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Frontiers in Microbiology 2024Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized for its global prevalence and potential progression to more severe liver diseases such as...
Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized for its global prevalence and potential progression to more severe liver diseases such as non-alcoholic steatohepatitis (NASH). The gut microbiota plays a pivotal role in the pathogenesis of NAFLD, yet the detailed characteristics and ecological alterations of gut microbial communities during the progression from non-alcoholic fatty liver (NAFL) to NASH remain poorly understood. Methods: In this study, we conducted a comparative analysis of gut microbiota composition in individuals with NAFL and NASH to elucidate differences and characteristics. We utilized 16S rRNA sequencing to compare the intestinal gut microbiota among a healthy control group (65 cases), NAFL group (64 cases), and NASH group (53 cases). Random forest machine learning and database validation methods were employed to analyze the data. Results: Our findings indicate a significant decrease in the diversity of intestinal flora during the progression of NAFLD ( < 0.05). At the phylum level, high abundances of Bacteroidetes and Fusobacteria were observed in both NAFL and NASH patients, whereas Firmicutes were less abundant. At the genus level, a significant decrease in Prevotella expression was seen in the NAFL group (AUC 0.738), whereas an increase in the combination of Megamonas and Fusobacterium was noted in the NASH group (AUC 0.769). Furthermore, KEGG pathway analysis highlighted significant disturbances in various types of glucose metabolism pathways in the NASH group compared to the NAFL group, as well as notably compromised flavonoid and flavonol biosynthesis functions. The study uncovers distinct microbiota characteristics and microecological changes within the gut during the transition from NAFL to NASH, providing insights that could facilitate the discovery of novel biomarkers and therapeutic targets for NAFLD.
PubMed: 38638907
DOI: 10.3389/fmicb.2024.1366744 -
Cell Death & Disease Apr 2024Dysbiosis of the oral microbiota is related to chronic inflammation and carcinogenesis. Fusobacterium nucleatum (Fn), a significant component of the oral microbiota, can...
Dysbiosis of the oral microbiota is related to chronic inflammation and carcinogenesis. Fusobacterium nucleatum (Fn), a significant component of the oral microbiota, can perturb the immune system and form an inflammatory microenvironment for promoting the occurrence and progression of oral squamous cell carcinoma (OSCC). However, the underlying mechanisms remain elusive. Here, we investigated the impacts of Fn on OSCC cells and the crosstalk between OSCC cells and macrophages. 16 s rDNA sequencing and fluorescence in situ hybridization verified that Fn was notably enriched in clinical OSCC tissues compared to paracancerous tissues. The conditioned medium co-culture model validated that Fn and macrophages exhibited tumor-promoting properties by facilitating OSCC cell proliferation, migration, and invasion. Besides, Fn and OSCC cells can recruit macrophages and facilitate their M2 polarization. This crosstalk between OSCC cells and macrophages was further enhanced by Fn, thereby amplifying this positive feedback loop between them. The production of CXCL2 in response to Fn stimulation was a significant mediator. Suppression of CXCL2 in OSCC cells weakened Fn's promoting effects on OSCC cell proliferation, migration, macrophage recruitment, and M2 polarization. Conversely, knocking down CXCL2 in macrophages reversed the Fn-induced feedback effect of macrophages on the highly invasive phenotype of OSCC cells. Mechanistically, Fn activated the NF-κB pathway in both OSCC cells and macrophages, leading to the upregulation of CXCL2 expression. In addition, the SCC7 subcutaneous tumor-bearing model in C3H mice also substantiated Fn's ability to enhance tumor progression by facilitating cell proliferation, activating NF-κB signaling, up-regulating CXCL2 expression, and inducing M2 macrophage infiltration. However, these effects were reversed by the CXCL2-CXCR2 inhibitor SB225002. In summary, this study suggests that Fn contributes to OSCC progression by promoting tumor cell proliferation, macrophage recruitment, and M2 polarization. Simultaneously, the enhanced CXCL2-mediated crosstalk between OSCC cells and macrophages plays a vital role in the pro-cancer effect of Fn.
Topics: Animals; Mice; Squamous Cell Carcinoma of Head and Neck; Carcinoma, Squamous Cell; Mouth Neoplasms; Fusobacterium nucleatum; NF-kappa B; In Situ Hybridization, Fluorescence; Mice, Inbred C3H; Macrophages; Cell Proliferation; Head and Neck Neoplasms; Cell Line, Tumor; Tumor Microenvironment
PubMed: 38637499
DOI: 10.1038/s41419-024-06640-7 -
Microbial Pathogenesis Jun 2024The human oral cavity is colonized by a diverse microbial community, which includes both native and transient colonizers. The microbial composition is crucial for... (Comparative Study)
Comparative Study
The human oral cavity is colonized by a diverse microbial community, which includes both native and transient colonizers. The microbial composition is crucial for maintaining oral homeostasis, but due to overgrowth or imbalances of these microbial communities, dysbiosis can occur. There is a lack of understanding of the research of native and transient colonizers in the oral cavity of the Indian subpopulation Therefore, in our present study, we explored the role and prevalence of transient and native colonizers between healthy and comorbid oral diseased human individuals. Culture-dependent techniques and culture-independent 16S r DNA metagenomic analyses were employed to isolate and study the interactions of native and transient colonizers from human oral samples. Among the 66 human individuals of both healthy and comorbid individuals, the most abundant isolate was found to be Bacillus amyloliquefaciens MCC 4424. In addition, the more prevalent culturable isolate from the healthy samples was Streptococcus salivarius MTCC 13009, whereas in comorbid samples Staphylococcus pasteuri MTCC 13076, Rothia dentocariosa MTCC 13010 and Pseudomonas aeruginosa MTCC 13077 were prevalent to a greater extent. 16S rDNA metagenomic analyses revealed the prevalence and abundance of genera such as Bacteroidetes and Proteobacteria in healthy individuals; consequently, Fusobacteria and Firmicutes were observed mostly in comorbid individuals. The significant differences in bacterial population density were observed in terms of the Shannon index (p = 0.5145) and Simpson index (p = 0.9061) between the healthy and comorbid groups. B. amyloliquefaciens MCC 4424 exhibits antagonistic behavior when grown as a dual-species with native and transient colonizers. This result is very consistent with the findings of antibiofilm studies using confocal laser scanning microscopy, which revealed a significant reduction in biofilm biovolume (73 %) and maximum thickness (80 %) and an increase in the rough coefficient of biofilms (30 %). Our data suggested that B. amyloliquefaciens MCC 4424 can be a native colonizer of Indian sub-populations. It may act as a novel candidate for oral healthcare applications and greatly aids in the regulation of transient species in the oral cavity.
Topics: Humans; Mouth; RNA, Ribosomal, 16S; Bacteria; India; DNA, Bacterial; Microbiota; Metagenomics; Adult; Male; Female; Dysbiosis; Young Adult; Middle Aged; Comorbidity
PubMed: 38631413
DOI: 10.1016/j.micpath.2024.106643 -
Nature Reviews. Gastroenterology &... Jun 2024
Topics: Humans; Colorectal Neoplasms; Fusobacterium nucleatum; Fusobacterium Infections
PubMed: 38627536
DOI: 10.1038/s41575-024-00930-3 -
Zhongguo Zhong Yao Za Zhi = Zhongguo... Mar 2024This paper investigates the intervention effect and mechanism of Banxia Xiexin Decoction(BXD) on colitis-associated colorectal cancer(CAC) infected with Fusobacterium...
This paper investigates the intervention effect and mechanism of Banxia Xiexin Decoction(BXD) on colitis-associated colorectal cancer(CAC) infected with Fusobacterium nucleatum(Fn). C57BL/6 mice were randomly divided into a control group, Fn group, CAC group [azoxymethane(AOM)/dextran sulfate sodium salt(DSS)](AOM/DSS), model group, and BXD group. Except for the control and AOM/DSS groups, the mice in the other groups were orally administered with Fn suspension twice a week. The AOM/DSS group, model group, and BXD group were also injected with a single dose of 10 mg·kg~(-1) AOM combined with three cycles of 2.5% DSS taken intragastrically. The BXD group received oral administration of BXD starting from the second cycle until the end of the experiment. The general condition and weight changes of the mice were monitored during the experiment, and the disease activity index(DAI) was calculated. At the end of the experiment, the colon length and weight of the mice in each group were compared. Hematoxylin-eosin(HE) staining was used to observe the pathological changes in the colon tissue. Enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of interleukin(IL)-2, IL-4, and IL-6 inflammatory factors in the serum. Immunohistochemistry(IHC) was used to detect the expression of Ki67, E-cadherin, and β-catenin in the colon tissue. Western blot was used to detect the protein content of Wnt3a, β-catenin, E-cadherin, annexin A1, cyclin D1, and glycogen synthase kinase-3β(GSK-3β) in the colon tissue. The results showed that compared with the control group, the Fn group had no significant lesions. The mice in the AOM/DSS group and model group had decreased body weight, increased DAI scores, significantly increased colon weight, and significantly shortened colon length, with more significant lesions in the model group. At the same time, the colon histology of the model group showed more severe adenomas, inflammatory infiltration, and cellular dysplasia. The levels of IL-4 and IL-6 in the serum were significantly increased, while the IL-2 content was significantly decreased. The IHC results showed low expression of E-cadherin and high expression of Ki67 and β-catenin in the model group, with a decreased protein content of E-cadherin and GSK-3β and an increased protein content of Wnt3a, β-catenin, annexin A1, and cyclin D1. After intervention with BXD, the body weight of the mice increased; the DAI score decreased; the colon length increased, and the tumor decreased. The histopathology showed reduced tumor proliferation and reduced inflammatory infiltration. The levels of IL-6 and IL-4 in the serum were significantly decreased, while the IL-2 content was increased. Meanwhile, the expression of E-cadherin was upregulated, and that of Ki67 and β-catenin was downregulated. The protein content of E-cadherin and GSK-3β increased, while that of Wnt3a, β-catenin, annexin A1, and cyclin D1 decreased. In conclusion, BXD can inhibit CAC infected with Fn, and its potential mechanism may be related to the inhibition of Fn binding to E-cadherin, the decrease in annexin A1 protein level, and the regulation of the Wnt/β-catenin pathway.
Topics: Mice; Animals; Colitis; beta Catenin; Cyclin D1; Fusobacterium nucleatum; Glycogen Synthase Kinase 3 beta; Colitis-Associated Neoplasms; Interleukin-6; Ki-67 Antigen; Annexin A1; Interleukin-2; Interleukin-4; Mice, Inbred C57BL; Cadherins; Body Weight; Dextran Sulfate; Disease Models, Animal; Azoxymethane; Drugs, Chinese Herbal
PubMed: 38621974
DOI: 10.19540/j.cnki.cjcmm.20231114.701 -
European Journal of Clinical... Jun 2024Fusobacterium necrophorum is a common cause of pharyngotonsillitis. However, no guidelines exist on when to diagnose or treat it. We aimed to investigate associations... (Observational Study)
Observational Study
OBJECTIVES
Fusobacterium necrophorum is a common cause of pharyngotonsillitis. However, no guidelines exist on when to diagnose or treat it. We aimed to investigate associations between clinical criteria and F. necrophorum-positivity in pharyngotonsillitis and assess the predictive potential of a simple scoring system.
METHODS
Pharyngotonsillitis patients who were tested for F. necrophorum (PCR) and presented to hospitals in the Skåne Region, Sweden, between 2013-2020 were eligible. Data were retrieved from electronic chart reviews and registries. By logistic regression we investigated associations between F. necrophorum-positivity and pre-specified criteria: age 13-30 years, symptom duration ≤ 3 days, absence of viral symptoms (e.g. cough, coryza), fever, tonsillar swelling/exudate, lymphadenopathy and CRP ≥ 50 mg/L. In secondary analyses, associated variables were weighted by strength of association into a score and its predictive accuracy of F. necrophorum was assessed.
RESULTS
Among 561 cases included, 184 (33%) had F. necrophorum, which was associated with the following criteria: age 13-30, symptom duration ≤ 3 days, absence of viral symptoms, tonsillar swelling/exudate and CRP ≥ 50 mg/L. Age 13-30 had the strongest association (OR5.7 95%CI 3.7-8.8). After weighting, these five variables had a sensitivity and specificity of 68% and 71% respectively to predict F. necrophorum-positivity at the proposed cut-off.
CONCLUSION
Our results suggest that F. necrophorum cases presenting to hospitals might be better distinguished from other pharyngotonsillitis cases by a simple scoring system presented, with age 13-30 being the strongest predictor for F. necrophorum. Prospective studies, involving primary care settings, are needed to evaluate generalisability of findings beyond cases presenting to hospitals.
Topics: Humans; Fusobacterium necrophorum; Sweden; Fusobacterium Infections; Male; Adolescent; Female; Adult; Tonsillitis; Young Adult; Pharyngitis; Middle Aged; Hospitals; Aged
PubMed: 38609699
DOI: 10.1007/s10096-024-04827-6 -
Cell Host & Microbe Apr 2024Krieger et al.'s study in this issue of Cell Host & Microbe reveals that Fusobacterium nucleatum subsp. animalis strains, previously underestimated, are significant in...
Krieger et al.'s study in this issue of Cell Host & Microbe reveals that Fusobacterium nucleatum subsp. animalis strains, previously underestimated, are significant in disease-affected oral areas. This challenges the long-held notion of the dominance of Fusobacterium nucleatum subsp. nucleatum, reshaping our understanding of Fusobacterium distribution in the oral microbiome.
Topics: Fusobacterium; Fusobacterium nucleatum
PubMed: 38604121
DOI: 10.1016/j.chom.2024.03.009 -
ACS Infectious Diseases May 2024, a pathobiont inhabiting the oral cavity, contributes to opportunistic diseases, such as periodontal diseases and gastrointestinal cancers, which involve microbiota...
, a pathobiont inhabiting the oral cavity, contributes to opportunistic diseases, such as periodontal diseases and gastrointestinal cancers, which involve microbiota imbalance. Broad-spectrum antimicrobial agents, while effective against infections, can exacerbate dysbiosis. This necessitates the discovery of more targeted narrow-spectrum antimicrobial agents. We therefore investigated the potential for the fusobacterial enoyl-ACP reductase II (ENR II) isoenzyme FabK (C4N14_ 04250) as a narrow-spectrum drug target. ENRs catalyze the rate-limiting step in the bacterial fatty acid synthesis pathway. Bioinformatics revealed that of the four distinct bacterial ENR isoforms, specifically encodes FabK. Genetic studies revealed that was indispensable for growth, as the gene could not be deleted, and silencing of its mRNA inhibited growth under the test conditions. Remarkably, exogenous fatty acids failed to rescue growth inhibition caused by the silencing of . Screening of synthetic phenylimidazole analogues of a known FabK inhibitor identified an inhibitor (i.e., 681) of FabK enzymatic activity and growth, with an IC of 2.1 μM (1.0 μg/mL) and a MIC of 0.4 μg/mL, respectively. Exogenous fatty acids did not attenuate the activity of 681 against . Furthermore, FabK was confirmed as the intracellular target of 681 based on the overexpression of FabK shifting MICs and 681-resistant mutants having amino acid substitutions in FabK or mutations in other genetic loci affecting fatty acid biosynthesis. 681 had minimal activity against a range of commensal flora, and it was less active against streptococci in physiologic fatty acids. Taken together, FabK is an essential enzyme that is amenable to drug targeting for the discovery and development of narrow-spectrum antimicrobial agents.
Topics: Fusobacterium nucleatum; Anti-Bacterial Agents; Humans; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); Microbial Sensitivity Tests; Bacterial Proteins; Fatty Acids; Fusobacterium Infections; Enzyme Inhibitors
PubMed: 38597503
DOI: 10.1021/acsinfecdis.3c00710 -
Oncology Letters May 2024Liver metastasis is a major cause of mortality in patients with advanced stages of colorectal cancer (CRC). The gut microbiota has been demonstrated to influence the...
Liver metastasis is a major cause of mortality in patients with advanced stages of colorectal cancer (CRC). The gut microbiota has been demonstrated to influence the progression of liver diseases, potentially providing novel perspectives for diagnosis, treatment and research. However, the gut microbial characteristics in CRC with liver metastasis (LM) and with no liver metastasis (NLM) have not yet been fully established. In the present study, high-throughput 16S RNA sequencing technology was employed, in order to examine the gut microbial richness and composition in patients with CRC with LM or NLM. A discovery cohort (cohort 2; LM=18; NLM=36) and a validation cohort (cohort 3; LM=13; NLM=41) were established using fresh feces. In addition, primary carcinoma tissue samples were also analyzed (LM=8 and NLM=10) as a supplementary discovery cohort (cohort 1). The findings of the present study indicated that the intestinal microbiota richness and diversity were increased in the LM group as compared to the NLM group. A significant difference was observed in species composition between the LM and NLM group. In the two discovery cohorts with two different samples, the dominant phyla were consistent, but varied at lower taxonomic levels. Phylum Fusobacteria presented consistent and significant enrichment in LM group in both discovery cohorts. Furthermore, with the application of a random forest model and receiver operator characteristic curve analysis, Fusobacteria was identified as a potential biomarker for LM. Moreover, Fusobacteria was also a poor prognosis factor for survival. Importantly, the findings were reconfirmed in the validation cohort. On the whole, the findings of the present study demonstrated that CRC with LM and NLM exhibit distinct gut microbiota characteristics. Fusobacteria detection thus has potential for use in predicting LM and a poor prognosis of patients with CRC.
PubMed: 38596264
DOI: 10.3892/ol.2024.14368 -
NPJ Biofilms and Microbiomes Apr 2024Dysbiosis of the human oral microbiota has been reported to be associated with oral cavity squamous cell carcinoma (OSCC) while the host-microbiota interactions with...
Dysbiosis of the human oral microbiota has been reported to be associated with oral cavity squamous cell carcinoma (OSCC) while the host-microbiota interactions with respect to the potential impact of pathogenic bacteria on host genomic and epigenomic abnormalities remain poorly studied. In this study, the mucosal bacterial community, host genome-wide transcriptome and DNA CpG methylation were simultaneously profiled in tumors and their adjacent normal tissues of OSCC patients. Significant enrichment in the relative abundance of seven bacteria species (Fusobacterium nucleatum, Treponema medium, Peptostreptococcus stomatis, Gemella morbillorum, Catonella morbi, Peptoanaerobacter yurli and Peptococcus simiae) were observed in OSCC tumor microenvironment. These tumor-enriched bacteria formed 254 positive correlations with 206 up-regulated host genes, mainly involving signaling pathways related to cell adhesion, migration and proliferation. Integrative analysis of bacteria-transcriptome and bacteria-methylation correlations identified at least 20 dysregulated host genes with inverted CpG methylation in their promoter regions associated with enrichment of bacterial pathogens, implying a potential of pathogenic bacteria to regulate gene expression, in part, through epigenetic alterations. An in vitro model further confirmed that Fusobacterium nucleatum might contribute to cellular invasion via crosstalk with E-cadherin/β-catenin signaling, TNFα/NF-κB pathway and extracellular matrix remodeling by up-regulating SNAI2 gene, a key transcription factor of epithelial-mesenchymal transition (EMT). Our work using multi-omics approaches explored complex host-microbiota interactions and provided important insights into genetic and functional basis in OSCC tumorigenesis, which may serve as a precursor for hypothesis-driven study to better understand the causational relationship of pathogenic bacteria in this deadly cancer.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Epigenomics; Dysbiosis; Mouth Neoplasms; Carcinoma, Squamous Cell; Bacteria; Fusobacterium nucleatum; Head and Neck Neoplasms; Epigenesis, Genetic; Microbiota; Tumor Microenvironment
PubMed: 38589501
DOI: 10.1038/s41522-024-00511-x