Gut Microbes最新文献

While extracellular vesicles (EVs) are established mediators of intra-species signaling, their contribution to cross-kingdom communication remains incompletely understood. Here, we investigate the EV-mediated interactions between human colon epithelial cells and both Gram-positive and Gram-negative gut bacteria. We show that bacterial EVs (BEVs) derived from Lacticaseibacillus casei, Enterococcus faecalis, and Proteus mirabilis induce distinct transcriptomic changes in Caco-2 cells depending on the bacterial species, with up to ~6,000 differentially expressed genes, including CCL20, CXCL8, or CXCL10. Transfection of BEV-derived RNA independently induces a subset of similar effects, indicating that the EV-mediated communication is partially driven by the RNA cargo. Conversely, we demonstrate that bacteria interact with Caco-2-derived EVs and miR-192-5p, which is highly abundant (~36.4-fold higher) in EVs isolated from conditioned medium compared with EVs from unconditioned medium, with modest effects on bacterial growth. Furthermore, we show that lipid-based packaging of miR-192-5p modulates its association with the bacteria. Our findings support a conceptual model in which EVs and their RNA cargo contribute to species-dependent host-microbe interactions. This study introduces a framework for understanding EVs as cross-kingdom regulators and underscores the importance of tailored, context-specific analyses for understanding the scope of EV-mediated interactions in microbiome-host homeostasis and disease.

Emerging evidence underscores bidirectional communication along the microbiota-gut-brain axis in neuropsychiatric disorders. However, the field lacks dedicated metagenomic resources with standardized phenotyping for these conditions. Existing single-cohort studies face inherent limitations due to restricted sample sizes, confounding heterogeneity, and methodological fragmentation, compromising reproducibility and mechanistic insights. To overcome these challenges, we constructed the Gut Microbiome in Multinational Integrated Neuropsychiatric Disorders (GutMIND) database, a comprehensive resource integrating shotgun metagenomic data with harmonized metadata. Adhering to a standardized preprocessing protocol and rigorous quality control workflow, this dataset represents the largest gut-brain microbiome repository to date, encompassing 31 studies across 12 countries (n = 3,492) spanning 14 neuropsychiatric conditions. Utilizing this dataset, we characterized microbial community heterogeneity, which was significantly elevated in patients compared to healthy controls. Subsequently, we developed a computational framework, MetaClassifier, enabling the diagnosis of neuropsychiatric disorders and the identification of microbial biomarkers. Employing a comprehensive two-stage validation strategy, we first assessed the model utilizing taxonomic abundance profiles via nested cross-validation in the high-quality discovery cohort (n = 2,734), achieving a mean AUROC of 0.69 (range: 0.55-0.78) across 8 disorders. Its robustness was further confirmed in an independent platform-extended validation cohort (n = 400), yielding a mean AUROC of 0.71 (range: 0.60-0.76). We also developed the Microbial Gut-Brain Axis Health Index (MGBA-HI), which effectively distinguished neuropsychiatric status in both the high-quality cohort and the platform-extended cohort. Furthermore, integrative analysis of health-abundant species, index-derived biomarkers, and ecological prevalence, we identified 9 core neuropsychiatric-protective microbiota. These species predominantly exhibited metabolic capacities linked to glutamate synthesis and acetate production. Building upon this, the GutMIND framework ensures robust cross-cohort comparability while minimizing technical heterogeneity, thereby enhancing inferential rigor in gut microbiome-neuropsychiatry research. Notably, the MetaClassifier, MGBA-HI, and core microbiota hold translational potential for developing microbiome-based prognostic tools and personalized therapeutic strategies in neuropsychiatric disorders. The source code and usage instructions for MetaClassifier are accessible at https://github.com/juyanmei/MetaClassifier.

Intestinal immune homeostasis is crucial for intestinal function and health. Increasing evidence suggests that certain gut microbiota can enhance the host's intestinal immune regulatory capacity. However, the mechanisms by which the microbiota confers beneficial traits and robust immunity to the host, as well as the cross-species reproducibility of these effects, remain unclear. This study, through multi-omics integration comparison and functional validation, revealed that Streptococcus hyointestinalis from Min pigs regulates macrophage polarization homeostasis by targeting and inhibiting the excessive activation of the STING signaling pathway and its downstream pro-inflammatory cascade reactions through its extracellular vesicles (EVs), thereby shifting them toward the M2 phenotype. This process ensures the integrity of the intestinal barrier and alleviates colitis induced by the combined effects of low temperature and sodium sulfate-induced colitis (DSS). Notably, in Sting^-/- mice, the EV-mediated intestinal protective effect was eliminated, confirming its targeted efficacy. Our data reveal a microbial EV‒STING‒macrophage axis in which symbiotic bacterial exosomes promote reparative macrophage programs by regulating STING signaling and maintaining intestinal integrity under environmental stress. These findings reveal a novel host-microbiota communication pathway with therapeutic potential for the treatment of inflammation-driven intestinal diseases.

The infant gut microbiota, orchestrated by human milk oligosaccharides (HMOs), forms a critical foundation for lifelong health. Despite their recognized importance, the molecular strategies through which HMOs govern microbial competition and niche establishment remain poorly understood. Moving beyond ecological observations, this review synthesizes current mechanistic evidence on the molecular machinery of HMO metabolism in microbial assembly. We explore the specialized enzymes that confer competitive advantages and the metabolic networks fueled by HMO breakdown. Furthermore, we distinguish substrate-driven effects from the hypothesized signaling roles of intact HMOs in modulating host-microbe interactions, indicating where the evidence is associative versus causal. By integrating these pathways, we provide a blueprint for leveraging HMO biology to develop targeted nutritional interventions for preventing early-life disorders.

Background: Antibiotics are not recommended to treat influenza A virus (IAV). However, antibiotic misuse for IAV persists worldwide. How to scientifically use antibiotics for IAV-infected patients remains a considerable challenge.

Results: Here, we investigated the impact of antibiotics on viral pathogenicity, pulmonary-intestinal antiviral immunity, and antiviral drug efficacy. Our findings indicated that antibiotic intervention exacerbated IAV-caused mortality and lung injury in mice, manifested as increased mortality rates, shortened survival time, aggravated pulmonary injury, and excessive inflammatory responses. Furthermore, antibiotic pretreatment significantly diminished the efficacy of antivirals. Metagenomic sequencing revealed that antibiotics reduced the diversity and abundance of beneficial gut microbiota, including Lactobacillus and Bifidobacterium, while promoting the proliferation of pathogenic bacteria such as Klebsiella pneumoniae and Escherichia coli. Mechanistically, antibiotic intervention exacerbated IAV-caused excessive inflammatory responses by the blockage of pulmonary-intestinal antiviral immune pathways, which were caused by the upregulation of PKR, RIG-I, ISG15, and TRIM25 levels while downregulating IPS-1 mRNA levels. However, it is noteworthy that the combination of antibiotics and antiviral drugs effectively offset the adverse effects of antibiotic pretreatment on influenza mortality by upregulating IPS-1 levels and partially restoring pulmonary-intestinal immune homeostasis.

Conclusions: Pulmonary-intestinal immune homeostasis imbalance caused by antibiotic misuse can not only markedly exacerbate the lethality of IAV, but also significantly attenuate the efficacy of antiviral drugs. A mechanistic study confirmed that gut microbes dysbiosis caused by antibiotic pretreatment exacerbates the homeostasis imbalance of host antiviral immunity by blocking the RIG/MDA5/IPS-1 antiviral signaling pathway. However, combination therapy with antibiotics and antivirals effectively reversed the fatal outcome exacerbated by antibiotic pretreatment. Collectively, our findings not only provide a scientific explanation from the perspective of antiviral immunity as to why antibiotics should not be arbitrarily used to treat viral infections but also lay the scientific foundation for the rational clinical use of antivirals and antibiotics for treating influenza.

Exposure to broad-spectrum antibiotics, particularly to third-generation cephalosporins (3GC), increases the risk of colonization by extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E). While clinical risk factors for ESBL-E acquisition are well established, the role of the gut microbiome and resistome remains unclear. We conducted a prospective study of patients with suspected bacterial infections receiving ceftriaxone to identify microbiome and resistome features associated with ESBL-E acquisition. Rectal samples collected before antibiotic administration, during treatment, and 30 d after initiation were analyzed by shotgun metagenomic sequencing. Among 80 patients, 12 (15%) acquired ESBL-E colonization by day 30. Ceftriaxone exposure induced a profound and sustained reduction in microbial richness and diversity across all patients. However, no specific taxonomic signature predicted subsequent ESBL-E colonization. In contrast, patients who did not acquire ESBL-E displayed a significantly richer and more diverse repertoire of β-lactamase-encoding genes at baseline, which was independently associated with protection against colonization. Moreover, patients exposed to multiple antibiotics experienced greater and more sustained microbiome disruption compared with those receiving ceftriaxone alone. These findings provide the first real-world evidence that pre-existing β-lactamasome diversity may confer ecological protection against antibiotic-driven colonization by ESBL-E in infected patients, highlighting the importance of functional resistome diversity over taxonomic composition in colonization resistance.

Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD). Mycobacterium avium, which causes Johne's disease in ruminants, has been suggested as a potential CD trigger due to shared pathology, but early epithelial responses remain unclear. This study established a mouse small intestinal organoid (mSIO) model of M. avium infection to assess CD-related inflammation. Infected mSIOs were examined by confocal microscopy, block-face scanning electron microscopy, and macrophage co-culture to track bacterial localization and immune cell behavior. The data give unprecedent dynamic and super high resolution insights in the responses of gut cells to mycobacterial infection. RNA-seq with GSEA revealed strong induction of inflammatory genes and enrichment of pro-inflammatory pathways. Comparative analysis with CD-humanized mouse data showed overlapping gene expression and enrichment of the IBD signaling pathway. Notably, Mmp7, which can be linked to epithelial remodeling and inflammation, was a common marker in both models. This study presents a robust mSIO model of M. avium infection that recapitulates features of CD-associated inflammation both with high-resolution imaging and transcriptomics and identifies Mmp7 as a potential molecular link between infection and CD-like pathology.

Ankylosing spondylitis (AS) is strongly associated with the human leukocyte antigen B27 (HLA-B27), yet how this genetic risk factor interacts with the gut microbiome remains unclear. We integrated fecal gut microbiota analysis, untargeted metabolomics, and clinical phenotyping in 88 participants, including HLA-B27-positive patients with AS (n = 28), HLA-B27-positive healthy controls (n = 30), and HLA-B27-negative healthy controls (n = 30). HLA-B27 positivity, particularly in AS, was associated with marked alterations in gut microbial composition and metabolic profiles, with forty bacterial species showing progressive disease-related shifts across cohorts. Integrated pathway and metabolomic analyses identified three amino acid-related pathways consistently disrupted in AS: tryptophan metabolism, cysteine metabolism, and pyruvate-centered biosynthesis of branched-chain amino acids, ornithine, and lysine. Correlation network analyses linking differential taxa, metabolites, and clinical indices revealed previously unrecognized microbial and metabolic signatures that robustly distinguished AS from both control groups. To explore causality, fecal microbiota transplantation (FMT) from clinical donors into antibiotic-treated mice recapitulated key disease-relevant features, including impaired intestinal barrier function, systemic inflammation, trabecular bone loss, and polarization of macrophages toward a proinflammatory M1 phenotype. Mechanistic validation identified cinnabarinic acid as a critical microbial-derived metabolite that suppresses M1 macrophage polarization via activation of the aryl hydrocarbon receptor (AhR) pathway and confers protection in the FMT model. Together, these findings support a model in which HLA-B27-associated gut dysbiosis and metabolic reprogramming promote AS pathogenesis through macrophage-mediated inflammation and osteocatabolic signaling, highlighting microbial-metabolic pathways as potential therapeutic targets.

Tamoxifen (TAM) is a widely used estrogen receptor modulator for breast cancer treatment. However, TAM exhibits significant hepatotoxicity in the clinic, affecting nearly 50% of patients and thereby limiting its clinical utility. The specific mechanisms underlying TAM-induced liver injury remain poorly understood. In this study, we elucidated the mechanistic role of the gut microbiota in the hepatotoxicity associated with TAM. TAM administration induced substantial liver injury and gut microbiota dysbiosis in mice, characterized by an increased abundance of Escherichia and a reduction in Lachnospiraceae NK4A136 group. These microbial shifts resulted in decreased levels of total fecal bile acids (BA), particularly hyodeoxycholic acid (HDCA), which was inversely correlated with TAM-induced liver injury. Additionally, TAM disrupted BA homeostasis by enhancing intestinal Farnesoid X receptor (FXR) activity and concurrently stimulating hepatic BA synthesis through an alternative nonintestinal FXR mechanism. Notably, gut microbiota depletion reversed these effects, demonstrating the critical role of the microbiota in modulating the gut‒liver FXR axis in TAM-induced liver injury. Fecal microbiota transplantation (FMT) further confirmed that TAM directly stimulated hepatic BA synthesis through a microbiota-dependent mechanism. The disruption of the gut‒liver BA‒FXR axis impaired enterohepatic BA circulation, contributing to the liver toxicity associated with TAM administration. Importantly, HDCA supplementation restored the gut‒liver BA‒FXR axis and alleviated TAM-induced liver injury. These findings highlight the intricate relationship between TAM, gut microbiota, and BA metabolism, suggesting that targeting the gut-liver FXR axis with HDCA may serve as a promising therapeutic strategy for alleviating TAM-associated liver injury.

Species of the genus Blautia are commonly found in the human gut and are known to be beneficial for the human well-being. However, only little is known about the physiology and the specific role of Blautia species in the human gut. In this study, we investigated the heterotrophic metabolism of the formate dehydrogenase lacking gut acetogen Blautia luti. We identified acetate, succinate, lactate, formate, and hydrogen as end products of sugar fermentation. Interestingly, formate is produced by the pyruvate-formate lyase reaction and used as electron acceptor in the Wood-Ljungdahl pathway of CO₂ fixation. Thus, formate connects the oxidative branch of glucose metabolism with the reductive branch. The use of formate as an intraspecies electron carrier seems to be common in gut acetogens. This study highlights the role of formate as electron carrier in the gut microbiome and improves our understanding of the physiology of Blautia species in the human gut. It also introduces B. luti as potential candidate for biotechnological applications due to the production of highly desired succinate.