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Volume 73,
Issue 10,
2024
Volume 73, Issue 10, 2024
- Microbiome and Microbial Ecology in Health
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Genetic association of gut microbiota with osteoarthritis: a multivariable Mendelian randomization study considering medication use
More LessBackground. The interplay among human gut microbiota (GM) composition, osteoarthritis (OA) and OA-related medication use has been extensively discussed. However, to date, there has been no exploration of the genetic correlation among these three factors.
Hypothesis/Gap. The potential causal link between GM and OA), and whether medications influence this relationship, remains unclear.
Methods. We utilized bidirectional Mendelian randomization (MR) to explore the genetic associations between GM and OA. We leveraged genome-wide association study (GWAS) summary statistics from the MiBioGen and GO consortia, which provided data on GM taxa and OA cases, respectively. We identified outlier single-nucleotide polymorphisms using radial-MR and assessed causal associations using inverse variance weighting (IVW), weighted median and MR-Egger methods. Robust outcomes, consistent across these methods, were reported. We addressed potential biases through tests for horizontal pleiotropy and heterogeneity, supplemented by the Mendelian randomization pleiotropy residual sum and outlier method. Multivariable MR techniques were applied to adjust for OA medication use using UK Biobank data.
Results. IVW estimates revealed a significant increase in hip OA risk for Gordonibacter and Eubacterium (brachy group) [odds ratio (OR): 1.09, 95% confidence interval (CI): 1.04–1.15, P=7.82E-04; OR: 1.09, 95% CI: 1.03–1.16, P=4.67E-03, respectively]. Conversely, Senegalimassilia, Slackia and Streptococcus exhibited protective effects (OR: 0.88, P=2.14E-02; OR: 0.88, P=3.33E-02; 0.91, P=4.29E-02). Sutterella increased the risk of knee OA (OR=1.15, 95% CI: 1.07–1.25, P=4.06E-04), while Haemophilus decreased it (OR=0.94, 95% CI: 0.88–1.00, P=4.26E-02). No significant heterogeneity or horizontal pleiotropy was observed in the results. Even after accounting for the potential confounding effect of medication, the results remained consistent. No reverse causation was detected.
Conclusions. Our MR study reveals gut microbiome links to OA risk. Associations hold after adjusting for medication, indicating a potential causal connection between GM and OA.
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- Pathogenesis, Virulence and Host Response
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Abf1 negatively regulates the expression of EPA1 and affects adhesion in Candida glabrata
More LessIntroduction. Adherence is a major virulence trait in Candida glabrata that, in many strains, depends on the EPA (epithelial adhesin) genes, which confer the ability to adhere to epithelial and endothelial cells of the host. The EPA genes are generally found at subtelomeric regions, which makes them subject to subtelomeric silencing. In C. glabrata, subtelomeric silencing depends on different protein complexes, such as silent information regulator and yKu complexes, and other proteins, such as Repressor/activator protein 1 (Rap1) and Abf1. At the EPA1 locus, which encodes the main adhesin Epa1, we previously found at least two cis-acting elements, the protosilencer Sil2126 and the negative element, that contribute to the propagation of silencing from the telomere to the subtelomeric region.
Hypothesis. Abf1 binds to the regulatory regions of EPA1 and other regions at the telomere E-R, thereby negatively regulating EPA1 transcription.
Aim. To determine whether Abf1 and Rap1 silencing proteins bind to previously identified cis-acting elements on the right telomere of chromosome E (E-R subtelomeric region), resulting in negative regulation of EPA1 transcription and infer Abf1 and Rap1 recognition sites in C. glabrata.
Methodology. We used chromatin immunoprecipitation (ChIP) followed by quantitative PCR to determine the binding sites for Abf1 and Rap1 in the intergenic regions between EPA1 and EPA2 and HYR1 and EPA1, and mutants were used to determine the silencing level of the EPA1 promoter region.
Results. We found that Abf1 predominantly binds to the EPA1 promoter region, leading to negative regulation of EPA1 expression. Furthermore, the mutant abf1-43, which lacks the last 43 amino acids at its C-terminal end and is defective for subtelomeric silencing, exhibits hyperadherence to epithelial cells in vitro compared to the parental strain, suggesting that EPA1 is derepressed. We also determined the motif-binding sequences for Abf1 and Rap1 in C. glabrata using data from the ChIP assays.
Conclusion. Together these data indicate that Abf1 negatively regulates EPA1 expression, leading to decreased adhesion of C. glabrata to epithelial cells.
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Phenotypic diversity of type III secretion system activity in enteropathogenic Escherichia coli clinical isolates
More LessIntroduction. Enteropathogenic Escherichia coli (EPEC) strains pose a significant threat as a leading cause of severe childhood diarrhoea in developing nations. EPEC pathogenicity relies on the type III secretion system (T3SS) encoded by the locus of enterocyte effacement (LEE), facilitating the secretion and translocation of bacterial effector proteins.
Gap Statement. While the regulatory roles of PerC (plasmid-encoded regulator) and GrlA (global regulator of LEE-activator) in ler expression and LEE gene activation are well-documented in the EPEC prototype strain E2348/69, understanding the variability in LEE gene expression control mechanisms among clinical EPEC isolates remains an area requiring further investigation.
Aim. This study aims to explore the diversity in LEE gene expression control mechanisms among clinical EPEC isolates through a comparative analysis of secretion profiles under defined growth conditions favouring either PerC- or GrlA-mediated activation of LEE expression.
Methodology. We compared T3SS-dependent secretion patterns and promoter expression in both typical EPEC (tEPEC) and atypical EPEC (aEPEC) clinical isolates under growth conditions favouring either PerC- or GrlA-mediated activation of LEE expression. Additionally, we conducted promoter reporter activity assays, quantitative real-time PCR and Western blot experiments to assess gene expression activity.
Results. Significant differences in T3SS-dependent secretion were observed among tEPEC and aEPEC strains, independent of LEE sequence variations or T3SS gene functionality. Notably, a clinical tEPEC isolate exhibited increased secretion levels under repressive growth conditions and in the absence of both PerC and GrlA, implicating an alternative mechanism in the activation of Ler (LEE-encoded regulator) expression.
Conclusion. Our findings indicate that uncharacterized LEE regulatory mechanisms contribute to phenotypic diversity among clinical EPEC isolates, though their impact on clinical outcomes remains unknown. This challenges the conventional understanding based on reference strains and highlights the need to investigate beyond established models to comprehensively elucidate EPEC pathogenesis.
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- Prevention, Therapy and Therapeutics
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Tissue response in a rat model of denture stomatitis treated with tissue conditioner containing antifungal complexed with β-cyclodextrin
More LessIntroduction. Tissue conditioners modified with antifungals are a potential alternative to denture stomatitis (DS) treatment.
Gap Statement. Information on tissue response to this treatment before its clinical application is lacking.
Aim. This study aimed to evaluate the tissue response of a tissue conditioner modified with antifungals in a rat model of DS.
Methodology. After DS induction for 4 days under antibiotic therapy, Wistar rats had their intraoral devices (IODs) relined with the tissue conditioner Softone without (Soft) or with the MICs against Candida albicans of nystatin (Nys) or chlorhexidine (Chx) complexed or not with β-cyclodextrin (Nys:βCD and Chx:βCD). Three controls were included: healthy rats [negative control (Nc)], rats using a sterile IOD [sterile device (Sd)] and rats with DS that did not receive treatment (DS). After 4 days of treatment, the palatal mucosa under the IODs underwent histological processing for morphohistopathological and histometric analyses, morphology of collagen fibres (birefringence), immunohistochemistry for the expression of cell proliferation (proliferating cell nuclear antigen) and cytokine (IL-1β).
Results. The Nc and Sd groups were similar (P>0.05), displaying epithelial and connective tissues without any discernible changes in the parameters assessed. The DS and Soft groups exhibited pronounced epithelial alterations, cell proliferation and expression of the cytokine IL-1β. In groups treated with drug incorporation (Nys, Chx, Nys:βCD and Chx:βCD), all samples demonstrated a reduction in tissue inflammation or complete tissue recovery, with an epithelium compatible with health. For the immunohistochemical parameters, the Chx, Nys:βCD and Chx:βCD groups were comparable with Nc (P>0.05).
Conclusion. The proposed treatment could be promising for DS, as it led to the tissue recovery of the palatal mucosa. Nevertheless, much lower concentrations of complexed antifungals were required to achieve a similar or higher degree of tissue response compared with uncomplexed drugs in a modified tissue conditioner formulation.
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EDTA, aspirin and d-mannose inhibit the biofilm formation of Proteus vulgaris by hindering its adhesion to catheter devices: a proposed strategy for CAUTI prevention
More LessIntroduction. Catheter-associated urinary tract infection (CAUTI) is a common nosocomial infection treated with antibiotics, but biofilm and antibiotic resistance have led researchers to seek preventive strategies rather than treatment.
Gap statement. No preventive strategy for CAUTI has been developed to date.
Aim. We studied the anti-biofilm potentials of three non-antibiotics to develop a strategy for CAUTI prevention.
Methodology. Isolates were collected from urine specimens of catheterized inpatients; one of them was identified as Proteus vulgaris (Pv).
Results. Pv swarmed exhibiting a unique bull’s-eye pattern on the surface of 1.25% solidified agar, but it was not well-swarmer with distinguished swarming rafts on the surface of traditional media used for swarming (1.5%). EDTA, aspirin and d-mannose significantly inhibited the biofilm-forming ability of Pv on the surface of the urinary catheter device. EDTA was the strongest followed by aspirin and d-mannose. The concentrations of drugs for 50% inhibition of biofilm (BIC50) were estimated at ~0.2, 0.4 and 0.95 mM for EDTA, aspirin and d-mannose, respectively. All drugs hindered Pv cells from attaching to the catheter surface at the initiation stage of biofilm. The functional groups, –COOH for EDTA and aspirin, interfered with the cell adhesion process of Pv through pili-to-surface interaction.
Conclusion. The inner surface of a urine drainage bag coated with EDTA, and the oral administration of aspirin and d-mannose at their therapeutic doses would be an excellent preventive strategy for CAUTI.
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- Corrigenda
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Volumes and issues
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Volume 74 (2025)
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Volume 73 (2024)
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Volume 72 (2023 - 2024)
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Volume 71 (2022)
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