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PubMed2025

Microbiome therapeutic PMC101 inhibits the translocation of carbapenem-resistant Klebsiella while enhancing eubiosis in antibiotic-induced dysbiosis mice.

Carbapenem-resistant Enterobacteriaceae (CRE), known for their extensive antibiotic resistance, pose a severe global medical threat. Therefore, developing novel therapeutics beyond conventional antibiotics is urgently needed, and the importance of microbiome therapeutics is increasingly being recognized. This study explores the expanded systemic efficacy of PMC101, a microbiome therapeutic, beyond intestinal CRE infections and investigates its mechanism of action from a microbiome perspective. First, the genetic characteristics of the novel strain were identified through whole-genome analysis, and a scalable cultivation process was established as part of the overall development of this microbiome therapeutic. PMC101 increased the survival rate to 100%, significantly reduced disease severity scores, and prevented weight loss in CRE-infected mice treated with antibiotics. These effects are attributed to the inhibition of CRE growth in stool and the reduced detection of CRE in the lungs and kidneys, indicating suppression of systemic translocation. Metagenomic analysis revealed that PMC101 prevented the reduction in microbial population caused by antibiotics and CRE infection, restored species diversity indices, and mitigated dysbiosis while promoting eubiosis. This CRE translocation suppression was closely associated with increased CRE translocation-microbiome index, defined as the ratio of Bacteroidetes to Proteobacteria. This relationship was further confirmed through simulations using a human intestinal microbial ecosystem model. Additionally, increases in short-chain fatty acids, reductions in excessive inflammatory responses, and decreases in tissue damage were observed, all of which contribute to preventing CRE translocation. Finally, pathogen inhibition effects and safety tests were conducted, confirming the prophylactic potential of PMC101 as a microbiome therapeutic. These findings strongly support PMC101 as a promising candidate for future microbiome-based therapies against CRE infections.

Animals↗
PubMed2025

The role of mobile genetic elements in adaptation of the microbiota to the dynamic human gut ecosystem.

The human intestinal microbiota is a dynamic ecosystem shaped by extensive horizontal gene transfer, particularly in individuals from industrialized populations. In this review, we discuss recent advances in our understanding of how mobile genetic elements (MGEs) contribute to microbial ecology and evolution in this diverse community, focusing on MGEs carrying fitness-conferring genes. Bacteroidales species can colonize individuals for decades and serve as major hubs for MGE exchange. Most MGEs are highly variable across individuals and geographies. Occasionally, conserved MGEs can spread across geography and lifestyles. Functional characterizations of MGEs reveal their roles in antibiotic resistance, interbacterial antagonism, biofilm formation, immune evasion, and nutrient acquisition, among others. Substantive progress in our understanding of MGEs in the gut microbiome offers promising avenues for therapeutic microbiome interventions. However, major challenges remain in functional prediction, host-MGE linkage, and experimental characterization.

Humans↗
PubMed2026

Beyond antibiotics: artificial intelligence-enabled anti-infective ecosystems for next-generation precision therapeutics against antimicrobial resistance.

The rapid global expansion of antimicrobial resistance (AMR) threatens to undermine decades of progress in infectious disease management and highlights the limitations of conventional antibiotic-centered therapeutic strategies. Although emerging technologies-including antimicrobial peptides, bacteriophage therapy, CRISPR-based antimicrobials, microbiome therapeutics, anti-virulence approaches, nanotechnology-enabled drug delivery, and artificial intelligence (AI)-have individually demonstrated considerable promise, they are predominantly being developed as independent interventions rather than as coordinated components of an integrated therapeutic strategy. This Perspective proposes the Intelligent Anti-Infective Ecosystem (IAIE) as a conceptual systems-level framework that computationally integrates multimodal diagnostics, pathogen genomics, microbiome profiling, AI-assisted decision support, programmable precision therapeutics, ecological monitoring, and longitudinal clinical feedback within a continuously learning dynamically optimized workflow. Unlike existing paradigms that primarily optimize individual technologies or therapeutic decisions, IAIE emphasizes closed-loop coordination among complementary antimicrobial approaches to support precision-guided infection management while preserving microbiome integrity and mitigating resistance selection pressure. We further outline the core components, operational principles, translational challenges, and technology readiness of the major therapeutic platforms that could contribute to such an ecosystem, while distinguishing clinically established interventions from emerging experimental strategies. Importantly, IAIE should be interpreted as a prospective conceptual architecture rather than an existing clinical platform. Its proposed clinical value remains to be established through sequential computational, preclinical, and prospective clinical investigations using standardized microbiological, ecological, and patient-centered outcome measures. By framing antimicrobial innovation within an responsive systems perspective, IAIE provides a roadmap for future multidisciplinary research aimed at integrating artificial intelligence and systems microbiology to enable sustainable management of antimicrobial resistance.

Humans↗
PubMed2026

Targeting Microbial Bile Salt Hydrolase Reprograms Bile Acid Metabolism and Ameliorates Metabolic Dysfunction-Associated Steatohepatitis in Mice.

Microbial bile salt hydrolase (BSH) plays a central role in shaping bile acid composition and gut-liver metabolic signaling, yet its therapeutic potential in metabolic dysfunction-associated steatohepatitis (MASH) remains incompletely defined. Here, we evaluated the efficacy of the non-absorbable BSH inhibitor GR-7 in a diet induced mouse model of steatohepatitis using early and late intervention strategies with different dosing regimens. GR-7 reduced food intake and exerted stage- and dose-dependent therapeutic effects, with early intervention robustly suppressing hepatic fibrosis even at low dose, whereas late-stage administration of high-dose GR-7 markedly reduced hepatic steatosis and inflammation, as evidenced by decreased liver weight, hepatic triglyceride and cholesterol levels, and plasma ALT. Although late intervention did not result in statistically significant histological reversal of fibrosis, a trend toward improvement was observed, together with suppression of fibrogenic gene expression, suggesting that prolonged treatment may further enhance antifibrotic efficacy. Mechanistically, GR-7 effectively inhibited microbial BSH activity in vivo, leading to reduced cecal unconjugated primary and secondary bile acids-including deoxycholic acid and lithocholic acid, which was associated with improved gut barrier integrity and reduced hepatic inflammation. In parallel, BSH inhibition reprogrammed hepatic bile acid metabolism toward activation of the alternative CYP27A1-mediated synthesis pathway, accompanied by reduced food intake, thereby contributing to improved hepatic lipid accumulation. Furthermore, late-stage high-dose treatment selectively remodeled the hepatic immune landscape rather than fully restoring homeostasis, highlighting immune recalibration as a key component of therapeutic response. Together, these findings identify microbial BSH inhibition as a promising microbiome-targeted therapeutic strategy for MASH.

Gut microbiome↗
PubMed2026

Targeting microbial bile salt hydrolase reprograms bile acid metabolism and ameliorates metabolic dysfunction-associated steatohepatitis in mice.

Microbial bile salt hydrolase (BSH) plays a central role in shaping bile acid composition and gut-liver metabolic signaling, yet its therapeutic potential in metabolic dysfunction-associated steatohepatitis (MASH) remains incompletely defined. Here, we evaluated the efficacy of the non-absorbable BSH inhibitor GR-7 in a diet-induced mouse model of steatohepatitis using early and late intervention strategies with different dosing regimens. GR-7 reduced food intake and exerted stage- and dose-dependent therapeutic effects, with early intervention robustly suppressing hepatic fibrosis even at a low dose, whereas late-stage administration of high-dose GR-7 markedly reduced hepatic steatosis and inflammation, as evidenced by decreased liver weight, hepatic triglyceride and cholesterol levels, and plasma ALT. Although late intervention did not result in statistically significant histological reversal of fibrosis, a trend toward improvement was observed, together with suppression of fibrogenic gene expression, suggesting that prolonged treatment may further enhance antifibrotic efficacy. Mechanistically, GR-7 effectively inhibited microbial BSH activity in vivo, leading to reduced cecal unconjugated primary and secondary bile acids-including deoxycholic acid and lithocholic acid, which was associated with improved gut barrier integrity and reduced hepatic inflammation. In parallel, BSH inhibition reprogrammed hepatic bile acid metabolism toward activation of the alternative CYP27A1-mediated synthesis pathway, accompanied by reduced food intake, thereby contributing to reduced hepatic lipid accumulation. Furthermore, late-stage high-dose treatment selectively remodeled the hepatic immune landscape rather than fully restoring homeostasis, highlighting immune recalibration as a key component of therapeutic response. Together, these findings identify microbial BSH inhibition as a promising microbiome-targeted therapeutic strategy for MASH.

Animals↗
PubMed2026

Spatial scaling of metagenomic diversity reveals ecological disruption in the gut microbiome of gout patients.

Gout, a painful inflammatory arthritis, is characterized by hyperuricemia and monosodium urate crystal deposition, with growing evidence linking its pathogenesis to gut microbiome dysbiosis. However, traditional diversity metrics fail to capture the complex spatial organization of microbial communities. This study addresses this gap by applying the novel metagenomic Diversity-Area Relationship (m-DAR) model to investigate scaling laws in the gout microbiome-quantifying how metagenomic diversity changes with the number of individuals sampled. Our analysis of gut microbiomes from gout patients and healthy controls revealed fundamental ecological disruptions. We found that gout microbiomes exhibited significantly altered scaling patterns: they showed greater inter-individual dissimilarity (higher z-values) at the level of rare genes (q = 0), but weaker scaling of dominant genes (q = 1-3) compared to healthy controls. Crucially, the maximal accrual diversity (MAD) was substantially lower in gout patients, indicating a severely constrained potential for total microbial gene diversity. Furthermore, profiling of metagenomic functional gene clusters (MFGCs) uncovered widespread functional perturbations, including increased diversity scaling for carbohydrate-active enzymes (CAZy) but decreased scaling in essential metabolic pathways (KEGG, KO). These results demonstrate that the gout gut microbiome is defined by a loss of ecological structure, featuring reduced homogeneity in dominant taxa, expanded rare biosphere variation, and an overall collapsed diversity capacity. This work introduces an ecological framework for characterizing dysbiosis in gout that complements traditional diversity metrics and may inform the development of microbiome-based therapeutic strategies. Further research is needed to translate these ecological patterns into clinical applications.

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

Enteral Nutrition Is Associated with a Distinct Gut Microbiome Composition and Fermentation Capacity Profile After Acute Colonic Injury in Rats.

Enteral nutrition (EN) is known to promote mucosal healing in inflammatory bowel disease, and multi-omics data suggest that the gut microbiome mediates its therapeutic effects. However, the impact of EN and its components on the gut community during recovery from acute epithelial injury remains incompletely understood. We used whole-genome metagenomic sequencing to investigate the effect of an EN formula based on extruded amaranth flour and pea protein on the gut microbiome in a dextran sulfate sodium (DSS) rat model of acute colonic injury. Three groups were compared, as follows: an unchallenged control (n = 9) with standard chow, a colonic injury (5% DSS; n = 9) group with standard chow, and a colonic injury (5% DSS; n = 9) group with EN. Injury was confirmed histologically (median MCHI score was 2, indicating epithelial damage without inflammation). DSS caused significant weight loss. Animals receiving EN regained baseline weight faster, by day 14, whereas animals on standard chow achieved recovery only by day 21. Differences in energy intake should be further investigated to validate the effect of EN on body weight recovery. At day 21, both injury groups demonstrated higher relative abundances of Bacteroidaceae and Erysipelotrichaceae, including the mucin-degrader Allobaculum mucilyticum, compared with the control group. Conversely, Lactobacillus abundance, notably Lactobacillus acidophilus, was higher in the EN group than in both other groups, as was the inferred capacity for lactate-producing fermentation. These findings suggest that EN is associated with a distinct microbial composition and inferred metabolic profile during the post-injury period, with lactobacilli as one of the potential mediators of its effects.

Animals↗
PubMed2026

Divergent microbial preludes to necrotising enterocolitis defined by gut phages and bacterial resistomes.

BACKGROUND: Translating microbiome correlations into robust predictive features for complex gut disorders remains elusive, partly due to oversimplified models of pathogenesis and neglect of the virome, a key player in microbial ecosystems. Necrotising enterocolitis (NEC), a devastating disease of preterm infants with no reliable clinical predictors, exemplifies this challenge. OBJECTIVE: To determine the predictive potential of the gut prophageome and polymicrobial aetiologies for NEC. DESIGN: We applied integrated metagenomic and metatranscriptomic analyses and machine learning to 1825 longitudinal stool samples from 43 preterm infants who later developed NEC and 86 gestational age-matched and birthweight-matched controls across three US hospitals. We characterised gut prophageome acquisitions and their association with clinical exposures, including antibiotics, diet and pharmacotherapies. To predict NEC risk, we integrated pre-onset prophageome, antibacterial resistome and bacteriome profiles with neonatal pathology, stratifying the cohort by disease onset timing (early: ≤40 days; late: >40 days) for separate analysis. RESULTS: NEC cases exhibited distinct viral diversity trajectories before disease onset. Early-onset NEC was best predicted by phage-bacterial interaction signatures (75% accuracy, 81% sensitivity). Metatranscriptomics revealed increased phage DNA abundance with low gene expression, suggesting a lysogenic lifestyle that may stabilise pathobionts. These phages encode metabolic genes potentially enhancing pathobiont resilience. Late-onset NEC was best predicted by antibacterial resistome profiles (83% accuracy). CONCLUSION: The gut prophageome serves as both a source of pre-symptomatic predictive signals and an active modulator of NEC pathogenesis, with distinct microbial mechanisms driving early-onset and late-onset disease. These polymicrobial etiologies inform strategies for early detection, risk stratification and the development of microbiome-targeted preventive and therapeutic interventions.

BIOMARKERS↗
PubMed2026

Intratumoral Mycobacterium abscessus promotes cytidine deaminase mutagenesis in non-small cell lung cancer.

The intratumoral microbiota is increasingly recognized as an active component of the tumor microenvironment, yet whether it directly drives tumor mutagenesis remains unclear. Here, integrated multi-omics analysis of human non-small cell lung cancer (NSCLC) identifies Mycobacterium abscessus as a microbial determinant of APOBEC3A-associated mutagenesis. Mechanistically, the bacterial effector nucleoside diphosphate kinase (NDK) directly targets the host transcription factor IRF3 and installs a non-canonical 1-phosphohistidine modification at H263, thereby amplifying type I interferon signaling and sustaining APOBEC3A expression. This inter-kingdom phosphotransfer event links intratumoral microbial colonization to an endogenous mutational process that promotes genomic diversification. Genetic inactivation of NDK, or pharmacologic elimination using an engineered NDK-PROTAC, suppresses APOBEC3A activation and attenuates microbe driven mutagenesis. Together, these findings establish a direct microbial effector mechanism that promotes APOBEC3A-associated mutagenesis and provide a therapeutic framework to intercept microbiome driven mutagenesis in NSCLC.

Humans↗
PubMed2026

Faecalibacterium harmsenii sp. nov., an abundant but previously overlooked Faecalibacterium in the human gut.

Faecalibacterium is one of the most abundant anaerobes in the human colon. At the genus level, this bacterium shows a strong positive association with human health. Expanding collections of isolates and metagenome-assembled genomes have revealed its species diversity, yet species-level functions remain so far underexplored. Here, we describe a novel species, Faecalibacterium harmsenii. In addition, we reclassify another isolate as a member of the recently reported Faecalibacterium langellae species. Despite close genomic relatedness, these isolates exhibit distinct physiological and biochemical traits, including differences in carbohydrate utilization, stress tolerance, enzymatic activity, Gram-staining and fatty acid composition. Our present comparative genomics analyses further uncover extensive functional diversity and plasticity across type strains, with F. harmsenii being distinguished by an expanded carbohydrate gene repertoire and reduced defense systems, mobile genetic elements and antibiotic resistance genes. Extending to the species, we identify species-specific ecological niches across hosts and differential sensitivities to human diseases, highlighting certain species as reliable biomarkers of gut health. Together, these findings refine our understanding of Faecalibacterium diversity and provide a framework for its use in microbiome-based diagnostics and therapeutic development.

Faecalibacterium harmsenii↗
PubMed2026

Bridging the airway microbiome and targeted therapy in bronchiectasis: multi-omics insights, endotypes and emerging therapies.

Bronchiectasis is a heterogeneous chronic airway disease primarily driven by persistent infection, microbial dysbiosis and dysregulated host immunity. While culture-based microbiology has historically informed clinical management, advances in high-throughput sequencing and multi-omic technologies have transformed our understanding of the airway ecosystem, revealing that disease activity is shaped not only by individual pathogens, but by complex and dynamic host-microbe interactions. Despite the breadth of descriptive microbiome data, translation into clinically actionable diagnostics or therapies has been limited. Importantly, cross-sectional correlations between microbiota and inflammation do not establish cause and effect, underscoring the need to embed host-microbiome profiling within both longitudinal and interventional therapeutic trials. In this review, we critically appraise current microbial and host multi-omics research in bronchiectasis, integrating microbiome studies with host inflammatory, proteomic and immunophenotyping data. We highlight themes emerging across cohorts, including low microbial diversity, pathogen dominance, loss of commensal networks and neutrophil-driven inflammation, and discuss how these features align with biological endotypes associated with exacerbations and treatment response. Drawing on lessons from host-directed therapeutic successes, we examine translational roadblocks limiting microbiome-guided care. We further review emerging microbiome-modulating strategies such as pathogen-specific biologics, bacteriophage therapy, live biotherapeutic products, biofilm-targeting adjuncts and precision antibiotic stewardship. Finally, we propose a roadmap toward microbiome-informed precision medicine through harmonised methodologies, integration of host and microbial biomarkers into clinical trials, and embedding multi-omics pipelines within large international registries. Collectively, these advances have the potential to shift bronchiectasis research and clinical management towards rationally designed, precision medicine-driven therapeutic strategies.

Humans↗
PubMed2025

Unveiling novel antimicrobial peptides from the ruminant gastrointestinal microbiomes: A deep learning-driven approach yields an anti-MRSA candidate.

INTRODUCTION: Antimicrobial peptides (AMPs) present a promising avenue to combat the growing threat of antibiotic resistance. The ruminant gastrointestinal microbiome serves as a unique ecosystem that offers untapped potential for AMP discovery. OBJECTIVES: The aims of this study are to develop an effective methodology for the identification of novel AMPs from ruminant gastrointestinal microbiomes, followed by evaluating their antimicrobial efficacy and elucidating the mechanisms underlying their activity. METHODS: We developed a deep learning-based model to identify AMP candidates from a dataset comprising 120 metagenomes and 10,373 metagenome-assembled genomes derived from the ruminant gastrointestinal tract. Both in vivo and in vitro experiments were performed to examine and validate the antimicrobial activities of the AMP candidates that were selected through bioinformatic analysis and subsequently synthesized chemically. Additionally, molecular dynamics simulations were conducted to explore the action mechanism of the most potent AMP candidate. RESULTS: The deep learning model identified 27,192 potential secretory AMP candidates. Following bioinformatic analysis, 39 candidates were synthesized and tested. Remarkably, all synthesized peptides demonstrated antimicrobial activity against Staphylococcus aureus, with 79.5% showing effectiveness against multiple pathogens. Notably, Peptide 4, which exhibited the highest antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), confirmed this effect in a mouse model with wound infection, exhibiting a low propensity for resistance development and minimal cytotoxicity and hemolysis towards mammalian cells. Molecular dynamics simulations provided insights into the mechanism of Peptide 4, primarily its ability to disrupt bacterial cell membranes, leading to cell death. CONCLUSION: This study highlights the power of combining deep learning with microbiome research to uncover novel therapeutic candidates, paving the way for the development of next-generation antimicrobials like Peptide 4 to combat the growing threat of MRSA would infections. It also underscores the value of utilizing ruminant microbial resources.

Animals↗
PubMed2026

Integrative machine learning models to unravel gut microbial dysbiosis and functional disruption in polycystic ovary syndrome.

OBJECTIVE: To study gut microbial diversity and metabolic pathway disruptions in women with PolyCystic Ovary Syndrome (PCOS) compared with healthy controls, and to evaluate the diagnostic potential of microbiome-driven machine learning models. DESIGN: Case-controlled metagenomic data analysis SUBJECTS: Gut metagenomic data from women diagnosed with PCOS and age-matched healthy female controls EXPOSURE: Presence of PCOS MAIN OUTCOME MEASURES: The primary outcome measures will include gut microbial alpha and beta diversity indices, microbial taxon abundance, functional pathway profiles, predicted metabolite levels, microbe-functional pathway-metabolite interaction networks, and the diagnostic accuracy of microbiome-based machine learning models. RESULTS: Alpha and beta diversity analyses revealed marked gut microbial dysbiosis in women with PCOS, despite comparable species richness to healthy controls. Differential abundance analysis identified 41 significantly altered microbial species, including enrichment of proinflammatory taxa, such as Bacteroides vulgatus and Ruminococcus gnavus, and depletion of beneficial commensals, including Roseburia hominis and Prevotella copri. These compositional shifts indicate a proinflammatory microbial community structure in PCOS. Functional profiling demonstrated the upregulation of pathways involved in nucleotide turnover, lipid and carbohydrate metabolism, and neurotransmitter synthesis, potentially contributing to metabolic and neuroendocrine disruption. Network analysis revealed fragmented and unstable microbial-metabolite associations in PCOS compared with cohesive networks in controls. Microbiome-based machine learning models achieved a diagnostic accuracy of 84.25% (area under the curve 0.93), underscoring their predictive potential. CONCLUSION: The gut microbiome in PCOS is characterized by a proinflammatory community structure and disrupted metabolic pathways. These findings demonstrate the diagnostic potential of microbiome-based models and underscore the gut microbiome as a promising target for therapeutic interventions in the management of PCOS.

Polycystic Ovary Syndrome↗
PubMed2026

Microbial diversity: the essential foundation for life on our planet.

The biological basis of life on Earth is microbial diversity that ensures human health, agricultural productivity, ecological balance, and ecosystem functioning. Microorganisms enable ecosystem restoration through bioremediation, maintain soil fertility, support plant growth, manage vital biogeochemical cycles, and contribute to climate resilience. Precision probiotics, postbiotics, faecal microbiota transplantation, and personalized microbiome medicine are the examples of emerging microbiome-based therapies that offer promising therapeutic opportunities. In humans, the gut microbial community is essential for immune regulation, metabolism, and disease prevention. In terrestrial ecological systems, interactions between plants, fungi, bacteria, and other soil microorganisms improve carbon sequestration, nutrient cycling, stress resilience, and sustainable agricultural productivity in the given effects of climate change. Emerging uses in agriculture, environmental restoration, and medicine are made possible by advancements in multi-omic techniques, synthetic microbial genomes, microbiome engineering, and artificial intelligence. Considering these developments, issues with ecological complexity, long-term validation, standardization, and field scale application still exist. Therefore, preserving microbial diversity is important for conserving ecological resilience and strengthening the One Health framework, which highlights the mutual dependance of health of animal, human, plant, and environment. This review summarizes what has been discovered about ecological and biomedical relevance of microbiome, identifies important research gaps, highlighting emerging technologies, and evaluates potential future directions for using microbiome to support planetary sustainability.

Bioremediation↗
PubMed2026

Metagenome-scale modeling to assess microbiome metabolic complementarity for precision microbiota transplantation therapies.

Fecal microbiota transplantation (FMT) holds therapeutic promise beyond recurrent Clostridioides difficile infection, but clinical outcomes remain unpredictable and donor-selection strategies remain limited, in part because the role of donor‒recipient metabolic interactions in shaping the post-FMT community remains poorly understood. Here, we leverage metagenome-scale metabolic modeling to quantify metabolic niche complementarity between donor and recipient microbiomes and predict post-FMT community composition. Using MICOM-derived metabolic models, we show that donor genomes whose metabolic flux profiles are more dissimilar from the recipient community colonize at significantly higher rates in a murine FMT model. In a human IBS trial, the same metric predicted post-FMT community composition via leave-one-out cross-validation and captured known disease-associated alterations in short-chain fatty acid, sulfur, and gas metabolism. We then performed 2,548 in silico FMT simulations between IBS-D/M patients and donors from the OpenBiome biobank to evaluate personalized donor screening, identifying super-donors characterized by high taxonomic diversity, broad metabolic niche coverage, and community interaction networks dominated by cross-feeding rather than competition. Together, these results support metabolic niche complementarity as a potential determinant of post-FMT community composition and provide a mechanistic basis for evaluating donor-recipient metabolic compatibility. This framework offers a scalable approach for generating testable hypotheses for personalized donor selection.

Fecal Microbiota Transplantation↗
PubMed2025

Plasma metabolites mediate the causal relationship between gut microbiota and erectile dysfunction: insights from Mendelian randomization study.

BACKGROUND: While the relationship between gut microbiota and erectile dysfunction (ED) has been reported, the specific pathways involved remain unclear. AIM: This study aims to investigate the causal relationship between gut microbiota and ED, and to identify the potential role of plasma metabolites as mediators. METHODS: Utilizing aggregated genome-wide association study (GWAS) data, a comprehensive two-sample Mendelian randomization (MR) analysis was performed involving 196 gut microbiota taxa, 1400 plasma metabolites and ED. Causal relationships between gut microbiota, plasma metabolites and ED were explored. In addition, mediation analysis was applied to identify the pathway from gut microbiota to ED mediated by plasma metabolites. OUTCOMES: This study reveals that plasma metabolites act as mediators regulating the influence of gut microbiota on ED. RESULTS: MR analysis identified causal relationships between six gut microbial taxa and ED, with Butyrivibrio increasing the risk of ED, while Alistipes, Prevotella 9, Dialister, Marvinbryantia, and LachnospiraceaeUCG010 exhibited protective effects. Additionally, 45 plasma metabolites demonstrated causal associations with ED. Finally, mediation analysis revealed four mediation relationships. Sensitivity analysis indicated no heterogeneity or pleiotropy in this study. CLINICAL IMPLICATIONS: Modulating gut microbiota or targeting specific metabolites may offer new therapeutic approaches for ED, highlighting the potential for microbiome-based interventions. STRENGTHS AND LIMITATIONS: The MR approach and large-scale GWAS data provide robust causal evidence, but the findings are limited by their focus on European populations and lack of experimental validation. Further studies are needed to confirm these mechanisms in diverse cohorts and functional models. CONCLUSION: This study establishes a causal link between gut microbiota, plasma metabolites, and ED, identifying specific microbial taxa and metabolites as key contributors to ED risk. The mediating role of plasma metabolites highlights potential therapeutic strategies, such as probiotics or dietary interventions targeting harmful metabolites.

Mendelian randomization↗
PubMed2025

Integrative oral and gut microbiome profiling highlights microbial correlates of complications in type 1 diabetes: a cross-sectional analysis.

BACKGROUND/OBJECTIVE: Chronic vascular complications are the primary threat in long-standing type 1 diabetes (T1D) patients. We examined the associations between oral-gut microbiome dysbiosis and these complications, offering novel insights into therapeutic strategies and underlying mechanisms. METHODS: This cross-sectional study enrolled 75 T1D participants (disease duration ≥ 10 years) and 43 healthy controls who underwent comprehensive clinical assessment, including blood glucose, lipid profile, and complication-related examinations. Fecal and oral rinse samples were collected for shotgun metagenomic sequencing. T1D participants were stratified by the presence of microvascular (retinopathy, nephropathy, or neuropathy) or macrovascular complications separately. Microbial differences across groups were assessed. RESULTS: Significant differences in oral and gut microbiota compositions were observed between T1D participants with and without complications (both microvascular and macrovascular). A core set of 26 gut and 8 oral microbial species was specifically associated with vascular complications. Butyrate-producing gut bacteria (Blautia wexlerae, Anaerobutyricum hallii, Roseburia inulinivorans, A. soehngenii) and specific oral Neisseria species were enriched in T1D without complications individuals, suggesting protective effects against complications. Mediation analysis indicated associations consistent with partial mediation between certain microbial species and the relationships of glycemic control or insulin resistance (HbA1c, glucose risk index, estimated glucose disposal rate) with complication risk. Moreover, potential oral-gut microbiome interconnections were implicated in complication development. Finally, classification models integrating both oral and gut microbial features significantly outperformed models based on either site alone in distinguishing T1D patients with complications. CONCLUSIONS: Distinct oral and gut microbiome features are associated with chronic vascular complications in T1D. These findings highlight the potential of microbiome-targeted strategies for understanding and preventing T1D-related complications.

Humans↗