IntroductionTo analyze metabolic alterations associated with pulmonary cryptococcosis (PC) using metabolomic profiling of exhaled breath condensate (EBC) and investigate metabolic differences between fungal infections through comparison with patients with pulmonary aspergillosis (PA).MethodsWe enrolled 32 patients with PC, 16 patients with PA, and 14 healthy controls (NC) between September 2022 and September 2025. EBC samples were analyzed using ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS). Differential metabolites were identified using t-test, fold-change and PLS-DA. Discriminatory ability was evaluated using receiver operating characteristic (ROC) curves, and potential biological significance was explored through correlation analysis and KEGG pathway.ResultsForty-five differential metabolites were putatively annotated in the PC versus NC comparison, with 24 remaining significant after FDR correction (q < 0.05). Pathway analysis nominally implicated glycerophospholipid and amino acid metabolism pathways, suggesting that dysregulated lipid metabolism may contribute to the pathogenesis and progression of PC. ROC analysis in this single-center discovery cohort, without independent validation, revealed that alpha-ionone (AUC = 0.8482) and N,N-dimethylsphingosine (AUC = 0.8348) exhibited favorable preliminary discriminatory potential, reflecting distinct metabolic alterations associated with PC. Phenethylamine and phytosphingosine showed moderate preliminary discriminatory potential (AUC = 0.7679 and 0.7567, respectively), and their altered levels raise the possibility of an association with Cryptococcus virulence-related processes. Phytosphingosine was positively correlated with interleukin-6 (IL-6) (r = 0.73, raw P = 0.040), although not after FDR correction (q = 0.423). PC versus PA comparison putatively annotated eight differential metabolites (raw P < 0.05), none remaining significant after FDR correction (q = 0.535); these metabolites were nominally implicated in glycerophospholipid metabolism and polyunsaturated fatty acid-related pathways. Beta-ionone, butaxamine, and cimiracemoside D exhibited gradient trends across the three groups, while cimiracemoside D was positively correlated with erythrocyte sedimentation rate (ESR) (ρ = 0.48, raw P = 0.022), although not after FDR correction (q = 0.423), suggesting metabolic differences between fungal infections may reflect differences in inflammatory responses.DiscussionEBC metabolomic analysis revealed significant inflammation-related and lipid metabolism-related alterations in patients with PC versus healthy controls, while comparisons with PA suggested that these metabolic changes mainly reflected shared host responses rather than pathogen-specific features.
BackgroundSevere fever with thrombocytopenia syndrome (SFTS) is an emerging tick - borne zoonotic infectious disease. Severe SFTS cases exhibit an extremely high fatality rate, but there remain no effective clinical treatments.MethodsPropensity Score Matching (PSM) and logistic regression analysis were used to assess the efficacy, safety, and baseline factors influencing patient prognosis of tocilizumab in the treatment of SFTS.ResultsA total of 833 SFTS cases were included, of whom 171 received tocilizumab. After PSM, a higher recovery rate was observed in the tocilizumab group than in the control group (76.61% vs 67.70%, P = 0.039). However, the between-group difference in in-hospital mortality did not reach statistical significance after matching (16.96% vs 15.22%, P = 0.322). Regarding selected adverse events (AEs) such as co-infection, the between-group differences did not reach statistical significance; these represent observed differences in retrospectively recorded data and should not be interpreted as evidence of safety. Multivariable logistic regression showed that age ≥ 65 years, vasopressor therapy, platelet transfusion, and Ct value were associated with prognosis among tocilizumab-treated patients, with vasopressor use and platelet transfusion likely reflecting disease severity rather than independent causal determinants.ConclusionIn this retrospective cohort, after PSM, tocilizumab use was associated with a higher recovery rate in SFTS patients, although the between-group difference in in-hospital mortality did not reach statistical significance. Observed differences in selected AEs were based on retrospectively recorded data and should not be interpreted as evidence of safety. Given the exploratory nature, prospective studies are warranted.
ObjectiveTo compare peripheral blood immune–inflammatory profiles between patients with pulmonary tuberculosis complicated by central nervous system tuberculosis (PTB + CNS-TB) and those with pulmonary tuberculosis alone (PTB), and to identify laboratory parameters associated with disease severity in PTB + CNS-TB.MethodsThis retrospective study included 4,829 inpatients with tuberculosis (January 2018–March 2026), comprising a PTB group (n = 4,578) and a PTB + CNS-TB group (n = 251). Propensity score matching (1:4) was performed using sex, age, body mass index, albumin, and hemoglobin, yielding 246 PTB + CNS-TB patients and 954 matched PTB controls. PTB + CNS-TB cases were further stratified by Medical Research Council (MRC) grading (Grade I: n = 165; Grades II–III: n = 86). Covariate-adjusted analyses with FDR correction were used to screen severity-associated parameters; LASSO and Firth’s logistic regression were applied to identify mutually independent factors and to construct a severity assessment model.ResultsAfter matching, PTB + CNS-TB patients exhibited a distinct bidirectional pattern characterized by reduced peripheral lymphocyte counts and lower peripheral T-cell counts (CD3+, CD4+, and CD8+) and CD45+ lymphocytes counts, alongside increased neutrophil-related inflammatory indices (including neutrophil count, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and systemic immune-inflammation index) (all P < 0.05). Within the PTB + CNS-TB cohort, severe disease was associated with higher white blood cell and neutrophil-related measures (notably NEU% and NLR) and more pronounced cerebrospinal fluid (CSF) abnormalities, particularly elevated CSF protein and decreased CSF chloride, whereas peripheral T-cell subset parameters did not differ significantly by severity. Multivariable modeling identified CSF protein, NEU%, and albumin as mutually independent factors associated with severe disease. A combined model including these three markers showed good internal discrimination (AUC = 0.772; bootstrap-corrected AUC = 0.767) and calibration.ConclusionsPTB + CNS-TB is associated with reduced peripheral lymphocyte/T-cell subset counts accompanied by heightened a neutrophil-predominant inflammatory profile. Among PTB + CNS-TB patients, disease severity shows a closer association with neutrophil-related indices and routine CSF parameters, particularly CSF protein, than with peripheral T-cell subset counts. A model incorporating NEU%, CSF protein, and albumin may aid in severity assessment.
Heat stress (HS) is an increasingly prevalent environmental and exertional challenge. In severe cases, HS may progress to heatstroke, a life-threatening clinical syndrome characterized by severe hyperthermia, systemic inflammation, and multi-organ dysfunction. This review synthesizes evidence from laboratory rodent models and suggests that gut microbiota dysbiosis may act as a mediator and amplifier of HS-induced pathology. Across diverse rodent models, HS remodels the gut microbiota by reducing microbial diversity. These compositional changes are accompanied by decreased short-chain fatty acids, altered bile acid profiles, and increased lipopolysaccharide burden, although the specific metabolites affected vary across models. Causal evidence from fecal microbiota transplantation and gnotobiotic experiments supports microbiota-dependent amplification of intestinal barrier failure, hepatic inflammation, and neuroinflammation. In contrast, evidence for the gut-reproductive, gut-kidney, gut-heart, gut-muscle, and gut-adipose axes remains predominantly associative or derived from interventional correlations without formal causality testing. Targeting the gut-organ axis through probiotics, prebiotics, antioxidants, or functional amino acids offers promising but largely preclinical adjunctive strategies, with rapid cooling and supportive care remaining the foundation of heatstroke management. Future research should prioritize temporally resolved human studies, multi-omics integration, and causal validation to define the translational potential of microbiome-directed interventions.
Wild animals play a crucial role in the maintenance of tick-borne pathogens, acting as reservoir and sentinel hosts within natural ecosystems. The ongoing expansion of tick populations across Europe has intensified the circulation of zoonotic tick-borne pathogens, including Anaplasma phagocytophilum. Although the epidemiology of this bacterium has been extensively investigated in domestic animals and small wild mammals, the contribution of large omnivores such as the brown bear (Ursus arctos) remains poorly understood, particularly with respect to their exposure to genetically distinct lineages with zoonotic potential, which requires further molecular characterization. This study aimed to determine the detection rate of Anaplasma spp. in free-ranging brown bears (n = 76) and to molecularly characterize detected A. phagocytophilum isolates regarding their potentially zoonotic lineages. Spleen and liver samples were screened for Anaplasma spp. by nested PCR targeting the 16S rRNA gene, with subsequent molecular characterization focused on groEL gene and ankA gene. In total, 8 out of 76 samples were positive for Anaplasma spp., corresponding to a PCR detection rate of 10.53% (95% CI: 4.7–19.7%), with subsequent sequence analysis confirming the presence of A. phagocytophilum. Phylogenetic reconstruction based on groEL and ankA gene fragments allowed classification of the isolates into known European genetic lineages. This research confirms A. phagocytophilum exposure within the Slovak brown bear populations, identifying genetic variants relevant to public and veterinary health. These results suggest that brown bears may be exposed to A. phagocytophilum and could potentially play a role in its enzootic cycle, though further studies are needed.
The genomes of pathogenic bacteria typically encode a diverse array of virulence factors, which constitute the fundamental basis for resisting host immunity and establishing infection. Given the high energetic cost of virulence gene expression, pathogens must precisely orchestrate the activation and silencing of these genes in accordance with the infection process, thereby flexibly executing diverse biological functions within the constraints of their energy budget. To sustain efficient infection, pathogens have evolved multiple mechanisms governing gene expression, enabling them to maintain competitive advantages over both their hosts and microbial competitors across diverse niches. Pseudomonas plecoglossicida is an important Gram-negative pathogen in aquaculture that combines strong environmental adaptability with host invasiveness. It frequently causes explosive epidemics such as visceral white spot disease, inflicting substantial economic losses, and represents one of the principal pathogens threatening the sustainability of aquaculture. An in-depth dissection of its complex virulence mechanisms and hierarchical regulatory networks will provide critical molecular insights into the dynamic interplay between P. plecoglossicida and its hosts. Accordingly, this review focuses on the key virulence factors of P. plecoglossicida, including secretion systems (the type III secretion system and its effector PP_ExoU, and the fish-pathogen-specific type VI secretion system T6SS-1), extracellular products, the flagellar system, metal nutrient acquisition systems, and outer membrane barriers, together with their hierarchical regulatory networks comprising sigma factors, two-component systems, quorum sensing, the second messenger cyclic di-GMP, and small RNAs. We summarize the core functions of these virulence factors and dissect the molecular mechanisms by which this pathogen senses environmental signals and modulates virulence expression, aiming to provide a theoretical basis for the development of novel antivirulence strategies and therapeutic interventions.
This mini-review synthesizes four decades of Mexican fusariosis literature, organizing cases into four clinical categories: ocular, superficial/cutaneous, invasive/disseminated, and central nervous system (CNS) disease. It identified significant gaps in national surveillance, molecular diagnostics, antifungal susceptibility testing, access to effective therapies, specialized mycology infrastructure, and highlights the urgent need for a coordinated clinical mycology network in Mexico. Fusariosis, caused by Fusarium species, presents a broad clinical spectrum, from keratitis and onychomycosis in immunocompetent individuals to disseminated disease in those with hematologic conditions. In Mexico, most reported cases stem from clinical case reviews rather than systematic national surveillance. Exceptions include a 10-year retrospective study published in 2023, and a Fusarium solani meningitis outbreak in Durango and Matamoros during 2022–2023, which together represent the largest global clusters of healthcare-associated fungal meningitis including an antifungal-resistant isolate in Matamoros that required investigational treatments such as Fosmanogepix. Keratitis by Fusarium spp. is the most documented manifestation, with 380 cases reported, most of them in clinical centers for diagnosis in Ciudad de Mexico, where F. solani predominated and ocular trauma was the primary risk factor. Additionally, 49 cases of invasive fusariosis have been reported across six states, mainly linked to burn injuries and hematological malignancies. Collectively, this review provides a national framework for understanding fusariosis and informs future research and public health strategies to address this emerging threat.
The debate between post-treatment Lyme disease syndrome (PTLDS) and chronic Lyme disease (CLD) reflects different views about the causes and treatment of persistent symptoms attributed to Lyme disease, including symptoms that continue after recommended antibiotic treatment. This study examines how competing positions in the controversy draw on different scientific evidence domains, and how findings from those domains are extended into broader clinical and mechanistic claims. We analysed a 2000–2024 literature corpus using a prompt-optimised three-model large language model ensemble to classify abstracts by stance, theme and model-derived study design. We then conducted targeted full-text audits of selected retreatment and treatment-duration trials, and preclinical persistence studies. Across the higher-volume evidence domains, model-derived claim orientations differed by study-design tier. Observational studies and commentaries showed PTLDS-oriented distributions, whereas case reports or series, animal models, and in vitro studies showed CLD-oriented distributions. The smaller RCT and guideline tiers were also PTLDS-oriented, but the small numbers and wide confidence intervals made this direction uncertain. The clinical trial audit showed that some trials reported short-term or symptom-specific improvements, while the interpretation of these findings depended on their durability, endpoint consistency, eligibility criteria, treatment burden, and safety. The citation-conditioned preclinical audit identified findings that support several candidate mechanisms and generate hypotheses for further study, but these findings did not by themselves establish viable infection as the cause of persistent human symptoms or demonstrate the efficacy of prolonged antimicrobial treatment. The findings show a recurring distinction between mechanism-level evidence and the evidence needed to establish patient-level causation or durable clinical benefit. They map how these different forms of evidence are distributed and translated across the PTLDS–CLD literature.
BackgroundEarly identification and precise prognosis of sepsis are of great significance. Traditional biomarkers, such as procalcitonin (PCT) and lactate (Lac), do not reflect the immune dysregulation at the center of sepsis pathophysiology. Interferon - γ -induced protein 10 (IP-10) is an important chemokine for septic immune dysregulation responses and may have good predictive value. Our research aims to establish and validate a clinically applicable nomogram that combines IP-10 and conventional clinical parameters to predict the 28-day mortality in septic patients in the emergency department (ED).MethodsThis study recruited 655 patients who met the criteria of sepsis 3.0 from the ED of Beijing Chao-Yang Hospital from November 2023 to May 2025. A total of 580 patients were analyzed and randomly divided into the training group and the validation group in a 7:3 ratio. The variable selection in this study was conducted using the Least Absolute Shrinkage and Selection Operator (LASSO) regression, and our research employed multivariate logistic regression to determine independent predictors of 28-day mortality. The study scientifically evaluated nomogram using receiver operating characteristic (ROC) curves, calibration plots, Decision Curve Analysis (DCA), and Clinical Impact Curves (CIC).ResultsAmong the 580 patients, the 28-day mortality rate was 12.9% (75 non-survivors). Multivariate analysis identified five independent risk factors: IP-10 (OR = 1.978, 95% CI: 1.964-1.992), Sequential Organ Failure Assessment (SOFA) score (OR = 1.526, 95% CI: 1.365-1.758), Lac (OR = 1.447, 95% CI: 1.281-1.711), PCT (OR = 1.562, 95% CI: 1.341-1.924), and Acute Physiology and Chronic Health Evaluation II (APACHE II) score (OR = 1.658, 95% CI: 1.515-1.840). The nomogram showed excellent discriminatory ability. The area under the curve (AUC) of the training set and validation set was 0.952 (95% CI: 0.930-0.974) and 0.946 (95% CI: 0.911-0.981), respectively. Calibration was satisfactory, and DCA/CIC analyses confirmed that within the risk threshold range, the clinical net benefit was significant.ConclusionIt is the first time to develop and validate a prognostic nomogram model for 28-day mortality based on IP-10 and clinical parameters in septic patients in the ED. This tool may assist clinicians in early risk stratification and clinical decision-making.
The evolutionary origin of vertebrate adaptive immunity has been a longstanding problem in evolutionary biology. The diversified proteins that orchestrate this complex system are present throughout the jawed vertebrates but are absent in extant jawless vertebrates and invertebrates. From work initially carried out in the sea lamprey (Petromyzon marinus) and subsequently extended to other lampreys and hagfishes, we now know that, instead of immunoglobulin domain-based receptors, jawless vertebrates have leucine-rich repeat-based variable lymphocyte receptors (VLRs). Like immunoglobulins (Igs) and T cell receptors (TCRs), these proteins are somatically diversified in lymphocyte-like cells. Of the six VLR loci described in the sea lamprey (VLRA-VLRF), five are expressed exclusively as transmembrane receptors on T-like lymphocytes (VLRA and VLRC-VLRF). Here we focus on VLRB which, like jawed vertebrate immunoglobulins, is expressed both as a cell surface receptor on B-like cells and as a secreted, polyvalent VLRB antibody. Although little is known about the mucosal functions of VLR antibodies, VLRB-expressing cells diversify in gut-associated lymphopoietic tissues and are present in the gut epithelium and other regions of the intestine. We discuss what is known about VLRB and some future directions for understanding its gut-associated functions in relation to what is known in the jawed vertebrates.
BackgroundPulmonary mucormycosis is a life-threatening fungal infection with a mortality rate exceeding 50%, and diabetes mellitus is one of its strongest risk factors. However, the molecular mechanisms linking diabetes to impaired pulmonary innate immunity remain poorly understood.MethodsA streptozotocin-induced type 1 diabetes (T1D) mouse model was used to investigate host responses to intratracheal Cunninghamella bertholletiae infection. Genetic Axl deficiency, pharmacological Axl inhibition with BGB324, histopathological analyses, and ex vivo and in vitro macrophage assays were performed to define the role of the Gas6/Axl axis in antifungal immunity.ResultsT1D mice exhibited rapid mortality after pulmonary C. bertholletiae infection, accompanied by markedly impaired early neutrophil recruitment. Elevated lung and serum levels of growth arrest-specific protein 6 (Gas6) were intrinsic features of the diabetic state and correlated with blood glucose levels. Genetic ablation or pharmacological blockade of Axl restored macrophage chemokine responses, increased neutrophil recruitment into the airspace, reduced fungal burden, and significantly improved survival in T1D mice. Mechanistically, the Gas6/Axl axis directly suppressed fungus-induced chemokine production by alveolar macrophages, establishing a pre-existing state of innate immune hyporesponsiveness before infection.ConclusionsThese findings identify the Gas6/Axl axis as a mechanistic link between diabetes and impaired pulmonary innate immunity. Targeting this pathway may represent a promising host-directed therapeutic strategy for pulmonary mucormycosis in patients with diabetes.
BackgroundSepsis-associated encephalopathy (SAE) is a common complication of sepsis. Its underlying mechanisms remain incompletely understood, and effective treatments are still lacking. Recent studies have shown that the microbiota-gut-brain axis may play a key role in the pathogenesis of SAE, but its potential mechanisms have not yet been clarified.MethodsIn this study, we used a lipopolysaccharide (LPS)-induced zebrafish endotoxemia model and systematically characterized microbiota–gut–brain axis-associated alterations using multi-omics profiling combined with histopathology, behavioral assessment, and blood–brain barrier integrity assays.ResultsOur results showed that LPS exposure induced intestinal inflammation and barrier disruption, neurovascular dysfunction, anxiety-like behavior, and impaired cognitive function in zebrafish. Gut microbiota profiling revealed marked compositional alterations, accompanied by widespread metabolic disturbances in intestinal and brain tissues. Brain transcriptomic analysis showed that the differentially expressed genes were closely associated with the PI3K-Akt signaling pathway, cell adhesion, and autophagy-related pathways. Cross-omics association analyses suggested potential associations among gut microbial dysbiosis, metabolic disturbances, and brain molecular responses.ConclusionThese findings suggest that disruption of the microbiota–gut–brain axis may contribute to LPS-induced SAE-like neurobehavioral abnormalities and provide a basis for further mechanistic and therapeutic studies.
BackgroundLimited by small sample size, single-institution design, and insufficient comprehensive external validation across heterogeneous healthcare systems, no study to date has systematically validated the predictive performance of machine learning models for sepsis occurrence in an intensive care unit (ICU) population with concomitant pulmonary fibrosis through multiple large-scale databases.MethodsThis retrospective multi-database study utilized two large databases to establish and validate a machine learning model for predicting the probability of sepsis occurrence in ICU patients with pulmonary fibrosis. In this study, 542 patients from the MIMIC-IV database were divided into a training set (381 patients) and an internal validation set (161 patients) in a 7:3 ratio, and external validation was performed on the MIMIC-III (186 patients) database. Six machine learning algorithms were employed: Decision Tree (DT), Extreme Gradient Boosting (XGBoost), Logistic Regression (LR), Lightweight Gradient Boosting Machine (LightGBM), Support Vector Machine (SVM), and Artificial Neural Network (ANN). Baseline variables were screened using least absolute shrinkage and selection operator (Lasso) regression to identify potential predictors. The interpretability of the model was evaluated using Shapley Additive Explanations (SHAP) analysis.ResultsThe entire cohort consisted of 728 ICU patients with pulmonary fibrosis. We identified nine consistently crucial clinical characteristics, including gender, dementia, pneumonia, antibiotics, nephrotoxic drugs, glucocorticoids, sequential organ failure assessment (Sofa) score, red blood cell distribution width, and total serum calcium. The ANN algorithm performed optimally, with an area under the curve (AUC) of 0.878 in the training set, 0.837 in the internal validation set, and 0.857 in the MIMIC-III external validation set. SHAP analysis indicated that Sofa was the most influential predictor, followed by antibiotics and pneumonia. Additionally, a web tool was developed to facilitate the prediction of sepsis probability in clinical practice.ConclusionsThis study is the first to develop and validate a machine learning model for predicting sepsis in ICU patients with pulmonary fibrosis across multiple databases. The ANN model, combined with SHAP interpretability, provides a reliable decision-making tool for clinical decision support, and its consistency has been verified in two databases, including our internal validation cohort.
Colorectal cancer (CRC) is one of the most common malignancies worldwide and a leading cause of cancer-related mortality. The gut microbiome has attracted growing attention because of its involvement in CRC initiation and progression, early detection, prognostic evaluation, and therapeutic response. However, CRC microbiome studies continue to face inconsistent findings and limited reproducibility, partly because of differences in specimen type. Directly comparing microbial signals from fecal, mucosal, and intratumoral samples may therefore bias mechanistic interpretation and mislead clinical translation. From a spatial-niche perspective, this review summarizes the distinct characteristics, formation mechanisms, interrelationships, and clinical implications of fecal, mucosal, and intratumoral microbiota during CRC progression. We further propose a “seed bank–colonizers–specialized populations” model to conceptualize the continuous but non-equivalent hierarchy among these niches. By providing a clearer spatially stratified framework, this review aims to help move CRC microbiome research beyond descriptive associations toward precision-oriented applications supported by mechanistic interpretability, reproducible evidence, and clinical translatability.
Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb). As primary host cells targeted by Mtb, macrophages play central roles in both innate and adaptive immunity. Accumulating evidence indicates that macrophage polarization is a key determinant of tuberculosis pathogenesis. In response to diverse microenvironmental cues, macrophages adopt functionally distinct polarization states, ranging from pro-inflammatory, microbicidal programs (M1-like) to anti-inflammatory, tissue-reparative programs (M2-like). These states differentially shape tuberculosis progression. Defining the remodeling of these context-dependent macrophage states is therefore critical for understanding Mtb infection, granuloma formation, and disease outcomes, as well as for guiding the development of next-generation vaccines, immunotherapies, and host-directed interventions. This Review synthesizes the molecular mechanisms underlying macrophage polarization during Mtb infection, integrates the bidirectional regulatory networks between pathogen-derived and host-derived factors, and highlights their roles in immune evasion, granuloma biology, and emerging therapeutic strategies in tuberculosis.
IntroductionMosquitoes (Diptera: Culicidae) are primary vectors of public health pathogens, yet their core viromes remain poorly characterized, particularly in Neotropical sylvatic lineages. This study investigated the RNA virome of multiple mosquito species across urban-to-forest gradients in São Paulo State, Brazil, including neglected sylvatic taxa such as Sabethes, Psorophora, Shannoniana, and Wyeomyia.MethodsThe RNA virome of multiple mosquito species was investigated across urban-to-forest gradients in São Paulo State, Brazil. Ecological analyses were performed to assess the effects of host taxonomy and environment on virome composition. Network analysis was conducted to investigate virus–host associations and viral sharing across ecological interfaces.ResultsOur analysis identified 919 viral contigs across 217 viral species and 37 distinct families, revealing a substantial fraction of “viral dark matter” with low amino acid identity (median < 40%) in predominantly sylvatic mosquito species. Although viral families containing known arboviruses, such as Flaviviridae, Phenuiviridae, and Peribunyaviridae, were detected, no high-consequence human pathogens were identified within the sensitivity limits of our sampling and sequencing depth. Ecological analyses demonstrated that virome composition was strongly structured by host taxonomy and environment (R2=0.570, p=0.001), with host species explaining 32.9% of the unique variance (PERMANOVA, R2=0.329, p=0.001), whereas ecotope played a secondary role (R2=0.029, p=0.001). Network analysis revealed a highly modular virus–host structure dominated by host-restricted specialists, with a limited number of bridge species facilitating viral sharing across ecological interfaces.DiscussionThese findings indicate that intrinsic mosquito biology is the main driver of viral community structure, while environmental gradients play a secondary role, and highlight the importance of host-associated processes in shaping viral diversity at the Neotropical forest–urban interface.
IntroductionKlebsiella pneumoniae is the most frequently encountered multidrug-resistant bacterial pathogen in humans, but its pathogenic effects on aquatic animals are not well documented. K. pneumoniae has recently been identified as a significant cause of death and illness in American bullfrogs (Rana catesbeiana). In the present study, the dominant bacteria were isolated from a diseased bullfrog with neurological signs in Hanchuan, Hubei Province, China.MethodsThe ZYRC75 isolate was identified by Gram staining, morphological observations, biochemical assays and 16S rRNA sequencing. Antimicrobial susceptibility testing and artificial infection testing were conducted to determine its resistance phenotype and pathogenicity. The whole genome of the ZYRC75 strain was also sequenced.ResultsThe isolate ZYRC75 was identified as K. pneumoniae and assigned to ST6839, a novel sequence type. It displayed multidrug resistance against penicillins (carbenicillin, piperacillin, ampicillin, penicillin), chloramphenicol, trimethoprim and tetracycline. Infection experiments confirmed the isolate exhibited significant pathogenicity in bullfrogs. ZYRC75 possessed a single circular chromosome of 5,454,922 bp, carrying 179 virulence‑related genes and 157 antimicrobial‑resistance genes.DiscussionThis investigation presents a detailed phenotypic and genomic profile of ZYRC75, revealing its antimicrobial resistance and virulence, and establishing a basis for future studies on the pathogenicity of K. pneumoniae.
BackgroundGut microbiota dysbiosis has been implicated in osteoarthritis (OA) through the gut–joint axis, but the clinical efficacy of gut microbiota-targeted interventions remains unclear. This systematic review and meta-analysis evaluated the effects of these interventions on clinical outcomes and inflammatory biomarkers in OA.MethodsPubMed, Embase, Web of Science, CNKI, and Wanfang were searched from inception to 20 January 2026 for randomized controlled trials (RCTs) of probiotics, prebiotics, synbiotics, or dietary modification in adults with OA. Primary outcomes were visual analog scale (VAS) pain, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, WOMAC function, and WOMAC total score; secondary outcomes included WOMAC stiffness, body weight, knee flexion angle, cartilage oligomeric matrix protein (COMP), high-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), interleukin (IL)-1β, and IL-6. Standardized mean differences (SMDs) with 95% CIs were pooled using random-effects models; risk of bias was assessed with RoB 2.0. Subgroup analyses, univariable meta-regression, trial sequential analysis (TSA), and GRADE were used to grade certainty.ResultsEighteen RCTs (2,080 participants) were included. Interventions reduced VAS pain (SMD = −0.66, 95% CI: −1.27 to −0.06, P = 0.03), WOMAC pain (SMD = −0.62, 95% CI: −0.97 to −0.27, P = 0.004), WOMAC function (SMD = −0.40, 95% CI: −0.64 to −0.17, P = 0.0006), and WOMAC total score (SMD = −0.78, 95% CI: −1.26 to −0.30, P = 0.009) and lowered hs-CRP, ESR, and IL-1β. WOMAC stiffness, WOMAC physical function, body weight, knee flexion angle, COMP, and IL-6 did not differ significantly. All 18 trials were rated “some concerns” overall on RoB 2.0. Probiotics showed larger effects than dietary interventions, with appreciable residual heterogeneity. Information accrual reached the required size only for WOMAC pain and WOMAC function; VAS pain, WOMAC total score, and hs-CRP were promising but not yet conclusive. GRADE certainty ranged from high (WOMAC function) to very low (VAS pain); unchanged COMP indicates no support for cartilage protection or disease modification.ConclusionGut microbiota-targeted interventions, particularly probiotics, may improve pain, physical function, and systemic inflammation in OA. The evidence is compatible with symptomatic benefit but does not support cartilage protection or disease modification. Because certainty ranges from high to very low and information accrual is incomplete for most outcomes, these findings are provisional pending larger standardized RCTs.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/home, identifier CRD42023472181.
IntroductionImmune checkpoint inhibitors (ICIs) have transformed the management of microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) colorectal cancer (CRC). However, a substantial proportion of patients exhibit primary resistance or eventually develop acquired resistance, highlighting the need for a better understanding of the biological mechanisms influencing therapeutic response. Increasing evidence suggests that the gut microbiome–immune axis is an important regulator of antitumor immunity through complex interactions among microbial communities, microbial metabolites, host immunity, and the tumor microenvironment.Main bodyThis narrative review summarizes current evidence regarding the role of the gut microbiome–immune axis in mediating primary and acquired resistance to immune checkpoint inhibition in MSI-H/dMMR CRC. We discuss the physiological interactions that maintain immune homeostasis and review the functional mechanisms through which alterations in microbial metabolic pathways, including short-chain fatty acids, bile acids, tryptophan-derived metabolites, inosine, and polyamines, may influence antitumor immune responses. We further examine microbial composition and functional biomarkers associated with immune checkpoint inhibitor response, together with emerging therapeutic strategies aimed at modulating the gut microbiome–immune axis, including dietary interventions, prebiotics, probiotics, selective antimicrobial approaches, fecal microbiota transplantation, live biotherapeutic products, and next-generation precision microbiome engineering. Finally, we discuss current translational challenges and future research priorities required for successful clinical implementation.ConclusionThe gut microbiome–immune axis represents a promising area of investigation for understanding resistance to immune checkpoint inhibition in MSI-H/dMMR CRC. While growing evidence supports its biological relevance, much of the current knowledge remains preclinical or is derived from early-phase clinical studies. Future progress will depend on mechanistic investigation, longitudinal multi-omic microbiome profiling, standardized methodologies, prospective biomarker validation, and the rational development of microbiome-directed therapeutic strategies to support precision immuno-oncology.
