npj Biofilms and Microbiomes最新文献

Major Depressive Disorder (MDD) affects around 20% of people globally and is often comorbid with anxiety. This study investigates prucalopride, a serotonin type 4 receptor (5-HT₄R) agonist approved for constipation, as a fast-acting anxiolytic/antidepressant using a mouse model of stress, based on corticosterone (CORT) administration. Behavioral effects of prucalopride (0.5 and 1.5 mg/kg/day) were compared to fluoxetine, a common SSRI, over 7 (subchronic) and 28 (chronic) days. Prucalopride showed faster and more significant improvements in emotionality scores than fluoxetine, reversing CORT-induced behavioral changes within 7 days. Gut microbiota analysis revealed CORT-induced changes at the subchronic timepoint. While chronic prucalopride did not alter microbial alpha diversity, it significantly shifted microbial composition (beta-diversity). Notably, prucalopride restored levels of the genus Ruminococcus, which were depleted by CORT. Our findings highlight prucalopride's rapid anxiolytic and antidepressant-like effects and its impact on gut microbiota, supporting the potential of 5-HT₄R-targeting molecules as therapeutic options for psychiatric disorders.

Exopolysaccharides (EPS) are critical components of the biofilm matrix, and ppGpp has been demonstrated to positively influence biofilm formation. Here, we elucidate the underlying mechanism by which ppGpp regulates EPS production by facilitating HpaR1 to modulate the expression of the gum cluster in the phytopathogen Xanthomonas campestris pv. campestris (Xcc). ppGpp affected the yield of EPS without influencing its primary or advanced structure, as confirmed by Fourier transform infrared spectroscopy and scanning electron microscopy. Expression of the gum cluster, which governs EPS biosynthesis in Xcc, was down-regulated in the ppGpp-deficient mutant (ΔrelAΔspoT) compared to the wild type (WT). Comparison of EPS production between knock-out mutants of the gum cluster and ppGpp-deficient mutant revealed that the gum cluster was a key determinant of EPS production, with ppGpp acting upstream of the gum cluster. Transcriptomic and qPCR analyses indicated that ppGpp modulated global transcription in Xcc, positively regulating expression of hpaR1, which encodes the transcription factor for the gum cluster. This regulatory role was further substantiated by electrophoretic mobility shift assays, which showed that ppGpp enhanced the DNA-binding activity of HpaR1. Furthermore, genetic complementation with hpaR1 restored EPS production, confirming its functional role in this regulatory pathway. In summary, these findings provide novel insights into the molecular mechanisms linking ppGpp signaling to EPS production in X. campestris pv. campestris.

Quorum sensing (QS) orchestrates collective microbial behaviors and functional acclimatization through chemical communication. However, QS in natural waters is challenged by dilution, alkaline hydrolysis, and enzymatic degradation of freely dissolved autoinducers. Here, we demonstrate that extracellular vesicles (EVs) act as selective, durable, and protective vectors for QS signal molecules under environmental stresses. Specifically, EVs preferentially package hydrophobic acyl‑homoserine lactones, concentrate them locally, and shield them from alkaline hydrolysis, and exhibiting long-distance transport. In addition, EVs possess specific affinity to recipients, thus influencing microbial community. Field investigation via multi-omics showed that EV abundance covaried with salinity, nutrients, chlorophyll a, and biomass, which were validated by culture experiments. Our statistical framework demonstrated that organisms producing moderate EV levels contributed significantly to maintaining community stability and ecosystem functions. Distinctively within this group, QS-active species (including Burkholderiaceae, Pseudomonadaceae, Rhodobacteraceae, Roseobacteraceae, Flavobacteriaceae etc.) emerge as key drivers facilitating these crucial ecological roles. Furthermore, metaproteomics of field EVs reveal QS receptor and synthesis proteins, suggesting coordinated transport of signals and proteins, which indicate new routes for QS crosstalk, particularly for taxa bearing luxR/I solos. Our results show that moderately generated EVs are the potentially important QS signal carriers and ecological regulation hubs in natural waters.

Renal injury is a common complication of hyperuricemia (HUA), which has been recognized as an independent risk factor for chronic kidney disease (CKD). The gut-kidney axis theory suggests that targeting the gut microbiota may be a potential treatment option for kidney disease. In this study, we utilized a spontaneous HUA rat model to demonstrate that Simiao decoction (SMD), a traditional Chinese medicine formula, can effectively alleviate HUA-induced renal injury by modulating gut microbiota and bacterial metabolism of tryptophan and tyrosine, thereby reducing gut-derived uremic toxins such as indoxyl sulfate (IS) and p-Cresol (PC). Fecal microbiota transplantation (FMT) further confirmed that the therapeutic effect of SMD was mediated by gut microbiota. Finally, in vitro studies revealed that IS promotes epithelial-mesenchymal transition (EMT) while PC induces cellular senescence in tubular cells. Collectively, our findings suggest that SMD can effectively alleviate HUA-induced renal injury through regulating gut dysbiosis and decreasing gut-derived uremic toxins. This study sheds light on a novel mechanism by which SMD exerts its effects on HUA-induced renal injury.

Cognitive impairment (CI) following mild traumatic brain injury (mTBI) poses a clinical challenge, with emerging evidence implicating gut microbiota. This study found that mTBI patients who developed CI exhibited decreased Hungatella hathewayi, while those without CI showed an increase. Microbiota transplantation in mTBI rats revealed that higher Hungatella hathewayi levels enriched beneficial, short-chain fatty acid (SCFA) -producing bacteria and reduced harmful ones. Elevated Hungatella hathewayi improved performance in the Morris water maze and novel object recognition tests, indicating enhanced spatial learning and memory. It also reduced gut and brain inflammation, shown by lower TNF-α and IL-6 mRNA expression, and promoted M2 microglia polarization in the peri-lesional cortex. Metabolomics identified increased fecal and serum butyrate, a SCFA with anti-neuroinflammatory properties. Thus, Hungatella hathewayi may mitigate Post-mTBI CI by boosting butyrate production, which alleviates intestinal inflammation, shifts microglia toward the protective M2 phenotype, reduces neuroinflammation, and supports neuroprotection, ultimately lowering CI risk after mTBI. This study was registered with the Chinese Clinical Trial Registry (ChiCTR) on May 31, 2023 (Registration number: ChiCTR2300072000, URL: https://www.chictr.org.cn/showproj.html?proj=197867).

Inflammatory bowel disease (IBD) involves chronic gastrointestinal inflammation with complex etiologies, where gut microbiota and metabolites have emerged as key pathogenic factors. While earlier studies predominantly focused on fecal bacteria, recent research has shifted to mucosa-associated bacteria, which reside in the intestinal mucus layer and directly interact with the epithelium-critical for IBD pathogenesis. This review synthesizes evidence showing that IBD patients exhibit mucosa-associated bacteria dysbiosis, characterized by increased facultative anaerobes and reduced beneficial taxa, alongside altered mucosal metabolites such as short-chain fatty acids (SCFAs) and trimethylamine-N-oxide (TMAO). Notably, mucosa-associated bacteria-driven metabolic changes show promise as early diagnostic markers for IBD. Mechanistically, mucosa-associated bacteria directly modulate intestinal barrier integrity and immune responses via pathways like TLR4-mediated inflammation and mucin degradation, distinct from luminal microbiota studied in fecal samples. This review highlights novel therapeutic strategies targeting mucosa-associated bacteria and mucosal metabolites, including probiotics, phage therapy against AIEC, and nanoparticle-based drug delivery systems for localized anti-inflammatory action. Understanding the mucosa-specific microbiota-metabolite-host interactions is pivotal for advancing precision medicine in IBD, bridging gaps in prior fecal-focused research.

Label-free optical imaging provides non-invasive, high-speed, high-resolution metabolic characterization of live bacteria with single-cell resolution. Here, we demonstrate the ability of label-free multiphoton autofluorescence microscopy to characterize the fast (between 0 and 30 min) metabolic changes in bacteria in response to antibiotic treatments and observe the cell-to-cell metabolic heterogeneity of planktonic bacteria and biofilms. Results indicate that bacteria exhibit a distinct measurable response to bactericidal treatments within seconds. Furthermore, S. aureus biofilms exhibit metabolic heterogeneity, with local pockets of high metabolic activity. Bacteria in biofilms exhibit altered metabolic profiles compared to planktonic bacteria for all four species examined: S. aureus, P. aeruginosa, M. catarrhalis, and S. pneumoniae. These results shed light on the spatial and temporal metabolic heterogeneity of bacteria and the quantification possibilities using label-free nonlinear optical microscopy.

Hepatocellular carcinoma (HCC) is a frequently seen malignant tumor globally. Huaier is the dried fruiting body of the fungus Trametes robiniophila Murr. Huaier granule (HEG), formulated from the Huaier extract, is a Class I innovative anti-cancer drug in China and exhibits significant anti-HCC effects in clinical settings. Nevertheless, the specific mechanisms underlying its efficacy remain incompletely understood. This research demonstrated that HEG effectively suppressed tumor development in the orthotopic HCC mouse model in a gut microbiota-dependent manner and modified the gut microbiota composition. Notably, the primary differential bacterial genera between the Model group and the HEG group included Adlercreutzia. HEG exerted anti-HCC effects by repairing the intestinal barrier, improving colon immunity, and ameliorating the immune microenvironment by suppressing the MAPK signaling pathway via the gut microbiota-gut-liver axis. By integrating 16S rRNA sequencing with metabolomics data, supplemented by literature mining and in vitro validation, Equol, produced by specific gut microbiota Adlercreutzia, was identified as a key metabolite through which HEG exerted its anti-HCC effects by modulating gut microbiota. Moreover, Equol was essential for the anti-HCC effects of HEG. Additionally, Equol ameliorated the immune microenvironment through inhibiting the MAPK signaling pathway, while concurrently inhibiting the growth of HCC cells by inducing the G₀/G₁ phase blockade through suppression of Cyclin E1-CDK2/Rb signaling pathway. This study provided a robust scientific foundation for the clinical use of HEG, with Equol emerging as a promising candidate for HCC treatment.

Emerging evidence underscores the critical role of dietary fiber in maintaining gut homeostasis. While extracellular vesicles (EVs) have recently gained attention as key mediators of host-microbe communication, their functional contribution to fiber deficiency-associated pathologies remains largely unexplored. In this study, we revealed that a fiber-free diet induces significant intestinal inflammatory damage in mice, an effect that can be faithfully reproduced through fecal microbiota transplantation. Importantly, we demonstrated that intestinal epithelial cells-derived EVs from fiber-deprived mice are sufficient to recapitulate the detrimental effects of fiber deficiency. Mechanistic studies revealed enrichment of miR-6240 in these EVs, which targeted the 3'UTR of STAT6 mRNA to suppress its expression. This impairment of STAT6 signaling inhibited M2 macrophage polarization, exacerbating intestinal inflammation. This novel pathway is further validated in primary macrophage adoptive transfer experiments. Our work unveils a previously unrecognized mechanism by which fiber deficiency exacerbates intestinal inflammation through IECs-derived EVs and miR-6240/STAT6-mediated macrophage dysfunction.

Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide and is increasingly recognized as the outcome of complex host-microbe interactions. Beyond established genetic and environmental drivers, the gut microbiome has emerged as a causal and mechanistic contributor to CRC initiation, progression, and therapy response. This review synthesizes current molecular, ecological, and translational evidence to explain how gut microbial communities reprogram immune, metabolic, neural, and endocrine networks within the tumor microenvironment. CRC-associated dysbiosis is characterized by enrichment of pathobionts such as Fusobacterium nucleatum, pks⁺ Escherichia coli, and enterotoxigenic Bacteroides fragilis, and by loss of protective, short-chain-fatty-acid-producing commensals. These microbes promote carcinogenesis through genotoxin-induced DNA damage, epithelial barrier disruption, metabolic rewiring, and chronic inflammation that collectively sustain immune suppression and tumor growth. Defined mutational signatures from bacterial metabolites, including colibactin, cytolethal distending toxin, and indolimines, now directly link microbial exposures to human cancer genomes. By integrating these findings, this review conceptualizes CRC as a biofilm-structured, microbiome-driven ecosystem disease, where polymicrobial consortia coordinate barrier breakdown, immune evasion, and metabolic cooperation. Finally, we highlight emerging microbiota-targeted strategies, including dietary modulation, pre- and probiotics, postbiotics, bacteriophage therapy, engineered live biotherapeutics, and fecal microbiota transplantation, that translate these insights into precision prevention and therapy. Through this integrative framework, the review aims to reposition the microbiome from a correlative feature to a tractable determinant of CRC pathogenesis and treatment response.