The steroidogenesis, aspartate, tryptophan (Trp), and urea cycle were the most significant pathways that concurrently contributed to CRC.Prominently, among other pathways, Trp metabolism was identified as a critical pathway, indicating a possible connection between the development of CRC and gut microbiota. In a nutshell the notable resulted metabolites reveal auspicious biomarkers for the initial diagnosis as well as surveilling of CRC progression. This preliminary study highlights the potential involvement that gut bacteria may contribute in CRC patients. Further investigation into the composition of the gut microbiome associated with this metabolic profile may lead to the identification of novel biomarkers for early detection and possible targets for treatment.

Decades of research have made clear that host-associated microbiomes touch all facets of health. However, effective therapies that target the microbiome have been elusive given its inherent complexity. Here, we experimentally examined diet-microbe-host interactions through a complex systems framework, centered on dietary oxalate. Using multiple, independent molecular, rodent, and in vitro experimental models, we found that microbiome composition influenced multiple oxalate-microbe-host interfaces. Importantly, the administration of the oxalate-degrading specialist, Oxalobacter formigenes, was only effective against a poor oxalate-degrading microbiota background and gives critical new insights into why clinical intervention trials with this species exhibit variable outcomes. Data suggest that, while heterogeneity in the microbiome impacts multiple diet-host-microbe interfaces, metabolic redundancy among diverse microorganisms in specific diet-microbe axes is a critical variable that may impact the efficacy of bacteriotherapies, which can help guide patient and probiotic selection criteria in probiotic clinical trials.

Colorectal cancer (CRC) is a major global health challenge. Emerging research highlights the pivotal role of the gut microbiota in influencing CRC risk, progression, and treatment response. Metagenomic approaches, especially high-throughput shotgun sequencing, have provided unprecedented insights into the intricate connections between the gut microbiome and CRC. By enabling comprehensive taxonomic and functional profiling, metagenomics has revealed microbial signatures, activities, and biomarkers associated with colorectal tumorigenesis. Furthermore, metagenomics has shown a potential to guide patient stratification, predict treatment outcomes, and inform microbiome-targeted interventions. Despite remaining challenges in multi-omics data integration, taxonomic gaps, and validation across diverse cohorts, metagenomics has propelled our comprehension of the intricate gut microbiome-CRC interplay. This review underscores the clinical relevance of microbial signatures as potential diagnostic and prognostic tools in CRC. Furthermore, it discusses personalized treatment strategies guided by this omics' approach.

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.

Diet impacts cancer in diverse manners. Multiple nutritional effects on tumors are mediated by dietary modulation of commensals, residing in mucosal surfaces and possibly also within the tumor microenvironment. Mechanistically understanding such diet-microbiome-host interactions may enable to develop precision nutritional interventions impacting cancer development, dissemination, and treatment responses. However, data-driven nutritional strategies integrating diet-microbiome interactions are infrequently incorporated into cancer prevention and treatment schemes. Herein, we discuss how dietary composition affects cancer-related processes through alterations exerted by specific nutrients and complex foods on the microbiome. We highlight how dietary timing, including time-restricted feeding, impacts microbial function in modulating cancer and its therapy. We review existing and experimental nutritional approaches aimed at enhancing microbiome-mediated cancer treatment responsiveness while minimizing adverse effects, and address challenges and prospects in integrating diet-microbiome interactions into precision oncology. Collectively, mechanistically understanding diet-microbiome-host interactomes may enable to achieve a personalized and microbiome-informed optimization of nutritional cancer interventions.

Fusobacterium nucleatum (Fn), an oral anaerobic commensal, has recently been identified as a crucial oncogenic contributor to colorectal cancer pathogenesis through its ectopic colonization in the gastrointestinal tract. Accumulating evidence reveals its multifaceted involvement in colorectal cancer initiation, progression, metastasis, and therapeutic resistance to conventional treatments, including chemotherapy, radiotherapy, and immunotherapy. This perspective highlights recent advances in anti-Fn strategies, including small-molecule inhibitors, nanomedicines, and biopharmaceuticals, while critically analyzing the translational barriers in developing targeted antimicrobial interventions. We further propose potential strategies to overcome current challenges in Fn modulation, aiming to pave the way for more effective therapeutic interventions and better clinical outcomes.

Colorectal cancer (CRC) represents a relevant public health problem, with high incidence and mortality in Western countries. CRC can occur as sporadic (65%-75%), common familial (25%), or as a consequence of an inherited predisposition (up to 10%). While unravelling its genetic basis has been a long trip leading to relevant clinical implementation over more than 30 years, other contributing factors remain to be clarified. Among these, micro-organisms have emerged as critical players in the development and progression of the disease, as well as for CRC treatment response. Fusobacterium nucleatum (Fn) has been associated with CRC development in both pre-clinical models and clinical settings. Fusobacteria are core members of the human oral microbiome, while being less prevalent in the healthy gut, prompting questions about their localization in CRC and its precursor lesions. This review aims to critically discuss the evidence connecting Fn with CRC pathogenesis, its molecular subtypes and clinical outcomes.

With advances in sequencing techniques, microbiota dysbiosis and pathogenic microbes that accelerate colorectal cancer progression have been identified and widely reported. However, few studies have focused on the microbiota taxa of rectal mucus in rectal cancer (RC) patients. Here, we analyzed the composition and characteristics of the rectal mucosa microbiota of RC patients from Wenzhou city, China, and compared the results with those of healthy controls.

To explore the changes in the characteristics of the rectal mucosal flora associated with RC, and identify biomarkers of microbe taxa for RC.

Rectal mucosa samples from a Chinese cohort of 72 recently diagnosed RC patients and 71 healthy controls were obtained. A validation cohort, which included 22 RC patients and 60 healthy controls, was also established. Changes in the rectal mucosal flora were observed by cultivation, 16S ribosomal DNA gene sequencing analysis and quantitative polymerase chain reaction analysis.

The 16S ribosomal DNA results demonstrated that RC patients presented increased bacterial community richness and alpha diversity as well as an altered rectal mucosal microbiota, with depletion of Proteobacteria and Thermi and enrichment of Bacteroidetes and Fusobacteria in cancerous mucosal tissues (CM) and enrichment of Firmicutes and Cyanobacteria in adjacent noncancerous mucosal tissues (AM). The culture results showed that the mean loads of Escherichia coli, Bifidobacterium, Enterococcus, and Lactobacillus were significantly reduced in RC patients. The ratios of Prevotella to Ruminococcus [areas under the receiver operating curve: 0.795 in AM vs normal control mucosa (NM), 0.77 in CM vs NM] and of Prevotella stercorea to Propionibacterium acnes (areas under the receiver operating curve: 0.808 in AM vs NM, 0.843 in CM vs NM) exhibited excellent abilities to differentiate between healthy controls and RC patients.

RC patients have an altered rectal mucosal microbiota, and the ratio of Prevotella to Ruminococcus or the ratio of Prevotella stercorea to Propionibacterium acnes may serve as a marker for RC diagnosis.

Fusobacterium nucleatum (F. nucleatum) is an anaerobic bacterium known for its association with periodontal disease and oral infections. It has been implicated in the development of gastrointestinal diseases such as inflammatory bowel disease and colorectal cancer. Ulcerative colitis (UC), which is characterized by chronic inflammation of the colon, is a condition of unknown etiology with a rising incidence rate, significantly affecting the quality of life for patients. The increased intestinal permeability during UC may facilitate the adherence or invasion of F. nucleatum into the damaged intestinal barrier, leading to exacerbated inflammation.

This article introduces the concept of the oral-gut axis, reviewing existing literature to analyze the role of F. nucleatum in the pathogenesis of UC and exploring its potential pathogenic mechanisms. It also summarizes the latest advances in treating patients with UC who have F. nucleatum and looks forward to prospective therapeutic strategies and the translational prospects of F. nucleatum within the oral-gut axis.

F. nucleatum may be a key player in the pathogenesis of UC, likely due to its invasiveness during periods of increased intestinal permeability. The paper also discusses innovative approaches for the prevention and management of UC exacerbated by F. nucleatum, paving the way for more effective treatment of UC.

The review offers new insights into the complex relationship between the oral microbiome and intestinal diseases, enhancing our understanding of their dynamic interactions. There is a paucity of literature on therapeutic approaches, indicating a need for further clinical research.

The landscape of clinical microbiome research has dramatically evolved over the past decade. By leveraging in vivo and in vitro experimentation, multiomic approaches and computational biology, we have uncovered mechanisms of action and microbial metrics of association and identified effective ways to modify the microbiome in many diseases and treatment modalities. This Review explores recent advances in the clinical application of microbiome research over the past 5 years, while acknowledging existing barriers and highlighting opportunities. We focus on the translation of microbiome research into clinical practice, spearheaded by Food and Drug Administration (FDA)-approved microbiome therapies for recurrent Clostridioides difficile infections and the emerging fields of microbiome-based diagnostics and therapeutics. We highlight key examples of studies demonstrating how microbiome mechanisms, metrics and modifiers can advance clinical practice. We also discuss forward-looking perspectives on key challenges and opportunities toward integrating microbiome data into routine clinical practice, precision medicine and personalized healthcare and nutrition.

Colorectal cancer (CRC) is a prevalent form of cancer in humans, with the gut microbiota playing a significant role in its pathogenesis. Although previous research has primarily focused on the role of primary metabolites produced by gut microbes in CRC development, the role of secondary metabolites remains largely unexplored. Secondary metabolites are known to mediate crucial interactions between the microbiota and the host, potentially influencing CRC progression. However, their specific relationship to CRC pathogenesis is poorly understood. To address this gap, we performed a meta-analysis using fecal metagenomic data from a cohort of CRC patients and healthy controls, aiming to identify CRC-associated microbial secondary metabolite biosynthetic gene clusters (BGCs). Our findings not only provide valuable insights into the pathogenicity and carcinogenicity of CRC but also shed light on the potential mechanisms underlying its development.

Coculture systems (CCSs) are experimental tools used to study the interactions of anaerobic bacteria among themselves and the gut epithelial cells under conditions simulating the human gut, unlike those in animal models. Although the studies on animal models are useful in determining the relationship between the causative agents of infections and human infections, they have disadvantages, such as ethical issues, in addition to the differences in the microbiota of the animal and humans. Therefore, the results obtained using animal models cannot be directly extrapolated to humans. CCSs can more completely reflect in vivo gut homeostasis and contribute to better understanding of the interplay between the intestinal cells and anaerobes, prevalent among the gut bacteria. Moreover, they provide new insights on the pathogenesis of infections and aid in assessing the usefulness of new probiotics and antibacterials. Therefore, CCSs, including the gut-on-a-chip models, can significantly improve microbiota-based therapy. Moreover, they can also be used to detect microbiota-derived metabolites such as those with mutagenic properties. The aim of this review was to explore selected CCS models of anaerobes with intestinal epithelium and their application in investigating intestinal homeostasis. The focus was to highlight the application of different CCSs and important data obtained from their implementation.

The human microbiome, an intricate ecosystem of trillions of microbes residing across various body sites, significantly influences cancer, a leading cause of morbidity and mortality worldwide. Recent studies have illuminated the microbiome's pivotal role in cancer development, either through direct cellular interactions or by secreting bioactive compounds such as metabolites. Microbial metabolites contribute to cancer initiation through mechanisms such as DNA damage, epithelial barrier dysfunction, and chronic inflammation. Furthermore, microbial metabolites exert dual roles on cancer progression and response to therapy by modulating cellular metabolism, gene expression, and signaling pathways. Understanding these complex interactions is vital for devising new therapeutic strategies. This review highlights microbial metabolites as promising targets for cancer prevention and treatment, emphasizing their impact on therapy responses and underscoring the need for further research into their roles in metastasis and therapy resistance.

Disease tolerance is a host response to infection that limits collateral damage to host tissues while having a neutral effect on pathogen fitness. Previously, we found that the pathogenic lactic acid bacterium Streptococcus pyogenes manipulates disease tolerance using its aerobic mixed-acid fermentation pathway via the enzyme pyruvate dehydrogenase, but the microbe-derived molecules that mediate communication with the host's disease tolerance pathways remain elusive. Here we show in a murine model that aerobic mixed-acid fermentation inhibits the accumulation of inflammatory cells including neutrophils and macrophages, reduces the immunosuppressive cytokine interleukin-10, and delays bacterial clearance and wound healing. In infected macrophages, the aerobic mixed-acid fermentation end-products acetate and formate from streptococcal upregulate host acetyl-CoA metabolism and reduce interleukin-10 expression. Inhibiting aerobic mixed-acid fermentation using a bacterial-specific pyruvate dehydrogenase inhibitor reduces tissue damage during murine infection, correlating with increased interleukin-10 expression. Our results thus suggest that reprogramming carbon flow provides a therapeutic strategy to mitigate tissue damage during infection.

Colorectal liver metastasis (CRLM) represents a major therapeutic challenge in colorectal cancer (CRC), with complex interactions between the gut microbiota and the liver tumor microenvironment (TME) playing a crucial role in disease progression via the gut-liver axis. The gut barrier serves as a gatekeeper, regulating microbial translocation, which influences liver colonization and metastasis. Through the gut-liver axis, the microbiota actively shapes the TME, where specific microbial species and their metabolites exert dual roles in immune modulation. The immunologically "cold" nature of the liver, combined with the influence of the gut microbiota on liver immunity, complicates effective immunotherapy. However, microbiota-targeted interventions present promising strategies to enhance immunotherapy outcomes by modulating the gut-liver axis. Overall, this review highlights the emerging evidence on the role of the gut microbiota in CRLM and provides insights into the molecular mechanisms driving the dynamic interactions within the gut-liver axis.

Background: Iron deficiency anemia (IDA) is a common type of anemia in children and pregnant women. The effects of iron deficiency on gut microbiota and metabolic profiles are not fully understood. Methods: Mendelian randomization (MR) analysis was conducted to explore associations among IDA, gut microbiota, and metabolites. MR analysis was conducted using computational methods, utilizing human genetic data. Data were obtained from genome-wide association studies (GWAS), with inverse-variance-weighted (IVW) as the primary method. Animal models evaluated the effects of IDA on gut microbiota and metabolic profiles. Results: IVW analysis revealed significant associations between gut microbial taxa and IDA. The genus Desulfovibrio was protective (OR = 0.85, 95% CI: 0.77-0.93, p = 0.001), while Actinomyces (OR = 1.12, 95% CI: 1.01-1.23, p = 0.025) and family XIII (OR = 1.16, 95% CI: 1.01-1.32, p = 0.035) increased IDA risk. Glycine was protective (OR = 0.95, 95% CI: 0.91-0.99, p = 0.011), whereas medium low density lipoprotein (LDL) phospholipids increased risk (OR = 1.07, 95% CI: 1.00-1.15, p = 0.040). Animal models confirmed reduced Desulfovibrio, increased Actinomyces, and altered metabolites, including amino acids and phospholipids. Conclusions: IDA significantly impacts gut microbiota and metabolic profiles, offering insights for therapeutic strategies targeting microbiota and metabolism.

Psychological stress causes gut microbial dysbiosis and cancer progression, yet how gut microbiota determines psychological stress-induced tumor development remains unclear. Here we showed that psychological stress promotes breast tumor growth and cancer stemness, an outcome that depends on gut microbiota in germ-free and antibiotic-treated mice. Metagenomic and metabolomic analyses revealed that psychological stress markedly alters the composition and abundance of gut microbiota, especially Akkermansia muciniphila (A. muciniphila), and decreases short-chain fatty acid butyrate. Supplement of active A. muciniphila, butyrate or a butyrate-producing high fiber diet dramatically reversed the oncogenic property and anxiety-like behavior of psychological stress in a murine spontaneous tumor model or an orthotopic tumor model. Mechanistically, RNA sequencing analysis screened out that butyrate decreases LRP5 expression to block the activation of Wnt/β-catenin signaling pathway, dampening breast cancer stemness. Moreover, butyrate as a HDAC inhibitor elevated histone H3K9 acetylation level to transcriptionally activate ZFP36, which further accelerates LRP5 mRNA decay by binding adenine uridine-rich (AU-rich) elements of LRP5 transcript. Clinically, fecal A. muciniphila and serum butyrate were inversely correlated with tumoral LRP5/β-catenin expression, poor prognosis and negative mood in breast cancer patients. Altogether, our findings uncover a microbiota-dependent mechanism of psychological stress-triggered cancer stemness, and provide both clinical biomarkers and potential therapeutic avenues for cancer patients undergoing psychological stress.

Colorectal cancer (CRC), an emerging public health concern, is one of the leading causes of cancer morbidity and mortality worldwide. An increasing body of evidence shows that dysfunction in metabolic reprogramming is a crucial characteristic of CRC progression. Specifically, metabolic reprogramming abnormalities in glucose, glutamine and lipid metabolism provide the tumour with energy and nutrients to support its rapid cell proliferation and survival. More recently, microRNAs (miRNAs) appear to be involved in the pathogenesis of CRC, including regulatory roles in energy metabolism. In addition, it has been revealed that dysbiosis in CRC might play a key role in impairing the host metabolic reprogramming processes, and while the exact interactions remain unclear, the link may lie with miRNAs. Hence, the aims of the current review include first, to delineate the metabolic reprogramming abnormalities in CRC; second, to explain how miRNAs mediate the aberrant regulations of CRC metabolic pathways; third, linking miRNAs with metabolic abnormalities and dysbiosis in CRC and finally, to discuss the roles of miRNAs as potential biomarkers.

Decades of research have made clear that host-associated microbiomes touch all facets of health. However, effective therapies that target the microbiome have been elusive given its inherent complexity. Here, we experimentally examined diet-microbe-host interactions through a complex systems framework, centered on dietary oxalate. Using multiple, independent molecular, animal, and in vitro experimental models, we found that microbiome composition influenced multiple oxalate-microbe-host interfaces. Importantly, administration of the oxalate-degrading specialist, Oxalobacter formigenes, was only effective against a poor oxalate-degrading microbiota background and gives critical new insights into why clinical intervention trials with this species exhibit variable outcomes. Data suggest that, while heterogeneity in the microbiome impacts multiple diet-host-microbe interfaces, metabolic redundancy among diverse microorganisms in specific diet-microbe axes is a critical variable that may impact the efficacy of bacteriotherapies, which can help guide patient and probiotic selection criteria in probiotic clinical trials.

There are many factors associated with chronic pain, including changes in the nervous and musculoskeletal systems and so on. Recently, it has become clear that the gut microbiota (GM) influences these factors, and there are many reports of GM dysbiosis in patients with chronic pain. However, the relationship between pain and GM remains unclear. Our previous study reported that defecation status, which reflects GM composition, was associated with pain intensity and that this relationship was different for each pain site. Our study investigated the association between pain site and the GM composition of feces in chronic pain patients.

The subjects were 136 patients with chronic pain and 125 healthy controls. Patients were classified into four groups, whole body (WB) pain, lower back and lower extremity (LL) pain, headache, and upper back and upper extremity pain, based on the site of pain, and we investigated differences in GM taxonomy groups compared with healthy subject.

Chronic pain patients had a lower alpha diversity (effect size=0.16, p=0.02). But each pain site group did not differ in alpha diversity. WB pain patients showed higher Eggerthellaceae (LDA=3.09, p<0.01) and lower Halomonas (LDA =-2.72, p<0.01). LL pain patients had increased Fusobacterium and Sellimonas (LDA=4.09,3.03 p<0.01, 0.01) but reduced Halomonas (LDA=-2.59, p<0.01), and other key taxa.

WB and LL patients may have GM compositions different from healthy controls, but larger studies are needed to confirm this.

Over the past two decades, the "hallmarks of cancer" have revolutionized cancer research and highlighted the crucial roles of inflammation and immunity. Protumorigenic inflammation promotes cancer development along with inhibition of antitumor immunity, shaping the tumor microenvironment (TME) toward a tumor-permissive state and further enhancing the malignant potential of cancer cells. This immunosuppressive TME allows tumors to evade immunosurveillance. Thus, understanding the complex interplay between tumors and the immune system within the TME has become pivotal, especially with the advent of immunotherapy. Although immunotherapy has achieved notable success in many malignancies, primary liver cancer, particularly hepatocellular carcinoma, presents unique challenges. The hepatic immunosuppressive environment poses obstacles to the effectiveness of immunotherapy, along with high mortality rates and limited treatment options for patients with liver cancer. In this review, we discuss current understanding of the complex immune-mediated mechanisms underlying liver neoplasms, focusing on hepatocellular carcinoma and liver metastases. We describe the molecular and cellular heterogeneity within the TME, highlighting how this presents unique challenges and opportunities for immunotherapy in liver cancers. By unraveling the immune landscape of liver neoplasms, this review aims to contribute to the development of more effective therapeutic interventions, ultimately improving clinical outcomes for patients with liver cancer.

Colorectal cancer (CRC) is a significant threat to human health. The dynamic equilibrium between probiotics and pathogenic bacteria within the gut microbiota is crucial in mitigating the risk of CRC. An overgrowth of harmful microorganisms in the gastrointestinal tract can result in an excessive accumulation of bacterial toxins and carcinogenic metabolites, thereby disrupting the delicate balance of the microbiota. This disruption may lead to alterations in microbial composition, impairment of mucosal barrier function, potential promotion of abnormal cell proliferation, and ultimately contribute to the progression of CRC. Recently, research has indicated that intestinal presence of Fusobacterium nucleatum (Fn) significantly influences the onset, progression, and metastasis of CRC. Consequently, disrupting the interaction between CRC cells and Fn presents a promising strategy against CRC. Nanomaterials have been extensively utilized in cancer therapy and bacterial infection control, demonstrating substantial potential in treating bacteria-associated tumors. This review begins by elucidating the mechanisms of gut microbiota and the occurrence and progression of CRC, with a particular emphasis on clarifying the intricate relationship between Fn and CRC. Subsequently, we highlight strategies that utilize nanomaterials to disrupt the association between Fn and CRC. Overall, this review offers valuable insight and guidance for leveraging nanomaterials in CRC therapy.

Numerous associations have been identified between cancer and the composition and function of the human microbiome. As cancer remains the second leading global cause of mortality, investigating the carcinogenic contributions of microbiome members could advance our understanding of cancer risk and support potential therapeutic interventions. Although fluctuations in bacterial species have been associated with cancer progression, studying their small molecule metabolites offers one avenue to establish support for causal relationships and the molecular mechanisms governing host-microorganism interactions. In this Review, we explore the expanding repertoire of small molecule metabolites and their mechanisms implicated in the risk of developing gastrointestinal cancers.

An increasing number of studies have revealed that gut microbiota influences the development and progression of Colorectal cancer (CRC). However, whether a causal relationship exists between the two remains unclear, and the role of immune cells in this context is not well understood.

To elucidate the causal relationship between gut microbiota and CRC and to explore the potential mediating role of circulating immune cells.

To analyze the causal relationship between gut microbiota and CRC, we employed a univariable Mendelian randomization (UVMR) approach. Subsequently, a two-step multivariable Mendelian randomization (MVMR) to assess the potential mediating role of circulating immune cells. Primarily, applied the Inverse-Variance Weighted method to evaluate the causal relationship between exposure and outcome. To ensure the robustness of the results linking gut microbiota and CRC, we validated the findings using Robust Inverse-Variance Weighted, Penalized Inverse-Variance Weighted, and Penalized Robust Inverse-Variance Weighted methods. Additionally, we employed MR-Egger Intercept to mitigate the influence of horizontal pleiotropy. MR-PRESSO was used to detect and correct outliers by excluding anomalous instrumental variables. Finally, we supplemented our analysis with methods such as Bayesian Weighted Mendelian Randomization (BWMR), Maximum-Likelihood, Lasso, Debiased Inverse Variance Weighted, and Contamination Mixture to establish a robust and compelling causal relationship.

After accounting for reverse causality, horizontal pleiotropy, and various methodological corrections, Bifidobacterium kashiwanohense, GCA-900066755 sp900066755, Geminocystis, and Saccharofermentanaceae exhibited strong and robust causal effects on CRC. Specifically, CD40 on monocytes (2.82%) and CD45 on CD33+HLA-DR+CD14- cells (12.87%) mediated the causal relationship between Bifidobacterium kashiwanohense and CRC risk. Furthermore, CD45 on CD33-HLA-DR+ (3.94%) mediated the causal relationship between GCA-900066755 sp900066755 and CRC risk. Additionally, terminally differentiated CD4+T cells (11.55%) mediated the causal relationship between Geminocystis and CRC risk. Lastly, CD40 on monocytes (2.35%), central memory CD4+T cells (5.76%), and CD28 on CD28+CD45RA+CD8+T cells (5.00%) mediated the causal relationship between Saccharofermentanaceae and CRC risk.

Our mediation MR analysis provides genetic evidence suggesting that circulating immune cells may mediate the causal relationship between gut microbiota and CRC. The identified associations and mediation effects offer new insights into potential therapeutic avenues for CRC.

Intake of certain Lactiplantibacillus strains was recognized as a potential strategy for acute liver injury (ALI) prevention. This study is aimed at developing a selenium-enriched Lactiplantibacillus strain-based ALI prevention strategy. L. plantarum ZZU 8-12 was isolated from human fecal sample and screened out based on its adaption to intestinal microenvironment, inhibitive capability against pathogenic bacteria, and in vivo anti-inflammation response in DSS-induced colitis mice model. The strain was applied as a producer of nano selenium particles to produce selenium-enriched L. plantarum ZZU 8-12. Intake of selenium-enriched L. plantarum ZZU 8-12 upregulated the abundance of short-chain fatty acid-producing genera including Lactiplantibacillus, Phascolarctobacterium, Butyricicoccus, and Clostridiales bacterium in fecal microbiota and thus inhibited ALI induced by CCL4 injection in mice. This study drew the potential for selenium-enriched L. plantarum ZZU 8-12 as an ingredient for ALI protection.

The correlation between periodontitis and colorectal cancer (CRC) has drawn widespread attention. However, how periodontitis affects CRC progression remains unclear.

C57BL/6 mice were used to establish experimental periodontitis and CRC model. Histological alterations of periodontium and colon were observed by hematoxylin and eosin staining. Micro-computed tomography (micro-CT) was applied to evaluate alveolar bone loss (ABL). Tumor growth was detected by immunofluorescence. Gut bacteria were analyzed using 16S rRNA sequencing. Gas chromatography-mass spectrometry (GC-MS) was performed to observe the alterations of gut microbial metabolites. The detection of associated pathways was carried out using quantitative real-time PCR (qRT-PCR).

Experimental periodontitis significantly induced increases in tumor number in mice with CRC. Double immunofluorescence for Ki67 and β-catenin, as well as Cyclin D1 and β-catenin, indicated that experimental periodontitis observably promoted tumor growth. 16S rRNA sequencing and untargeted metabolomics analysis displayed that experimental periodontitis altered gut microbial community and metabolite profiles in CRC mice. Notably, we found that experimental periodontitis dramatically increased the level of three oncometabolites (serotonin, adenosine, and spermine) in mice with CRC.

Alterations of gut microbial community and metabolites might be relevant in experimental periodontitis deteriorating CRC.

This review summarizes the intricate relationship between the microbiome and cancer initiation and development. Microbiome alterations impact metabolic pathways, immune responses, and gene expression, which can accelerate or mitigate cancer progression. We examine how dysbiosis affects tumor growth, metastasis, and treatment resistance. Additionally, we discuss the potential of microbiome-targeted therapies, such as probiotics and fecal microbiota transplants, to modulate cancer metabolism. These interventions offer the possibility of reversing or controlling cancer progression, enhancing the efficacy of traditional treatments like chemotherapy and immunotherapy. Despite promising developments, challenges remain in identifying key microbial species and pathways and validating microbiome-targeted therapies through large-scale clinical trials. Nonetheless, the intersection of microbiome research and cancer initiation and development presents an exciting frontier for innovative therapies. This review offers a fresh perspective on cancer initiation and development by integrating microbiome insights, highlighting the potential for interdisciplinary research to enhance our understanding of cancer progression and treatment strategies.

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.