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PubMed2025

Alterations of gut microbiome in chronic rhinosinusitis: insights from a mendelian randomization study.

OBJECTIVE: Gut microbiome dysbiosis is associated with various diseases. Causal association between Chronic Rhinosinusitis (CRS) and gut microbiome is yet unknown. This study aimed to investigate the potential causal relationship between CRS and gut microbiome dysbiosis. METHODS: We used Genome-Wide Association Study (GWAS) data from FinnGen database for CRS. The Dutch Microbiome Project study provided data on gut microbiota species. A total of 334,182 individuals were included. Two-sample bidirectional Mendelian Randomization (MR) analysis was used to investigate causal relationship between CRS and gut microbiome. The main methods of evaluation were Inverse Variance Weighting (IVW), weighted median, weighted mode, and MR-Egger regression. Sensitivity analyses were performed to assess heterogeneity and pleiotropy. RESULTS: Forward MR analysis indicated CRS is potentially linked to decreased risk of Haemophilus parainfluenzae (OR = 0.79, 95% CI 0.66‒0.94, p = 0.009) and increased risk of Bilophila's (OR = 1.14, 95% CI 1.02-1.27, p = 0.023) within the gut. Reduced risks in gut microbiota-related pathways like UDP-N-acetyl-d-glucosamine biosynthesis I (OR = 0.85, 95% CI 0.77‒0.94, p = 0.002) and increased risk in pathway NAD biosynthesis I from aspartate (OR = 1.14, 95% CI 1.03-1.27, p = 0.010) were also linked to CRS. Reverse MR analyses, we obtained no positive results (p > 0.05/412). CONCLUSION: This study reveals CRS exerts a causal impact on shifts within the composition of the gut microbiome and also links to the changes of gut microbiota-related metabolic pathways. The risk of changes in gut microbiota should be of greater concern in patients with CRS than in the general population. LEVEL OF EVIDENCE: Mendelian Randomized (MR) studies are second only to randomized controlled trials in terms of the level of evidence.

Humans↗

PubMed2026

Impacts of host genetics on gut microbiome composition in Alzheimer's disease.

BACKGROUND: Host-microbiome interactions play essential roles in the development of Alzheimer's disease (AD), yet the host genetic impacts on gut microbial alterations in AD remain poorly understood. RESULTS: Here, we simultaneously profiled host genotype and gut microbiome in 252 Chinese individuals with varying degrees of cognitive disability. Using the latent Dirichlet allocation topic model, we identified the Anaerostipes-enriched enterosignature (ES-Ana) at the microbial subgroup level as significantly negatively associated with cognitive disability, which could be recapitulated in external cohorts. With the whole-genome sequencing data, we performed microbiome genome-wide association studies for the ES-Ana relative abundance. We prioritized 41 lead genetic variants and confirmed that the high ES-Ana relative abundance showed a negative correlation with the polygenic risk score of AD, indicating its protective effect against AD. Furthermore, we identified 174 ES-Ana-associated genes, which are enriched in AD-related biological functions and phenotypes, and exhibite pervasive underexpression in glial cells during brain aging. CONCLUSIONS: In summary, our study reveals the complex genetic effects on the gut microbiota in AD, and provides novel evidence for the roles of the gut-brain axis in AD. Video Abstract.

Alzheimer Disease↗

PubMed2025

Microbiota and kidney disease: the road ahead.

More than 850 million individuals worldwide, accounting for 10-15% of the adult population, are estimated to have chronic kidney disease. Each of these individuals is host to tens of trillions of microorganisms that are collectively referred to as microbiota - a dynamic ecosystem that both influences host health and is itself influenced by changes in the host. Available evidence supports the existence of functional connections between resident microorganisms and kidney health that are altered in the context of specific kidney diseases, including acute kidney injury, chronic kidney disease and renal stone disease. Moreover, promising data from preclinical studies suggest that targeting of gut microbial pathways may provide new therapeutic opportunities for the treatment of kidney disease. This Roadmap describes current understanding of the mechanisms by which microorganisms regulate host organ function, the effects of kidney disease on the gut microbiome, and how these insights may contribute to the development of microbe-targeted therapeutics. We highlight key knowledge gaps that remain to be addressed and strategies for addressing these, outlining both the promise and the potential pitfalls of leveraging our understanding of the gut microbiota to better understand and treat kidney disease.

Humans↗

PubMed2025

New evidence for the protective effect of gut microbiota regulation of ferroptosis-related proteins against osteoporosis.

Osteoporosis (OP), characterized by bone degradation and increased fracture susceptibility, constitutes a significant global health burden. Recent findings implicate gut microbiota and ferroptosis in the regulation of bone metabolism; however, causal evidence for the gut microbiota's influence on OP specifically via ferroptosis regulation remains to be established. This study employed two-sample Mendelian randomization (MR) using genome-wide association study (GWAS) summary statistics to investigate these causal relationships and delineate mediating pathways.We assessed causal links between gut microbiota, ferroptosis-related proteins, and OP risk. Associations for gut microbiota abundance and ferroptosis-related proteins were derived from GWAS data and Icelandic blood-derived protein quantitative trait loci, respectively. Outcome data for OP were obtained from the FinnGen Release R12. The primary analysis utilized the inverse variance weighted (IVW) method, supplemented by sensitivity analyses to evaluate heterogeneity and horizontal pleiotropy.  MR analysis identified 33 gut microbial taxa causally associated with OP risk: 13 protective and 20 detrimental. Similarly, 34 ferroptosis-related proteins were categorized as protective (18) or detrimental (16) for OP. Mediation analysis revealed that the protective effect of Terrisporobacter othiniensis on OP is partially mediated by the ferroptosis regulator MDM4 (indirect effect β = -0.020, 95% CI: -0.068 to 0.029), accounting for 6.8% of the total effect. Sensitivity analyses showed no significant evidence of heterogeneity or horizontal pleiotropy. This study provides the first genetically validated evidence supporting a causal relationship between specific gut microbiota, ferroptosis-associated proteins, and OP susceptibility. Specifically, Terrisporobacter othiniensis demonstrates a novel protective mechanism, modulating OP risk partly through the ferroptosis regulator MDM4. These findings broaden understanding of the "gut-bone axis" and highlight the gut microbiota-ferroptosis pathway, particularly the MDM4/p53 axis, as a promising target for novel OP prevention and therapeutic strategies.

Ferroptosis↗

PubMed2025

Mendelian randomization and FinnGen analysis of the causal relationship between 473 gut microbiota species and chronic sinusitis.

OBJECTIVE: To investigate the causal associations between Gut Microbiota (GM) and Chronic Sinusitis (CRS) using Mendelian Randomization (MR). METHODS: Genome-Wide Association Study (GWAS) summary statistics for 473 GM taxa were obtained from MiBioGen consortium. CRS data (22,099 cases vs. 371,520 controls) were sourced from the FinnGen R12 cohort. Causal effects were estimated via Inverse Variance-Weighted (IVW), MR-Egger, weighted median, and Bayesian-weighted MR methods. Sensitivity analyses (heterogeneity and horizontal pleiotropy tests) were performed to validate robustness. RESULTS: IVW analysis identified 20 GM taxa significantly associated with CRS risk (p < 0.05). Of these, 7 taxa (e.g., Francisellales, Roseibacillus, Merdibacter massiliensis) exhibited risk-increasing effects, while 13 taxa (e.g., Firmicutes I, Succinivibrionaceae) showed protective effects. Sensitivity analyses confirmed the absence of significant heterogeneity (Cochran's Q p > 0.05) or pleiotropy (MR-Egger intercept p > 0.05). Bayesian-weighted MR validated 18 causal relationships (posterior probability > 95%), except for RUG420 sp900317985 and UBA7703 (non-significant). CONCLUSIONS: This MR study provides genetic evidence supporting causal roles of specific GM taxa in CRS pathogenesis. These findings highlight the gut-sinus axis as a potential therapeutic target and underscore the utility of large-scale biobanks (e.g., FinnGen) in advancing precision medicine. LEVEL OF EVIDENCE: Level 5. Mendelian Randomized (MR) studies are second only to randomized controlled trials in terms of the level of evidence.

Humans↗

PubMed2024

Pangenomes of human gut microbiota uncover links between genetic diversity and stress response.

The genetic diversity of the gut microbiota has a central role in host health. Here, we created pangenomes for 728 human gut prokaryotic species, quadrupling the genes of strain-specific genomes. Each of these species has a core set of a thousand genes, differing even between closely related species, and an accessory set of genes unique to the different strains. Functional analysis shows high strain variability associates with sporulation, whereas low variability is linked with antibiotic resistance. We further map the antibiotic resistome across the human gut population and find 237 cases of extreme resistance even to last-resort antibiotics, with a predominance among Enterobacteriaceae. Lastly, the presence of specific genes in the microbiota relates to host age and sex. Our study underscores the genetic complexity of the human gut microbiota, emphasizing its significant implications for host health. The pangenomes and antibiotic resistance map constitute a valuable resource for further research.

Humans↗

PubMed2025

Investigation of associations between the neonatal gut microbiota and severe viral lower respiratory tract infections in the first 2 years of life: a birth cohort study with metagenomics.

BACKGROUND: Early-life gut microbiota affects immune system development, including the lung immune response (gut-lung axis). We aimed to investigate whether gut microbiota composition in neonates in the first week of life is associated with hospital admissions for viral lower respiratory tract infections (vLRTIs). METHODS: The Baby Biome Study (BBS) is a prospective birth cohort, which enrolled mother-baby pairs between Jan 1, 2016, and Dec 31, 2017, at three UK hospitals. In the present study, we only included BBS babies with a sequenced first-week stool sample and successful data linkage. Stool was collected in the first week of life for shotgun-metagenomic sequencing. We examined the following microbiota features: alpha diversity (Chao1, Shannon, and Simpson indices) and community structures (cluster-partitioning against medoids method). The participants were followed up through linkage to the Hospital Episode Statistics-Admitted Patient Care (HES-APC) database to determine vLRTI hospital admission incidence in the first 2 years of life. We used Poisson mixed-effects models for univariable and multivariable analyses to evaluate the association between microbiota features and vLRTI hospital admission incidence, adjusting for confounders identified through direct acyclic graphs. FINDINGS: 3305 (95%) of the 3476 BBS-enrolled babies for whom consent to data linkage was obtained were included in the present study. 1111 (34%) babies had a first-week sequenced stool sample, of whom 1082 (97%; 564 born vaginally and 518 born by caesarean section) were successfully linked to HES-APC, and had median follow-up of 2·0 years (IQR 1·4-2·9). Most babies were born at term (996 [92%] ≥37 weeks gestational age and 1070 [99%] >35 weeks gestational age) and healthy (1050 [97%] had no comorbidities), and 520 (48%) were female and 562 (52%) were male. Higher first-week gut microbiota alpha diversity was associated with reduced rates of vLRTI hospital admission (Chao1 Index adjusted hazard ratio [HR] 0·92 [95% CI 0·85-0·99]; Shannon Index adjusted HR 0·57 [0·33-0·98]; and Simpson Index adjusted HR 0·36 [0·11-1·20]). Three microbiota clusters were identified. Cluster 1 had a mixed composition and cluster 2 was dominated by Bifidobacterium breve, with both clusters observed in babies born vaginally and by caesarean section. Cluster 3 was found only in vaginally born babies and was dominated by Bifidobacterium longum. Having cluster 1 (mixed) or cluster 2 (B breve dominated) was independently associated with increased rates of vLRTI hospital admission compared with cluster 3 (B longum dominated; cluster 1 [mixed] 3·05 [1·25-7·41] and cluster 2 [B breve dominated] 2·80 [1·06-7·44]). INTERPRETATION: We report observational evidence that first-week gut microbiota differences are associated with clinically severe vLRTI in young children. This study identified bacterial species that could be of interest for vLRTI prevention. This finding has important implications for the design of future research and intervention strategies. FUNDING: The Wellcome Trust and Wellcome Sanger Institute core funding.

Humans↗

PubMed2026

Ferroptosis as a mediator of gut microbiota-driven inflammatory bowel disease: Evidence from genetic analyses.

Gut microbiota dysbiosis is increasingly recognized as a contributor to inflammatory bowel disease (IBD), yet causal relationships and underlying mechanisms remain unclear. Ferroptosis, an iron-dependent form of regulated cell death, plays a key role in epithelial barrier damage and inflammation. This study aimed to determine whether specific gut microbial taxa are causally associated with IBD and whether ferroptosis-related genes mediate this association using Mendelian randomization (MR). Two-sample MR and mediation MR analyses were performed using genome-wide association study summary data from the FinnGen consortium (IBD), the genome-wide association study catalog (473 gut microbial taxa), and the deCODE database (ferroptosis-related genes). Instrumental variables were selected with thresholds of P < 1 × 10-6 for microbes and P < 5 × 10-8 for traits, and linkage disequilibrium clumping (r2 < 0.001) was applied. Twenty-three microbial taxa showed significant causal associations with IBD (e.g., Chromatiales, OR = 0.51; Acetobacterales, OR = 2.61). Several ferroptosis-related genes were linked to IBD risk (e.g., GPX4, STAT3, IDO1). Mediation MR revealed that genes such as MUC1, IDO1, and ADAM23 partially mediated microbial effects on IBD, with mediation proportions up to 7.6%. This study provides novel genetic evidence supporting a gut microbiota-ferroptosis-IBD axis. Ferroptosis-related pathways may partially mediate microbial effects on IBD pathogenesis and represent promising targets for future therapeutic interventions.

Ferroptosis↗

PubMed2025

The Aggregated Gut Viral Catalogue (AVrC): A unified resource for exploring the viral diversity of the human gut.

The growing interest in the role of the gut virome in human health and disease, has led to several recent large-scale viral catalogue projects mining human gut metagenomes each using varied computational tools and quality control criteria. Importantly, there has been to date no consistent comparison of these catalogues' quality, diversity, and overlap. In this project, we therefore systematically surveyed nine previously published human gut viral catalogues. While these catalogues collectively screened >40,000 human fecal metagenomes, 82% of the recovered 345,613 viral sequences were unique to one catalogue, highlighting limited redundancy between the ressources and suggesting the need for an aggregated resource bringing these viral sequences together. We further expanded these viral catalogues by mining 7,867 infant gut metagenomes from 12 large-scale infant studies collected in 9 different countries. From these datasets, we constructed the Aggregated Gut Viral Catalogue (AVrC), a unified modular resource containing 1,018,941 dereplicated viral sequences (449,859 species-level vOTUs). Using computational inference tools, annotations were obtained for each vOTU representative sequence quality, viral taxonomy, predicted viral lifestyle, and putative host. This project aims to facilitate the reuse of previously published viral catalogues by the research community and follows a modular framework to enable future expansions as novel data becomes available.

Humans↗

PubMed2026

The Mediating Role of Immune Cells in the Genetically Predicted Relationship between Gut Microbiota and Puerperal Sepsis: A Mendelian Randomization Study.

INTRODUCTION: The causal relationship between gut microbiota and puerperal sepsis (PS) remains unclear, and there is a lack of in-depth research regarding the potential mediating role of immune cells in this context. OBJECTIVE: This study aims to investigate the causal relationship between gut microbiota and PS using Mendelian randomization (MR) analysis and to assess the mediating effects of immune cells on the risk of PS onset through mediation analysis. MATERIALS AND METHODS: We selected data from large-scale genome-wide association studies (GWAS) involving 473 gut microbiota species, 731 immune cell phenotypes, and PS datasets. Univariate MR (UVMR) analysis was employed to explore the causal relationship between gut microbiota and PS, with the primary statistical method being inverse variance weighting (IVW). Multiple statistical models were applied for sensitivity analysis to minimize the confounding effects of horizontal pleiotropy and heterogeneity. Subsequently, a two-step mediation MR analysis was conducted to evaluate whether immune cells mediate the relationship between gut microbiota and PS. RESULTS AND DISCUSSION: Analysis using various statistical models indicated that 11 gut microbiota species (e.g., Azorhizobium, Bacillus velezensis, CAG-245 sp000435175, Lentimicrobiaceae, and Providencia) exhibited a causal relationship with PS. Further reverse causal analysis between PS and gut microbiota ruled out the possibility of reverse causality. The two-step mediation MR analysis demonstrated that the percentage of IgD-CD27- B cells (10.26%) and CD62L- monocytes (17.29%) partially mediated the effect of CAG-245 sp000435175 on PS risk. CONCLUSION: This study provides evidence of a causal relationship between the abundance of certain gut microbiota species and PS, while also revealing a potential mediating role of immune cells. These findings offer valuable theoretical insights into personalized treatment strategies and the development of novel diagnostic biomarkers for PS.

Humans↗

PubMed2026

Gut Microbiota, Lipidome, and Metabolites Mediate Immune Dysregulation in Diabetic Microvascular Disease: A Two-sample Mendelian Randomization and Mediation Analysis.

INTRODUCTION: Diabetic microvascular disease (DMiVD) involves dysregulated immune cell function, but the precise pathogenic mechanisms remain unclear. MATERIALS AND METHODS: We conducted a two-sample Mendelian randomization (MR) study using comprehensive GWAS and FinnGen summary statistics, encompassing 731 immune cell phenotypes, 473 gut microbial taxa, 91 inflammatory proteins, 179 lipid types, 1,400 plasma metabolites, 20 micronutrients, and DMiVD cases. The analysis aimed to evaluate causal associations between these variables and DMiVD. We further explored potential mediating roles of gut microbiota, plasma lipidome, and metabolites using mediation analysis, with multiple sensitivity tests confirming the robustness of our findings. RESULTS: We identified 20 immune cell phenotypes, 33 gut microbial taxa, 31 lipid types, and 83 plasma metabolites with significant causal associations with DMiVD. Mediation analysis revealed that the risk effect of CD3+ resting Tregs on diabetic nephropathy was partly mediated by phosphatidylcholine (16:0_18:2) (10.7%). Additionally, the protective effect of CX3CR1 on monocytes against DMiVD was partly mediated by Unclassified Bacilli A (35%), Species CAG-177 sp003538135 (22.6%), and triacylglycerol (52:6) (25.5%). DISCUSSION: These findings advance understanding of DMiVD pathogenesis, highlighting that modulation of key metabolic pathways and immune regulatory nodes may represent promising therapeutic strategies. Further experimental studies are needed to validate these potential causal relationships. CONCLUSION: Using causal inference approaches, this study identifies immune cell-mediated mechanisms underlying DMiVD, involving gut microbiota, plasma lipids, and metabolites. The results suggest potential intervention targets for mechanistic studies and therapeutic development.

Mendelian Randomization Analysis↗

PubMed2025

Characterization of gut microbiota signatures in Indian preterm infants with necrotizing enterocolitis: a shotgun metagenomic approach.

INTRODUCTION: Necrotizing enterocolitis (NEC) is an inflammatory bowel disease that primarily affects preterm infants. Predisposing risk factors for NEC include prematurity, formula feeding, anemia, and sepsis. To date, no studies have investigated the gut microbiota of preterm infants with NEC in India. METHOD: In the current study, shotgun metagenomic sequencing was performed on fecal samples from premature infants with NEC and healthy preterm infants (n = 24). Sequencing was conducted using the NovaSeq X Plus platform, generating 2 × 150 bp paired-end reads. The infants were matched based on gestational age and postnatal age. RESULT: The median time to NEC diagnosis was 9 days (range: 1-30 days). Taxonomic analysis revealed a high prevalence of Enterobacteriaceae at the family level, with the genera Klebsiella and Escherichia particularly prominent in neonates with NEC. No statistically significant differences in alpha or beta diversity were observed between stool samples from infants with and without NEC. Linear regression analysis demonstrated that Enterobacteriaceae were significantly more abundant in stool samples from infants with NEC than without NEC (q < 0.05). Differential abundance analysis using Linear Discriminant Analysis Effect Size (LEfSe) identified Klebsiella pneumoniae and Escherichia coli as enriched in the gut microbiota of preterm infants with NEC. Functional analysis revealed an increase in genes associated with lipopolysaccharide (LPS) O-antigen, the type IV secretion system (T4SS), the L-rhamnose pathway, quorum sensing, and iron transporters, including ABC transporters, in stool samples from infants with NEC. CONCLUSION: The high prevalence of Enterobacteriaceae and enrichment of LPS O-antigen and T4SS genes may be associated with NEC in Indian preterm infants.

Humans↗

PubMed2026

From sequence space to ecological function: microbiome-derived antimicrobial peptides as community effectors and therapeutic leads.

Antimicrobial peptide research has long centred on host defence molecules, yet microbiomes themselves encode a diverse and increasingly important repertoire of peptide-based antimicrobials. These microbiome-derived antimicrobial peptides include bacteriocins, ribosomally synthesised and post-translationally modified peptides, cryptic short open reading frame-encoded peptides, embedded antimicrobial regions within larger proteins, and selected peptide antibiotics recovered from human, animal, plant and environmental microbiomes. Recent advances in genome mining, metagenomics, and machine learning have greatly expanded the scale of discovery, moving the field from a handful of landmark exemplars to large candidate catalogues spanning the global microbiome. In the clearest cases, these molecules are not only anti-infective leads but ecological effectors: they mediate microbial competition, enforce colonisation resistance, and influence community structure within densely occupied niches. The present review synthesises the field across discovery classes, microbiome sources, ecological roles, and translational bottlenecks, emphasizing a central limitation of the field: candidate catalogues are expanding at extraordinary scale, while evidence for native expression, producer assignment, ecological function, and in vivo relevance remains limited for the vast majority of predicted molecules. Progress will depend on workflows that connect sequence level prediction to biological context through expression support, producer assignment, community level validation, and perturbation-based approaches that distinguish ecological association from causal function. Microbiome-derived antimicrobial peptides are best understood not only as promising therapeutic leads, but also as molecular mediators of microbial social life whose ecological origins are central to their interpretation and future application.

Microbiota↗

PubMed2026

Benchmarking of Reference-Based Tools for Strain-Level Resolution of Plant Microbiome.

Strain-level identification of each microbe is crucial for understanding its role in the host. Most of the existing tools have primarily been evaluated on human metagenomic datasets, whereas the plant microbiome exhibits greater diversity and complexity and thus poses a challenge in the strain-level resolution of individual microbes. In this study, we conducted a comprehensive benchmarking of available reference-based tools for strain-level resolution of the plant microbiome. We evaluated seven tools on various performance parameters, like computational requirements, F1-score and relative abundances using synthetic datasets comprising microbes known to have strong associations with plants as well as real plant microbiome datasets. Our results demonstrated a better performance of StrainScan on the synthetic data, achieving higher F1-score and more accurate relative abundance estimates as compared to other tools, but its performance declined gradually with increasing strain diversity. However, StrainGE and StrainScan exhibited competitive performance on real plant metagenome data. Overall, though StrainGE exhibited better performance, it was more computationally expensive. However, StrainScan performed better in detecting low-abundance strains. Our findings suggest the comparative suitability of the available tools for the strain-level analysis of plant metagenome data and highlight the need for the development of more efficient and accurate taxonomic classifiers capable of handling the complex plant metagenome data while maintaining computational efficiency.

Microbiota↗

PubMed2025

Clostridium scindens: history and current outlook for a keystone species in the mammalian gut involved in bile acid and steroid metabolism.

Clostridium scindens is a keystone bacterial species in the mammalian gut that, while low in abundance, has a significant impact on bile acid and steroid metabolism. Numerous studies indicate that the two most studied strains of C. scindens (i.e. ATCC 35704 and VPI 12708) are important for a myriad of physiological processes in the host. We focus on both historical and current microbiological and molecular biology work on the Hylemon-Björkhem pathway and the steroid-17,20-desmolase pathway that were first discovered in C. scindens. Our most recent analysis now calls into question whether strains currently defined as C. scindens represent two separate taxonomic groups. Future directions include developing genetic tools to further explore the physiological role of bile acid and steroid metabolism by strains of C. scindens and the causal role of these pathways in host physiology and disease.

Bile Acids and Salts↗

PubMed2025

Leveraging chemical synthesis to discover metabolites from the gut microbiome.

The gut microbiome has the biosynthetic potential to make a variety of secondary metabolites or natural products, which serve as molecular messages between cells and organisms. These chemical signals are capable of affecting physiology and behavior in real time, and are, therefore, bioactive and can exhibit medicinal properties including anticancer, antimicrobial, or immunomodulating activities. It is clearly important to identify signaling molecules in the human gut, but elucidating their chemical structures can be challenging since traditional isolation methods are typically not available. The discovery of microbiome-related metabolites requires multidisciplinary collaboration, where chemical synthesis often plays an essential role. This review highlights examples where synthetic chemistry was used to study novel metabolites produced by the gut microbiota. In the first part, we describe examples where organic synthesis was utilized in traditional contexts, as a last step for validating structures and sourcing material for biological testing. The final section of this review discusses next-generation applications for chemical synthesis, where integration with metabolomic or genomic analysis simultaneously uncovers both structural and biological information about small molecules from the gut.

Gastrointestinal Microbiome↗

PubMed2026

Integrated immunoinformatics for the design of novel multi-epitope vaccine and identification of new drug targets against Stenotrophomonas maltophilia, a multidrug-resistant superbug.

BACKGROUND: Stenotrophomonas maltophilia is a multidrug-resistant opportunistic pathogen causing severe hospital-acquired infections, especially in immunocompromised patients. The absence of an effective vaccine and rising antibiotic resistance underscore the need for novel interventions. This study employed an integrated reverse vaccinology and computational analyses to identify new immunogenic targets, design a multi-epitope vaccine (MEV), and propose potential drug targets. METHODS: A comprehensive immunoinformatics pipeline was employed to assess antigenicity, allergenicity, human similarity, and physicochemical properties of S. maltophilia proteins. Both B- and T-cell epitopes were screened; however, only the top B-cell epitopes were selected for MEV construction, given the extracellular nature of S. maltophilia. MEV-TLR interactions were analyzed through molecular docking and dynamics simulations. In parallel, cytoplasmic proteins were screened via a subtractive genomics approach to identify essential, non-human homologous, and non-microbiome-similar proteins, which were further evaluated for druggability and interaction networks to propose novel therapeutic targets. RESULTS: From a total of 4111 proteins, seven potential immunogenic targets were identified: GspD (WP_108270537.1), FhuE (WP_049451370.1), fimbrial protein (WP_012479122.1), TonB-dependent receptor (WP_169448402.1), TolC family protein (WP_108270106.1), autotransporter beta-barrel OMP (WP_169448945.1), and a hypothetical protein (WP_005407892.1). Subsequently, an MEV was designed using five immunogenic epitopes derived from four of these targets: WP_005407892.1 (ADQDSSNM), WP_049451370.1 (SGKAEQ and GEESKTPS), WP_108270537.1 (GVTSTQSDSERT), and WP_169448945.1 (RELGGDRNE). Molecular docking and molecular dynamics simulations demonstrated strong, stable, and feasible interactions between the MEV and TLR-2 and TLR-4 receptors. Moreover, nine novel drug targets were predicted for S. maltophilia, providing new therapeutic insights. CONCLUSION: The designed MEV and identified immunogenic targets represent promising vaccine candidates against S. maltophilia. Further in vitro and in vivo studies are essential to confirm their safety, immunogenicity, and protective efficacy. Additionally, subtractive genomics analysis revealed nine novel, non-homologous drug targets, offering safer and more specific therapeutic avenues.

Drug targets↗

PubMed2002

The host-microbe interface within the gut.

Colonization with bacteria is critical for the normal structural and functional development and optimal function of the mucosal immune system. Unrestrained mucosal immune activation in response to bacterial signals from the lumen is, however, a risk factor for inflammatory bowel disease. Therefore, mucosal immune responses to indigenous flora require precise control and an immunosensory capacity for distinguishing commensals from pathogens. The use of germ-free animal models with selective colonization strategies combined with modern molecular techniques promises to clarify the molecular signals responsible for host-flora interactions in health and disease. At least half of the resident flora cannot be cultured by conventional techniques but are identifiable by molecular methods. Collectively, the resident flora represent a virtual organ with a metabolic activity in excess of the liver and a microbiome in excess of the human genome. An improved understanding of this hidden organ holds secrets relevant to several infectious, inflammatory and neoplastic disease mechanisms.

Animals↗