Oral and Gut Microbiota Dysbiosis Due to Periodontitis: Systemic Implications and Links to Gastrointestinal Cancer: A Narrative Review.

Periodontitis can disrupt oral and gut microbiota, leading to dysbiosis that affects overall systemic health. Besides the spread of periodontal pathogens by the hematogenous route, they can also be translocated into the gastrointestinal tract, possibly intervening in the neoplastic process in the gastrointestinal tract. This manuscript reviews the relationship between oral and gut microbiota due to periodontitis, discussing systemic health implications and potential links to gastrointestinal cancer. This article highlights the significance and effect of dysbiosis in the gut, emphasizing the importance of maintaining oral health to prevent systemic diseases. Lastly, it will go through therapeutic innovations such as probiotics and oral microbiota analysis tools for systemic disease detection. These findings will mark the integration of oral health management in clinical practice to lower systemic disease risk and improve overall patient outcomes. Aim of work: This manuscript aims to unravel the pathological interaction between oral and gut microbiota and their bidirectional effect on systemic diseases. Materials and methods: The review was performed using the MEDLINE and ScienceDirect databases. Reviewed articles were published in English between the year 2015 and 2024. The search used keywords such as ("oral microbiota" AND "periodontal disease") OR ("oral microbiota" AND "gastrointestinal cancer") OR ("Porphyromonas gingivalis" AND "periodontal disease") OR ("Helicobacter pylori" AND "gastric cancer") OR ("gut microbiome" AND "inflammatory bowel disease") OR ("oral microbiome" AND "systemic diseases"). Conclusions: The dysbiotic change in the oral cavity due to periodontitis is linked directly and indirectly to systemic diseases such as IBS, neurodegenerative diseases, muscle joint diseases, respiratory infections, and gastrointestinal cancer; this underscores the importance of maintaining oral hygiene for prophylaxis of oral diseases and the prevention of systemic diseases. A better understanding of the interconnections between oral health and systemic diseases will integrate oral health management to offer new prevention, diagnostic, and treatment opportunities to improve overall patient outcomes.

Identification of shared and disease-specific intratumoral microbiome-host gene associations in gastrointestinal tumors.

Intratumoral microbiota and host genes interact to promote gastrointestinal disorders, but how the two interact to influence host tumorigenesis remains unclear. Here, we utilized a machine learning-based framework to jointly dissect the paired intratumoral microbiome and host transcriptome profiles in patients with colon adenocarcinoma, hepatocellular carcinoma, and gastric cancer. We identified associations between intratumoral microbes and host genes that depict shared as well as cancer type-specific patterns. We found that a common set of host genes and pathways implicated in cell proliferation and energy metabolism are associated with cancer type-specific intratumoral microbes. In addition, we also found that intratumoral microbes that have been implicated in three gastrointestinal tumors, such as Lachnoclostridium, are correlated with different host pathways in each tumor, indicating that similar microbes can influence host tumorigenesis in a cancer type-specific manner by regulation of different host genes. Our study reveals patterns of association between intratumoral microbiota and host genes in gastrointestinal tumors, providing new insights into the biology of gastrointestinal tumors.NEW & NOTEWORTHY Our study constitutes a pivotal advancement in elucidating the intricate relationship between the intratumoral microbiome and host gene regulation, thereby gaining insights into the pivotal role that the intratumoral microbiome plays in the etiology of gastrointestinal tumors.

Gut microbial metabolites: Shaping future diagnosis and treatment against gastrointestinal cancer.

Gastrointestinal cancer is a worldwide health challenge due to its dramatically increasing prevalence and as a leading cause of cancer-related mortality. Increasing evidence has illustrated the vital role of gut microbes-derived metabolites in gastrointestinal cancer progression and treatment. Microbial metabolites are produced by the gut microbiota that utilizes both extrinsic dietary components and intrinsic host-generated compounds. Meanwhile, certain categories of metabolites such as short-chain fatty acids, bile acids, tryptophan, and indole derivatives, are linked to gastrointestinal malignancy. In this review, the major classes of microbial metabolites and their impacts on various gastrointestinal cancers including colorectal cancer, gastric cancer, and hepatocellular carcinoma, have been introduced. The application of microbial metabolites as predictive biomarkers for early diagnosis and prognosis of gastrointestinal cancer has also been explored. In addition, therapeutic potential of strategies that target microbial metabolites against gastrointestinal cancer is further evaluated.

A Narrative Review: Immunometabolic Interactions of Host-Gut Microbiota and Botanical Active Ingredients in Gastrointestinal Cancers.

The gastrointestinal tract is where the majority of gut microbiota settles; therefore, the composition of the gut microbiota and the changes in metabolites, as well as their modulatory effects on the immune system, have a very important impact on the development of gastrointestinal diseases. The purpose of this article was to review the role of the gut microbiota in the host environment and immunometabolic system and to summarize the beneficial effects of botanical active ingredients on gastrointestinal cancer, so as to provide prospective insights for the prevention and treatment of gastrointestinal diseases. A literature search was performed on the PubMed database with the keywords "gastrointestinal cancer", "gut microbiota", "immunometabolism", "SCFAs", "bile acids", "polyamines", "tryptophan", "bacteriocins", "immune cells", "energy metabolism", "polyphenols", "polysaccharides", "alkaloids", and "triterpenes". The changes in the composition of the gut microbiota influenced gastrointestinal disorders, whereas their metabolites, such as SCFAs, bacteriocins, and botanical metabolites, could impede gastrointestinal cancers and polyamine-, tryptophan-, and bile acid-induced carcinogenic mechanisms. GPRCs, HDACs, FXRs, and AHRs were important receptor signals for the gut microbial metabolites in influencing the development of gastrointestinal cancer. Botanical active ingredients exerted positive effects on gastrointestinal cancer by influencing the composition of gut microbes and modulating immune metabolism. Gastrointestinal cancer could be ameliorated by altering the gut microbial environment, administering botanical active ingredients for treatment, and stimulating or blocking the immune metabolism signaling molecules. Despite extensive and growing research on the microbiota, it appeared to represent more of an indicator of the gut health status associated with adequate fiber intake than an autonomous causative factor in the prevention of gastrointestinal diseases. This study detailed the pathogenesis of gastrointestinal cancers and the botanical active ingredients used for their treatment in the hope of providing inspiration for research into simpler, safer, and more effective treatment pathways or therapeutic agents in the field.

Intratumoral Microbiota: Metabolic Influences and Biomarker Potential in Gastrointestinal Cancer.

Gastrointestinal (GI) cancers impose a substantial global health burden, highlighting the necessity for deeper understanding of their intricate pathogenesis and treatment strategies. This review explores the interplay between intratumoral microbiota, tumor metabolism, and major types of GI cancers (including esophageal, gastric, liver, pancreatic, and colorectal cancers), summarizing recent studies and elucidating their clinical implications and future directions. Recent research revealed altered microbial signatures within GI tumors, impacting tumor progression, immune responses, and treatment outcomes. Dysbiosis-induced alterations in tumor metabolism, including glycolysis, fatty acid metabolism, and amino acid metabolism, play critical roles in cancer progression and therapeutic resistance. The integration of molecular mechanisms and potential biomarkers into this understanding further enhances the prognostic significance of intratumoral microbiota composition and therapeutic opportunities targeting microbiota-mediated tumor metabolism. Despite advancements, challenges remain in understanding the dynamic interactions within the tumor microenvironment (TME). Future research directions, including advanced omics technologies and prospective clinical studies, offer promising avenues for precision oncology and personalized treatment interventions in GI cancer. Overall, integrating microbiota-based approaches and molecular biomarkers into GI cancer management holds promise for improving patient outcomes and survival.

Metabolic interactions of host-gut microbiota: New possibilities for the precise diagnosis and therapeutic discovery of gastrointestinal cancer in the future-A review.

Gastrointestinal (GI) cancer continues to pose a significant global health challenge. Recent advances in our understanding of the complex relationship between the host and gut microbiota have shed light on the critical role of metabolic interactions in the pathogenesis and progression of GI cancer. In this study, we examined how microbiota interact with the host to influence signalling pathways that impact the formation of GI tumours. Additionally, we investigated the potential therapeutic approach of manipulating GI microbiota for use in clinical settings. Revealing the complex molecular exchanges between the host and gut microbiota facilitates a deeper understanding of the underlying mechanisms that drive cancer development. Metabolic interactions hold promise for the identification of microbial signatures or metabolic pathways associated with specific stages of cancer. Hence, this study provides potential strategies for the diagnosis, treatment and management of GI cancers to improve patient outcomes.

Intratumoral microbiome promotes liver metastasis and dampens adjuvant imatinib treatment in gastrointestinal stromal tumor.

Understanding the determinants of long-term liver metastasis (LM) outcomes in gastrointestinal stromal tumor (GIST) patients is crucial. We established the feature selection model of intratumoral microbiome at the surgery, achieving robust predictive accuracies of 0.953 and 0.897 AUCs in discovery (n = 74) and validation (n = 34) cohorts, respectively. Notably, despite the significant reduction in LM occurrence with adjuvant imatinib (AI) treatment, intratumoral microbiome exerted independently stronger effects on post-operative LM. Employing both 16S and full-length rRNA sequencing, we pinpoint intracellular Shewanella algae as a foremost LM risk factor in both AI- and non-AI-treated patients. Experimental validation confirmed S. algae's intratumoral presence in GIST, along with migration/invasion-promoting effects on GIST cells. Furthermore, S. algae promoted LM and impeded AI treatment in metastatic mouse models. Our findings advocate for incorporating intratumoral microbiome evaluation at surgery, and propose S. algae as a therapeutic target for LM suppression in GIST.

Implications of lncRNAs in Helicobacter pylori-associated gastrointestinal cancers: underlying mechanisms and future perspectives.

Helicobacter pylori (H. pylori) is a harmful bacterium that is difficult to conveniently diagnose and effectively eradicate. Chronic H. pylori infection increases the risk of gastrointestinal diseases, even cancers. Despite the known findings, more underlying mechanisms are to be deeply explored to facilitate the development of novel prevention and treatment strategies of H. pylori infection. Long noncoding RNAs (lncRNAs) are RNAs with more than 200 nucleotides. They may be implicated in cell proliferation, inflammation and many other signaling pathways of gastrointestinal cancer progression. The dynamic expression of lncRNAs indicates their potential to be diagnostic or prognostic biomarkers. In this paper, we comprehensively summarize the processes of H. pylori infection and the treatment methods, review the known findings of lncRNA classification and functional mechanisms, elucidate the roles of lncRNAs in H. pylori-related gastrointestinal cancer, and discuss the clinical perspectives of lncRNAs.

Host-Gut Microbiota Metabolic Interactions and Their Role in Precision Diagnosis and Treatment of Gastrointestinal Cancers.

The critical role of the gut microbiome in gastrointestinal cancers is becoming increasingly clear. Imbalances in the gut microbial community, referred to as dysbiosis, are linked to increased risks for various forms of gastrointestinal cancers. Pathogens like Fusobacterium and Helicobacter pylori relate to the onset of esophageal and gastric cancers, respectively, while microbes such as Porphyromonas gingivalis and Clostridium species have been associated with a higher risk of pancreatic cancer. In colorectal cancer, bacteria such as Fusobacterium nucleatum are known to stimulate the growth of tumor cells and trigger cancer-promoting pathways. On the other hand, beneficial microbes like Bifidobacteria offer a protective effect, potentially inhibiting the development of gastrointestinal cancers. The potential for therapeutic interventions that manipulate the gut microbiome is substantial, including strategies to engineer anti-tumor metabolites and employ microbiota-based treatments. Despite the progress in understanding the influence of the microbiome on gastrointestinal cancers, significant challenges remain in identifying and understanding the precise contributions of specific microbial species and their metabolic products. This knowledge is essential for leveraging the role of the gut microbiome in the development of precise diagnostics and targeted therapies for gastrointestinal cancers.

The current infection with Helicobacter pylori and association with upper gastrointestinal lesions and risk of upper gastrointestinal cancer: Insights from multicenter population-based cohort study.

The relationship between Helicobacter pylori (H. pylori) infection and upper gastrointestinal (UGI) cancers is complex. This multicenter, population-based cohort study conducted in seven areas in China aimed to assess the correlation between current H. pylori infection and the severity of UGI lesions, as well as its association with the risk of gastric cancer (GC) and esophageal cancer (EC). From 2015 to 2017, 27,085 participants (aged 40-69) completed a standardized questionnaire, and underwent a 13C-urea breath test. Then a subset underwent UGI endoscopy to assess the UGI lesion detection rates. All individuals were followed up until December 2021 to calculate the hazard ratios (HRs) for UGI cancers. H. pylori infection prevalence was 45.9%, and among endoscopy participants, 22.2% had gastric lesions, 19.2% had esophageal lesions. Higher detection rates of gastric lesions were noted in the H. pylori-positive population across all lesion severity levels. Over a median follow-up of 6.3 years, 104 EC and 179 GC cases were observed, including 103 non-cardia gastric cancer (NCGC) cases and 76 cardia gastric cancer (CGC) cases. H. pylori-infected individuals exhibited a 1.78-fold increased risk of GC (HR 1.78, 95% confidence interval [CI] 1.32-2.40) but no significant increase in EC risk (HR 1.07, 95% CI 0.73-1.57). Notably, there was a higher risk for both NCGC and CGC in H. pylori-infected individuals. This population-based cohort study provides valuable evidence supporting the association between current H. pylori infection and the risk of both NCGC and CGC. These findings contribute to the empirical basis for risk stratification and recommendations for UGI cancer screening.

Investigating the Influence of Gut Microbiota-related Metabolites in Gastrointestinal Cancer.

Gastrointestinal (GI) cancer is a major health concern due to its prevalence, impact on well-being, high mortality rate, economic burden, and potential for prevention and early detection. GI cancer research has made remarkable strides in understanding biology, risk factors, and treatment options. An emerging area of research is the gut microbiome's role in GI cancer development and treatment response. The gut microbiome, vital for digestion, metabolism, and immune function, is increasingly linked to GI cancers. Dysbiosis and alterations in gut microbe composition may contribute to cancer development. Scientists study how specific bacteria or microbial metabolites influence cancer progression and treatment response. Modulating the gut microbiota shows promise in enhancing treatment efficacy and preventing GI cancers. Gut microbiota dysbiosis can impact GI cancer through inflammation, metabolite production, genotoxicity, and immune modulation. Microbes produce metabolites like short-chain fatty acids, bile acids, and secondary metabolites. These affect host cells, influencing processes like cell proliferation, apoptosis, DNA damage, and immune regulation, all implicated in cancer development. This review explores the latest research on gut microbiota metabolites and their molecular mechanisms in GI cancers. The hope is that this attempt will help in conducting other relevant research to unravel the precise mechanism involved, identify microbial signatures associated with GI cancer, and develop targets.

Antibiotics, the microbiome and gastrointestinal cancers: A causal interference?

Our understanding of the gut microbiota has significantly evolved over the last two decades. Advances in the analysis of the gut microbiome continues to reveal complex microbial communities and discoveries about their role in health and diseases, including cancer development, are continuously growing. In addition, research has demonstrated that the use of antibiotics can modulate the gut microbiota composition negatively and influence cancer treatment outcomes, suggesting that antibiotics should be avoided if possible. In this article, we review the role of the gut microbiota in the formation of GI cancers. We show that specific bacterial populations can positively or negatively affect cancer formation with specific attention given to gastric and colorectal cancer. We also review the role of microbial-targeted therapies on cancer treatment outcomes.

Gut microbiome in gastrointestinal cancer: a friend or foe?

The impact of the gut microbiome on host health is becoming increasingly recognized. To date, there is growing evidence that the complex characteristics of the microbial community play key roles as potential biomarkers and predictors of responses in cancer therapy. Many studies have shown that altered commensal bacteria lead to cancer susceptibility and progression in diverse pathways. In this review, we critically assess the data for gut microbiota related to gastrointestinal cancer, including esophageal, gastric, pancreatic, colorectal cancer, hepatocellular carcinoma and cholangiocarcinoma. Importantly, the underlying mechanisms of gut microbiota involved in cancer occurrence, prevention and treatment are elucidated. The purpose of this review is to provide novel insights for applying this understanding to the development of new therapeutic strategies in gastrointestinal cancer by targeting the microbial community.

Non-bacteria microbiome (virus, fungi, and archaea) in gastrointestinal cancer.

The gastrointestinal tract houses millions of microbes collectively referred to as the gut microbiome. The gut microbes comprise of bacteria, viruses, fungi, archaea, and microscopic eukaryotes, which co-evolved or colonize the gut forming complex symbiotic and mutualistic relationships. A state of homeostasis is required between host and gut microbiome relationship to maintain several host beneficial processes. Alterations in the taxonomic and functional composition of the gut microbes are associated with several human diseases including gastrointestinal cancers. Owed to their overwhelming abundance and ease of characterization, several studies focus on the role of bacteria in gastrointestinal cancers. There is however growing evidence that non-bacteria gut microbes are associated with the pathogenesis of gastrointestinal cancers. This review details the association of non-bacteria gut microbes including fungi, viruses, and archaea and their potential manipulation in the prevention and treatment of human gastrointestinal cancers.

Prospects and Challenges of the Study of Anti-Glycan Antibodies and Microbiota for the Monitoring of Gastrointestinal Cancer.

Over the past decades, a large amount of data has been accumulated in various subfields of glycobiology. However, much clinically relevant data and many tools are still not widely used in medicine. Synthetic glycoconjugates with the known structure of glycans are an accurate tool for the study of glycan-binding proteins. We used polyacrylamide glycoconjugates (PGs) including PGs with tumour-associated glycans (TAGs) in immunoassays to assess the prognostic potential of the serum level of anti-glycan antibodies (AG Abs) in gastrointestinal cancer patients and found an association of AG Abs with survival. The specificity of affinity-isolated AG Abs was investigated using synthetic and natural glycoconjugates. AG Abs showed mainly a low specificity to tumour-associated and tumour-derived mucins; therefore, the protective role of the examined circulating AG Abs against cancer remains a challenge. In this review, our findings are analysed and discussed in the context of the contribution of bacteria to the AG Abs stimulus and cancer progression. Examples of the influence of pathogenic bacteria colonising tumours on cancer progression and patient survival through mechanisms of interaction with tumours and dysregulated immune response are considered. The possibilities and problems of the integrative study of AG Abs and the microbiome using high-performance technologies are discussed.

Gut Microbiota Modulation in the Context of Immune-Related Aspects of Lactobacillus spp. and Bifidobacterium spp. in Gastrointestinal Cancers.

Accumulating evidence has revealed the critical roles of commensal microbes in cancer progression and recently several investigators have evaluated the therapeutic effectiveness of targeting the microbiota. This gut microbiota-related approach is especially attractive in the treatment of gastrointestinal cancers. Probiotics supplementation is a microbiota-targeted strategy that appears to improve treatment efficacy; Lactobacillus spp. and Bifidobacterium spp. are among the most commonly used probiotic agents. These bacteria seem to exert immunomodulatory effects, impacting on the immune system both locally and systemically. The gut microbiota are able to affect the efficiency of immunotherapy, mainly acting as inhibitors at immune checkpoints. The effects of immunotherapy may be modulated using traditional probiotic strains and/or next generation probiotics, such as Akkermansia municiphila. It is possible that probiotics might enhance the efficiency of immunotherapy based on PD-1/PD-L1 and CTLA-4 but more data are needed to confirm this speculation. Indeed, although there is experimental evidence for the efficacy of several strains, the health-promoting effects of numerous probiotics have not been demonstrated in human patients and furthermore the potential risks of these products, particularly in oncologic patients, are rarely mentioned.

Frequencies of Porphyromonas gingivalis Detection in Oral-Digestive Tract Tumors.

Mounting evidence suggests a causal relationship between specific bacterial infections and the development of certain malignancies. In this study, we examined the presence of Porphyromonas gingivalis (P. gingivalis) in oral-digestive tract tumors by immunohistochemistry (IHC) and PCR and analyzed the correlation between P. gingivalis detection and clinicopathological characteristics and prognosis of oral and esophageal carcinoma. The IHC results showed that the positive rates of P. gingivalis were 60.00, 46.00, 20.00, 6.67, and 2.86% in oral, esophagus, cardiac, stomach, and colorectal cancer tissues, respectively. Likewise, PCR results showed rates of 56.00, 42.00, 16.67, 3.33, and 2.86%, respectively. The two methods were consistent, and the kappa value was 0.806, P < 0.001. In addition, P. gingivalis expression was significantly correlated with lymph node metastasis and the clinical stages of oral and esophageal cancer (P < 0.05). The overall survival rate of the P. gingivalis undetected group (86, 50%) was significantly higher than that of the P. gingivalis detected group (57, 14%) for oral and esophageal cancer, respectively. In conclusion, the detection rate of P. gingivalis showed a decreasing trend in oral-digestive tract tumors. Detection with P. gingivalis was associated with poor prognosis for oral and esophageal cancer.

Association between oral microflora and gastrointestinal tumors (Review).

The oral cavity contains the highest density and the most species of microorganisms compared with other parts of the body. Recent studies have determined that the species and abundance of oral microflora are closely associated with the development of upper gastrointestinal tumors, including oral, esophageal and gastric cancer. Additionally, differential abundant microbiota in patients with cancer and abnormal microorganisms inside the tumor tissue have been identified as critical markers of tumorigenesis. There is evidence to suggest that certain genera, including Firmicutes, along with various species, such as Porphyromonas, can increase the risk of oral cancer. Furthermore, Porphyromonas gingivalis is a risk factor for esophageal carcinoma, while Helicobacter pylori infections are a main cause of gastric cancer. Currently, as far as carcinogenic mechanisms of oral microorganisms are concerned, it has been hypothesized that the production of carcinogenic substances, chronic inflammation and altered cell metabolisms may be mechanisms by which oral microorganisms influence the development of upper gastrointestinal cancer. Certain phrases, including 'oral microbes', 'oral microorganism', 'oral microbiology', 'oral microflora', 'oral cancer', 'oral carcinoma', 'carcinoma of mouth', 'esophagus cancer', 'esophageal cancer', 'esophageal carcinoma', 'carcinoma of esophagus', 'gastric cancer', 'gastric carcinoma', 'stomach cancer', 'cancer of the stomach', 'carcinogenic mechanism' and 'carcinogenesis', were searched as key words in PubMed and Web of Science for articles published between 1975 to 2020. A total of 1,512 studies were obtained. After further searching the abstracts for key words, such as oral microorganisms, oral cancer, esophagus cancer, gastric cancer and carcinogenic mechanisms, 137 studies were selected. The current review systematically and comprehensively summarized the association between the oral microbiota and oral, esophageal and gastric cancer. Additionally, the current review described the carcinogenic mechanisms of oral microbes and attempted to identify common molecular mechanisms among different types of tumor. The association between upper gastrointestinal cancer therapy and oral microflora was also assessed. The present review may be used as a reference for future diagnosis and therapeutics for upper gastrointestinal tumors.

Machine learning on microbiome research in gastrointestinal cancer.

Gastrointestinal cancer maintains the highest incidence and mortality rate among all cancers globally. In addition to genetic causes, it has been reported that individuals' diet and composition of the gastrointestinal microbiome have profound impacts on gastrointestinal cancer development. Microbiome research has risen in popularity to provide alternative insights into cancer development and potential therapeutic effect. However, there is a lack of an effective analytical tool to comprehend the massive amount of data generated from high-throughput sequencing methods. Artificial intelligence is another rapidly developing field that has strong application potential in microbiome research. Deep learning and machine learning are two subfields under the umbrella of artificial intelligence. Here we discuss the current approaches to study the gut microbiome, as well as the applications and challenges of implementing artificial intelligence in microbiome research.