Gut Microbes最新文献

Responses to lung injury can vary between individuals with the diet and gut microbiome representing two underappreciated sources for this variability. The gut microbiome can influence lung injury outcomes through the gut‒lung axis, but exactly how diet and its effects on the microbiota are involved remains unclear. We hypothesized that dietary fiber interventions would favor the presence of short-chain fatty acid (SCFA)-producing fermentative bacteria presence in the gut microbiome, thereby influencing the resting lung immunometabolic tone as well as influencing downstream responses to lung injury and infection. To test this hypothesis, we fed mice fiber-rich (FR) and fiber-free (FF) diets, and observed changes in the steady-state transcriptional programming of alveolar macrophages (AM). Next, we examined the effects of the FR and FF diets on murine responses to sterile and infectious lung injury in vivo while simultaneously profiling the gut microbiota and SCFA levels transmitted along the gut‒lung axis. Finally, we validated our in vivo observations with mechanistic studies of the metabolic, signaling, and chromatin-modifying effects of specific SCFAs on lung AM ex vivo and in vitro. Overall, our fiber-rich diet reprogrammed AMs and attenuated lung inflammation after sterile injury while exacerbating lung infection. This effect of FR diets could be transferred to germ-free (GF) mice by fecal microbiome transplantation (FMT) and depended on the ability of the microbiota to produce propionate. Mechanistically, SCFAs altered the metabolic programming of AMs and lung tissue ex vivo without a clear role for free fatty acid receptors (FFAR) or chromatin remodeling. These findings demonstrate that the gut‒lung axis can regulate resting lung metabolic tone through dietary fiber intake and the enrichment of SCFA-producing gut bacteria, as well as influence sterile and non-sterile lung injury responses. These results provide evidence to support the development of therapeutic dietary interventions to preserve or enhance specific aspects of host pulmonary immunity.

Chronic intestinal pseudo-obstruction (CIPO) is characterized by bowel dilation and obstructive symptoms without any structural blockage. Although the microbiota is known to affect gastrointestinal function, its role in CIPO is poorly understood. We aimed to characterize the CIPO microbiota, investigate its role in disease expression and explore the therapeutic role of fecal microbiota transplantation (FMT). CIPO patients (n = 14) and healthy controls (HC, n = 12) were recruited from Italy and Canada. Microbiota profiles and functions were assessed by 16S rRNA sequencing and PICRUSt. Germ-free NIH Swiss mice were colonized with HC and CIPO microbiota, their intestinal transit and bowel distension were assessed by videofluoroscopy and computed tomography (CT), and the expression of host genes by NanoString®. The CIPO microbiota exhibited reduced microbial diversity with dominance of Proteobacteria and altered metabolic function. Mice with CIPO microbiota developed marked bowel distension and slow intestinal transit associated with altered expression of multiple genes related to immunity, the intestinal barrier and neuromuscular function. FMT from a HC improved the microbiota profile, intestinal transit and bowel distension in both CIPO mice and a selected CIPO patient, in whom a marked clinical improvement was sustained for 8 y. Thus, our findings support the use of microbiota-directed therapies to induce clinical improvement in CIPO patients.

Objective: This study investigates whether live Akkermansia muciniphila Muc^T supplementation can counteract obesity and metabolic dysfunctions induced by a high-fat diet (HFD) by modulating intestinal mucus production, secretion and composition.

Design: C57BL/6J mice were fed an HFD with or without live A. muciniphila Muc^T (2 × 10⁸ CFU per day) supplementation or a control diet for 6 weeks. Body weight, fat mass gain and metabolic markers were measured. Intestinal mucus characteristics were assessed via gene expression analysis of mucins and analysed mucin glycosylation by tandem mass spectrometry (MS/MS).

Results: Mice receiving live A. muciniphila Muc^T exhibited reduced body weight gain and fat mass accumulation compared to HFD controls, without changes in muscle mass. A. muciniphila improved gut barrier integrity by increasing antimicrobial peptide expression in the jejunum and in the colon of HFD-fed mice. Furthermore, live A. muciniphila Muc^T influenced markers of goblet cell differentiation and restored the expression of mucin markers altered by HFD. Specifically, live A. muciniphila Muc^T counteracted HFD-induced mucin 3 (Muc3) expression depletion in the colon. Although the overall mucus thickness was not affected by live A. muciniphila Muc^T, the bacteria significantly modulated mucin glycans composition. Live A. muciniphila Muc^T did not change the gut microbiota composition.

Conclusion: These findings highlight the protective effects of live A. muciniphila Muc^T against diet-induced metabolic dysfunctions by modulating adiposity, mucus layer composition, and glycan profiles. This reinforces its potential as a therapeutic strategy for metabolic disorders associated with gut microbiota alterations.

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.

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 reveals a strong connection between the gut microbiota and cancer. However, the exact role of gut microbiota dysbiosis in multiple myeloma (MM) is poorly understood, and the therapeutic potential of microbiota-targeted interventions represents a promising strategy that demands urgent mechanistic and translational investigation. First, we conducted a comprehensive microbiome-metabolite analysis between MM patients and healthy individuals. The result revealed a marked compositional difference characterized by reduced abundances of butyrate-producing bacteria and diminished butyrate levels in the MM cohort. Subsequent fecal microbiota transplantation demonstrated that the gut microbiota critically modulates MM progression, with healthy donor-derived microbiota reducing the tumor burden and concomitantly elevating serum butyrate. Furthermore, through function-based culturomics screening, Clostridium butyricum (C. butyricum) was identified as a key butyrate-producing specialist. C. butyricum or its metabolite butyrate significantly reduced the systemic tumor burden in 5TGM1 mice. Notably, C. butyricum and butyrate alleviated bone marrow inflammation and osteolytic lesions by suppressing Th17 cells and IL-17 levels in the bone marrow. Moreover, cellular assays and transcriptome sequencing further revealed that butyrate could induce MM cells' apoptosis via HDAC inhibition-mediated upregulation of PPARγ, leading to sequential suppression of the PI3K/AKT pathway and antiapoptotic BCL-2 expression. This apoptotic signaling cascade was reversed by PPARγ antagonism. The direct antitumor effect was further confirmed in M-NSG mice. Our research systematically verifies the specific role of the gut microbiota in MM and provides the first evidence of the immune and molecular mechanisms by which C. butyricum alleviates MM progression, offering preclinical support for probiotic-based therapies against MM.

The human gut microbiome carries a large array of biosynthetic gene clusters (BGCs) that encode the production of secondary metabolites, yet their temporal dynamics and role during microbial colonization remain largely unexplored. Here, we tracked BGCs profile over time in a cohort of healthy adults, and identified two distinct groups: persistent, which are stable over time, and transient, which are more sporadic. Functional annotations indicated persistent gene clusters are enriched in antibiotic resistance mechanisms, while transient ones more frequently carry virulence-associated genes. We then examined colonization of these two groups in the context of fecal microbiome transplantation. Our results show that persistent gene clusters exhibit higher colonization rates than transient ones. These findings contribute to our understanding of how microbial metabolites influence host health, potentially guiding future therapeutic strategies targeting the microbiome.

Bowel preparation is routinely performed before colonoscopy, yet its immediate effects on the spatial organization of the colonic microbiota at the mucosal interface remain poorly resolved. Here, we introduce a high-resolution endoscopic mucus-harvesting approach, combined with luminal aspirates and mucosal biopsies, to generate a high-resolution, within-subject trajectory of microbiota alterations across distinct colonic niches in healthy adults over the first 24 hours after purging. While luminal bacterial communities remained remarkably stable, with no significant changes in alpha or beta diversity and proportional washout of taxa. In contrast, mucus-associated and mucosal communities underwent a rapid but reversible ecological restructuring, characterized by immediate post-cleansing shifts in composition and transient blooms of Proteobacteria, particularly Enterobacteriaceae. These perturbations were strongest in the 0-12-hour window and varied by individual, consistent with the dominance of personalized baseline microbial signatures. Critically, spatially resolved sampling revealed a key refinement: the Enterobacteriaceae expansion was confined almost exclusively to the superficial mucus layer, a glycan-rich, dynamically oxygenated compartment that is particularly susceptible to mechanical disturbance during lavage, whereas deeper mucus and mucosa-associated communities remained comparatively stable. By 24 hours, both mucosal and mucus-associated microbiota had largely returned to their individualized pre-cleansing configurations, indicating rapid ecosystem resilience and suggesting that the deeper mucus layer functions as a protected microbial reservoir that reseeds the epithelium and lumen once normal physiology is restored. This compartment-specific recovery trajectory contrasts with the prolonged dysbiosis typically observed after antibiotics or infection, underscoring the need for spatially precise sampling to interpret microbiome data collected during clinical endoscopy. Together, these findings establish an endoscopic strategy for probing microbe-mucus interactions in humans and provide a conceptual and methodological framework for interpreting microbiome data obtained during clinical endoscopy.

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.