Gut Pathogens最新文献

Trichinella spiralis (T. spiralis) infection dynamically modulates macrophage polarization. It promotes M1 macrophage polarization, enhancing the pro-inflammatory pathways. This study investigates how ivermectin nanoparticles (IVM-NP) and Moringa oleifera leaf extract (MOL-NP) regulate these pathways to improve the pathophysiological outcomes of trichinosis. Thirty Swiss albino mice were infected with T. spiralis and divided equally into five groups of six mice each: healthy controls, infected untreated, IVM-NP-treated, MOL-NP-treated, and combined IVM-NP and MOL-NP-treated. IVM-NP were administered as a single oral dose of 200 µg/kg at the beginning of the experiment. MOL-NP were delivered orally at a dose of 400 mg/kg/day for 5 consecutive days starting from experiment initiation. Parasitological examination to detect the parasitic burden in addition to histopathological, immunohistochemical and quantitative histomorphometric assessment of intestinal tissue for nuclear factor kappa B (NF-κB) and inducible nitric oxide synthase (iNOS) were done. Furthermore, RT-PCR was performed to evaluate the relative gene expression of Arginase-1, TNF-α, and IL-10. Treatment with nanoparticle formulations of IVM and MOL modulated macrophage-related immune responses by reducing the pro-inflammatory markers iNOS, TNF-α and NF-κB, while increasing the relative gene expression of the anti-inflammatory cytokine IL-10. Combination therapy exhibited superior efficacy in decreasing parasite burden and mitigating intestinal pathology compared to monotherapy.

Vibrio vulnificus is a marine pathogen that is a significant cause of foodborne infections, leading to chronic diseases and primary septicemia. Wound infections caused by this bacterium can result in serious complications such as ulceration and tissue necrosis. The pathogenesis of V. vulnificus is influenced by quorum sensing and the secondary messenger cyclic diguanylate (c-di-GMP). The levels of c-di-GMP inside the cell are controlled by its synthesizer, diguanylate cyclase, and its degrader, phosphodiesterase. The phosphodiesterase VieA serves as a key transcriptional regulator in V. cholerae's virulence. However, the function of its diguanylate cyclase partner in locally controlling c-di-GMP-mediated virulence regulation in V. vulnificus remains unclear. This study identified a diguanylate cyclase, VV2380, which may interact with VieA in V. vulnificus based on a pulldown assay. The enzymatic properties of VV2380 showed that it is a metal ion-dependent diguanylate cyclase that synthesizes c-di-GMP. Activity tests demonstrated that reversible phosphorylation on residue D207 of VV2380 regulates GTP hydrolysis activity to increase c-di-GMP levels. The elevated c-di-GMP level mediated by VV2380 results in rugose colony morphology and reduced motility, but does not influence biofilm formation. The VV2380-VieA signaling network significantly suppressed the gene expression levels of vvpE and rtxA1, reducing cytolysin activity and Multifunctional-Autoprocessing Repeats-in-Toxin (MARTX) production, which led to lower cytotoxicity toward host cells. In summary, this study highlights that diguanylate cyclase VV2380 and phosphodiesterase VieA are part of a local c-di-GMP signaling network that modulates the phenotypic features and the pathogenesis. It offers a new explanation for how various diguanylate cyclases and phosphodiesterases in V. vulnificus regulate different responses.

Background: Hepatocellular carcinoma (HCC) remains a lethal complication of chronic hepatitis C virus (HCV) infection, even after successful direct-acting antiviral (DAA) therapy. The gut microbiome influences hepatocarcinogenesis through the gut‒liver axis; however, the microbial signatures associated with HCC in DAA-treated patients are poorly defined. This study aimed to elucidate the patterns of microbiomes in HCV-treated patients who developed HCC, with a focus on bacterial diversity, differentially represented taxa, and their associations with clinical markers (FIB-4) and metabolic profiles as potential biomarkers.

Results: A total of 138 participants were enrolled: 46 HCC patients with persistent HCV viremia (RHCC), 46 HCC patients with HCV eradication (THCC), and 46 healthy controls. RHCC patients exhibited pronounced dysbiosis, characterized by reduced alpha diversity (Kruskal-Wallis; H = 14.37, p = 0.00076) and an elevated Firmicutes/Bacteroidetes (F/B) ratio (1.55 vs. 1.05 in controls; Mann-Whitney U test, U = 87.32, padj = 0.00079). At the genus level, Asteroleplasma was significantly enriched in RHCC (log₂FC = + 2.8, padj = 0.008), whereas the butyrate-producing genus Faecalibacterium was depleted (log₂FC = - 2.1, padj = 0.006). Machine learning identified Asteroleplasma, Moryella, Lachnoclostridium, Fournierella, Eubacterium xylanophilum, Succinivibrio, and Faecalibacterium as the top classifiers of RHCC (AUC = 0.81). Functional profiling revealed a 58% reduction in butyrate synthesis (padj = 0.0032) and increased lipopolysaccharide biosynthesis (log₂FC = + 3.2, padj = 0.002) in RHCC, both of which correlated with clinical deterioration (FIB-4 scores, r = 0.62).

Conclusions: Distinct gut microbial signatures distinguish HCC patients with persistent HCV viremia from those who achieve viral clearance, with implications for risk stratification and therapeutic targeting. The F/B ratio, abundance of Asteroleplasma, and functional pathway disruption (butyrate depletion) could serve as potential biomarkers for HCC progression. These findings underscore the influential role of the gut microbiome in hepatocarcinogenesis and its potential utility in personalized HCC management.

Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune disease. Current therapeutic options are limited, with some patients responding poorly to first-line treatment with ursodeoxycholic acid. However, second-line drugs are difficult to develop. There are no drugs available to treat liver dysfunction. Currently, the etiology of PBC is unknown, and the intestinal flora affects the liver through the gut‒liver axis. The hypothesis of intestinal dysbiosis has gradually been accepted and involves mechanisms such as leaky gut, abnormal bile acids metabolism, and dysregulated immune tolerance. We found that gut microbiota-targeted therapy, including antibiotics, dietary regulation, probiotic supplementation, and fecal microbiota transplantation, can effectively improve liver function, remodel the intestinal microbiota, and alleviate symptom. However, this therapy has limitations, such as large individual differences and unknown long-term efficacy and safety. Large-scale and long-term clinical studies are expected to promote the broad application of gut microbiota-targeted therapy in the clinic.

Background: Herpangina is an acute pediatric illness caused by enteroviruses, yet the predominant circulating serotype in mainland China has not been well characterized. In this study, Coxsackievirus A2 (CV-A2) emerged as the dominant serotype among herpangina cases in Yuhuan City, Zhejiang Province. These findings underscore the importance of further research into the epidemiological distribution and molecular features of CV-A2 in this region.

Methods: A total of 133 child herpangina cases were included during May and June 2024. Enteroviruses were detected using RT-PCR, followed by serotyping and sequencing. Phylogenetic and recombination analyses were performed to assess genetic diversity and evolutionary relationships.

Results: Among the 133 cases (median age: 3 years), 88.7% tested positive for enteroviruses. CV-A2 was predominant (78.0%), followed by CV-A4, CV-A5, CV-A10, CV-A16, and CV-B4. Fever (95.5%) and oral vesicles (98.5%) were the most common symptoms. Compared to other serotypes, CV-A2 cases had a higher incidence of fever (P = 0.008) and peak temperature (P = 0.042), with significantly elevated neutrophil percentages (> 70.0%) and reduced lymphocyte percentages (< 20.0%). Phylogenetic analysis identified genotype D accounted for 97.8% (90/92) of CV-A2 strains; two genotype C strains clustered with European isolates. Recombination analysis revealed intra- and inter-serotype events involving CV-A2, A4, and A5.

Conclusion: CV-A2 has re-emerged as the dominant herpangina-associated enterovirus in Eastern China, demonstrating distinct clinical and hematological features. This shift in serotype prevalence underscores the need for continued surveillance to monitor its spread and interactions with other serotypes.

Background: Campylobacter jejuni, commonly present in the intestinal tract of poultry, is a major causative agent of human gastroenteritis. To successfully colonize the chicken gut, C. jejuni needs to have access to certain amino acids. However, the amino acid profile and its availability in the gut is dependent on the type of ingested protein and its digestibility. Therefore, manipulating the digestibility of different protein sources, using an exogenous protease, may be a promising way to control Campylobacter colonization in chickens.

Results: Chickens were fed with an exclusive vegetarian protein source diet (veggy diet) or a diet also containing animal proteins (animal diet), with or without exogenous protease from one day of age. At 14 days of age, all chickens were inoculated with two C. jejuni strains. At 7 days post infection (dpi) and 21 dpi, liver, ileal, and cecal contents were collected and used to enumerate C. jejuni by bacterial culture. Ileal and cecal contents were also used to analyze intestinal microbiota through 16S rRNA gene sequencing. The protease supplementation of the vegetarian protein source diet reduced cecal colonization levels of C. jejuni, increased its ileal amounts, and inhibited its hepatic dissemination. The addition of exogenous protease to the vegetarian protein source diet also altered alpha and beta diversities of the cecal microbiota but not of the ileal microbiota. The protease supplementation of the animal protein-based diet had no effect on Campylobacter colonization or on alpha diversity, unlike the beta diversity of the cecal content. Moreover, protease addition to the plant protein diet increased the cecal abundance of several genera such as UBA1819, Faecalibacterium, and Anaerostipes. In contrast, this supplementation decreased the cecal abundance of genera such as Tuzzerella, Monoglobus, and Fournierella. Using microbial co-occurrence networks, we observed that Campylobacter was positively linked to Negativibacillus in the vegetarian protein source diet group, while it was positively linked to Anaerotruncus and Tuzzerella and negatively linked to Faecalibacterium in the supplemented vegetarian protein diet group.

Conclusions: Adding a commercially available protease to a vegetarian protein source diet appears to reduce C. jejuni colonization of the intestine, inhibit its translocation to the liver, and modify the cecal microbiota. These findings lead to further research questions on the interplay between C. jejuni strains, feed protein types, and commercial protease feed supplementation.

Background: Gestational subclinical hypothyroidism (SCH), marked by elevated Thyroid-stimulating hormone (TSH) with normal free thyroxine (FT4), links to adverse perinatal outcomes. During early pregnancy (< 20 weeks), maternal thyroid hormones are crucial for fetal neurodevelopment, with deficiencies risking irreversible deficits. SCH pregnancies show gut microbiota alterations and metabolic dysregulation. Emerging evidence suggests these changes may drive Th(helper T cells)1/Th2/Th17 immune imbalance, though mechanisms remain unclear. This study combines metagenomics and lipidomics to investigate gut microbiota-Th1/Th2/Th17 interactions in patients with SCH in the first 20 weeks during pregnancy.

Methods: This study included 20 pregnant women with SCH (SCH group) in the first half of pregnancy (≤ 20 gestational weeks) and 20 normal pregnant women (CON group) in the same period. Collect fecal and blood samples from both groups. Metagenomic sequencing was used to determine the differences in the composition of the intestinal microbiota between the two groups, and non-targeted lipidomics was used to compare the lipid differences between the two groups. Flow cytometry was used to assess Th1, Th2 and Th17 cells in peripheral blood, and a cell microbead array was used to determine cytokine levels.

Results: (1) Metagenomic sequencing showed an increased abundance of Faecalibacterium prausnitzii and a decreased abundance of Bacteroides uniformis in the SCH group. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated significant enrichment in lipid and polysaccharide biosynthesis and mucopolysaccharide biodegradation pathways in the SCH group. (2) Lipidomics identified 692 different lipids, with Triglyceride (TG) being the most significant. KEGG pathway analysis revealed that TG was mainly concentrated in the Th1, Th2, and Th17 cell differentiation pathways. (3) Additionally, serological indicators of the two groups showed that TSH, Interleukin (IL)-2,IL-10, Tumor necrosis factor (TNF)-α, TG, Th1, and Th17 in the SCH group were higher than those in the CON group, while Th2 was significantly lower (P < 0.05).

Conclusion: In the first half of pregnancy, patients with SCH may experience intestinal microbiota disorder, characterized by increased levels of Faecalibacterium prausnitzii and decreased levels of Bacteroides uniformis, at the same time, it was accompanied by an increase in TG synthesis and a Th1/Th2/Th17 imbalance, these factors may be involved in the occurrence of SCH during pregnancy.

Background: Colorectal cancer (CRC) is a significant global health burden, ranking amongst the top causes of cancer-associated mortality. Emerging evidences implicate gut microbiota as a prominent mediator of cell signalling, immune, and metabolic pathways in the pathophysiology of CRC.

Methods: We analysed 16S rRNA amplicon sequencing data (PRJEB7774) from faecal samples of 46 CRC patients and 63 healthy controls to assess shifts in microbial composition, diversity, and biomarker taxa. Differential abundances of microbiota were determined using Linear Discriminant Analysis Effect Size (LEfSe) and Random Forest (RF) models. Host-microbiota interactions were explored using the Human Microbiome Affect the Host Epigenome (MIAOME) and Host Genetic and Immune Factors Shaping Human Microbiota (GIMICA) databases, with key host genes validated using Gene Expression Profiling Interactive Analysis (GEPIA) and The Cancer Genome Atlas (TCGA) datasets. Functional enrichment analyses were performed to uncover associated biological processes and pathways.

Results: CRC samples exhibited significantly reduced alpha diversity and distinct beta diversity profiles, compared to controls. Taxonomic profiling revealed an enrichment of potentially pathogenic bacteria, including Prevotella copri, Methanobrevibacter smithii, Bacteroides eggerthii, and Dialister invisus, and depletion of beneficial microbes such as Bifidobacterium animalis and Ruminococcus sp. Predicted host-microbe interactions highlighted associations between key microbial biomarkers and inflammation-related genes (CD44, CXCL8, DUSP16, FOXP3, IFNGR2, IL18), all significantly overexpressed in CRC samples. Enrichment analyses linked these genes to immune pathways, including NF-κB, TLR and cytokine signalling.

Conclusions: Our study reveals a distinct gut microbiota signature in CRC and suggests functional interactions between microbial dysbiosis and host inflammatory responses. These findings emphasize the potential of microbiota-based interventions and microbial metabolites as adjunctive strategies for the management of CRC.

Background: Inflammatory bowel disease (IBD) commonly coexists with non-alcoholic fatty liver disease (NAFLD). Despite metabolic factors being less involved, IBD patients exhibit a higher risk of developing NAFLD compared to non-IBD individuals. Given the shared role of gut dysbiosis in the pathogenesis of both diseases, this study investigated the involvement of gut microbiota and associated metabolic pathways in IBD-associated NAFLD (COMO).

Methods: A retrospective analysis of clinical profiles from 490 IBD, 89 NAFLD, and 68 COMO patients was conducted. Fecal samples from 30 IBD, 32 NAFLD, 26 COMO patients and 29 healthy controls were prospectively collected and subjected to 16 S rRNA gene sequencing for microbial community analysis and functional pathway prediction. Subsequently, machine learning modeling was employed for feature importance analysis and identification of COMO patients.

Results: Demographic analysis revealed that COMO patients developed NAFLD earlier than NAFLD alone, with fewer metabolic associations with hypertension, hyperlipidemia and glucose dysregulation. Compared with IBD and NAFLD groups, COMO microbiota exhibited lower alpha diversity, with beta diversity aligning with IBD but distinct from NAFLD group. Shared microbial signatures included increased Lactococcus and decreased Coprococcus 3 and Ruminococcus 2, which was correlated with 11 metabolic pathways: five vitamin B pathways (thiamine, vitamin B6, biotin, folate and riboflavin), isoflavonoid, caffeine, phosphonate, cyanoamino acid, lipoic acid and ubiquinone pathways. Integrated microbial-metabolic machine learning models (logistic regression, random forest, support vector machine, and XGBoost) achieved AUC of 0.818-0.864 for COMO identification.

Conclusions: Our findings implicate microbiota-mediated metabolic reprogramming in IBD-associated NAFLD pathogenesis, highlighting potential therapeutic targets for the treatment and prevention of NAFLD in IBD.

Colorectal cancer (CRC) is a major source of cancer-related deaths, but early detection at the adenoma stage markedly improves outcomes. Existing tools such as colonoscopy and fecal immunochemical testing (FIT) are invasive or insensitive to early lesions. To develop a non-invasive screening strategy, we analyzed five publicly available 16 S rRNA sequencing datasets from North American and East Asia. Using Analysis of Compositions of Microbiome with Bias Correction (ANCOM-BC) and chi-square testing, we identified 109 discriminatory microbial taxa and trained random forest (RF) classification models to distinguish healthy controls, adenomas, and CRC. The models performed well in internal validation (AUC = 0.90, 95% CI: 0.869-0.931) and external validation (AUC = 0.82), indicating cross-population generalizability. We further developed a microbial risk score (MRS), inspired by polygenic risk score (PRS), methodology, which was significantly elevated in CRC across cohorts. Enrichment of CRC-associated pathogens such as Fusobacterium nucleatum and Porphyromonas gingivalis supports the biological relevance of the findings. These results demonstrate the potential of gut microbiome signatures combined with machine learning as scalable, non-invasive approach for early CRC and adenomas detection.