Extensive herbicide residues in the black soil of northeastern China are considered a significant agricultural pollution threat, yet effective bioremediation of this complex and persistent mixture remains a challenge. We identified 16 bacterial species that associated with these herbicide residues in situ, nine of which were culturable and could degrade multiple herbicides. From these strains, we constructed a four-member synthetic microbial community (SynCom) that degrades multiple herbicides, stabilizes colonization, increases soil bacterial biodiversity, and alters soil enzyme activity. Under laboratory conditions, the SynCom degraded eight herbicides within 48 h with >60% efficiency, and accumulated carbon on the cell surface of the constituent species. In black soil microcosm trials, the SynCom achieved 60%−99% degradation efficiency of the endogenous herbicides over 35 days and was able to consistently maintain biomass above 104 cfu/g soil. Additionally, SynCom application resulted in an accumulation of carbohydrate-active enzymes and microbial necromass-associated carbon, which suggests activation of soil microbial carbon metabolism. In support of this, metagenomic analyses identified a significant increase in the abundance of genes involved in the tricarboxylic acid cycle, pyruvate metabolism, and glycolysis. This SynCom represents a compelling bioremediation solution that simultaneously improves soil microbial carbon metabolism activity in polluted soils.
Porcine deltacoronavirus (PDCoV) is a significant pathogen of swine with a global distribution, leading to severe gastrointestinal disease and substantial economic losses. Furthermore, PDCoV poses a potential threat to human health, as evidenced by the recent identification of three cases of infection in Haitian children. This study aimed to investigate the effects of PDCoV infection on host intestinal microbiota and bile acid metabolism, as well as the antiviral effects of lithocholic acid (LCA) in vitro and in vivo. Our results revealed that PDCoV infection caused microbiota dysbiosis in piglets, significantly reducing the intestinal abundance of Bacteroides fragilis (B. fragilis), a reduction that correlated with disruptions in bile acid metabolism. Colonization with bile salt hydrolase (BSH)-producing B. fragilis increased the levels of unconjugated bile acids and inhibited PDCoV infection, highlighting the role of microbiota-associated bile acid metabolism in viral pathogenesis. LCA, a prominent unconjugated bile acid, was shown to effectively inhibit PDCoV infection in porcine small intestinal epithelial cells and porcine intestinal enteroids. Notably, LCA inhibited PDCoV replication independently of bile acid receptor signaling and innate immune modulation. Mechanistic studies indicated that LCA prevents PDCoV infection by disrupting the viral entry process, specifically inhibiting the binding between the PDCoV spike protein and its cellular receptor, aminopeptidase N. In vivo experiments further confirmed that LCA significantly inhibited PDCoV infection in piglets. These results collectively highlight the potential of LCA as a therapeutic agent against PDCoV by targeting and disrupting the viral entry process, providing a novel strategy to control zoonotic PDCoV infections.
Polycystic ovary syndrome (PCOS) is a prevalent endocrine and reproductive disorder affecting women of reproductive age. While the gut microbiota has been implicated in PCOS pathophysiology, the role of microbial-derived metabolites as mediators of host–microbe interactions remains poorly defined. Here, we integrated untargeted gut metabolomics with metagenomic profiling in patients with PCOS and identified a marked depletion of 3,4-dihydroxyphenylacetic acid (DHPAA), a flavonoid-derived microbial catabolite. Oral administration of DHPAA ameliorated PCOS-like phenotypes in two mouse models by suppressing bone morphogenetic protein signaling and reducing anti-Müllerian hormone (AMH) levels. We found that DHPAA production depends on gut microbial degradation of dietary flavonoids. We further identified a bacterial species, Streptococcus thermophilus, consistently depleted in PCOS across two human cohorts and a mouse model, restored DHPAA levels and improved reproductive outcomes in mice. Conversely, a β-galactosidase-deficient mutant of S. thermophilus failed to confer these benefits, highlighting β-galactosidase as a critical enzyme in DHPAA biosynthesis. Our findings establish DHPAA as a key microbial metabolite linking diet, microbiota, and reproductive health, and propose its potential as a novel therapeutic candidate for PCOS.
Lipopolysaccharides (LPS) derived from intestinal symbionts plays a critical role in modulating and maintaining mucosal immunity. In this study, we investigated the chemical characteristics and antiobesity properties of Akkermansia muciniphila HW07 LPS (ALPS). ALPS was identified as hypo-acylated, mono/bis-phosphorylated, rough-type LPS. Compared to Escherichia coli LPS (ELPS), ALPS functions as a weak agonist of TLR4/TLR2. Intraperitoneal administration of ALPS in diet-induced obese (DIO) mice suppressed weight gain, improved metabolic parameters, restored gut barrier integrity, and modulated the gut microbiota. Notably, ALPS treatment significantly increased plasma interleukin (IL)-22 levels. Furthermore, neutralizing IL-22 with an antibody eliminated the antiobesity effects of ALPS in DIO mice. Mechanistically, ALPS upregulated the expression of both IL-22 and its upstream cytokine IL-23 in a TLR4-dependent manner. These findings confirm that activation of the TLR4−IL-23−IL-22 immune axis is a key mechanism underlying the antiobesity effect of ALPS. In acute toxicity assessment, no fatalities were observed in ALPS-treated mice, whereas ELPS treatment led to a 40% mortality rate. Collectively, our results demonstrate that hypo-acylated LPS from A. muciniphila functions as a metabolically beneficial immune modulator that exerts immunomodulatory effects through the TLR4−IL-22 axis and suggests ALPS as a promising novel therapeutic strategy for metabolic disorders.
Hepatocellular carcinoma (HCC) is associated with high mortality rates despite the widespread application of radiofrequency ablation (RFA), which has limited therapeutic efficacy as a monotherapy. This study investigated ribonucleotide reductase M2 (RRM2) upregulation in post-RFA HCC tissues and developed a targeted nanoco-delivery system (red blood cell membrane/cRGD-modified pH-sensitive liposomes [sS@RBCM/cRGD-phLips]) to increase RFA efficacy through specific RRM2 knockout. RRM2 knockout synergistically amplified RFA-induced tumor cell death by promoting ferroptosis and immunogenic cell death. Mechanistically, RRM2 knockout upregulated the STAT1–IRF1–ACSL4 axis, which potentiated lipid peroxidation and ferroptosis. Furthermore, the nanocarrier system enhanced dendritic cell maturation and cytotoxic T cell infiltration, thereby remodeling the tumor immune microenvironment. In vivo experiments revealed that the combination of RFA and RRM2-targeted nanoparticles significantly suppressed tumor growth and prolonged survival in HCC-bearing mice with minimal systemic toxicity. Notably, the dual-loaded nanoparticles also enhanced the efficacy of anti-programmed cell death protein 1 therapy, suggesting a promising combinatorial approach for HCC treatment. This study presents a novel therapeutic strategy that integrates RRM2-targeted gene editing with RFA, offering a robust and synergistic approach for improving HCC outcomes.
The human microbiome is now recognized as a central regulator of cancer biology, intricately shaping tumor development, immune dynamics, and therapeutic response. This comprehensive review delineates the multifaceted roles of bacteria, viruses, and fungi in modulating the tumor microenvironment and systemic immunity across diverse cancer types. We synthesize current evidence on how microbial dysbiosis promotes carcinogenesis via chronic inflammation, metabolic reprogramming, genotoxic stress, immune evasion, and epigenetic remodeling. This review emphasizes organ-specific microbiome signatures and highlights their potential as non-invasive biomarkers for early detection, treatment stratification, and prognosis. Furthermore, we explore the impact of intratumoral microbiota on cancer therapies, uncovering how microbial metabolites and host–microbe interactions shape therapeutic efficacy and resistance. Finally, advances in microbiome-targeted strategies, such as probiotics, fecal microbiota transplantation, and engineered microbes offer new avenues for adjunctive cancer therapy. This review provides a roadmap for future investigation and underscores the transformative promise of microbiome modulation in cancer prevention and treatment.
Gemcitabine resistance drives bladder cancer recurrence and progression. Using high-throughput drug screening in bladder cancer cells, we identified Bavachalcone (Bava) as a potent gemcitabine sensitizer. Mechanistically, Bava simultaneously targets transferrin receptor (TFRC) and epidermal growth factor receptor (EGFR). It competes with transferrin (Tf) for TFRC binding, reducing cellular iron influx, and inhibits EGFR-mediated phosphorylation of TFRC at tyrosine 20 (Y20). These actions disrupt mitochondria iron utilization and impairs respiration. The combination of Bava and gemcitabine synergistically inhibits the repair of gemcitabine-induced DNA damage, while suppressing the iron-dependent ATR-CHEK1-E2F1 pathway and downregulating RRM1 expression. Patient-derived xenograft models confirmed the superior antitumor efficacy of the Bava-gemcitabine co-treatment compared to monotherapies. Clinically, elevated TFRC and RRM1 expression correlates with poor prognosis, supporting their utility as biomarkers of bladder cancer. Our study identified Bava as the first small-molecule TFRC inhibitor that overcomes gemcitabine resistance through iron modulation, providing both mechanistic insights and a promising therapeutic strategy for bladder cancer.
The emergence of hypervirulent carbapenem-resistant Klebsiella pneumoniae (hvCRKP) represents an alarming convergence of enhanced virulence and extensive drug resistance. Here, we present a comprehensive genomic analysis of 2563 clonal complex 23 (CC23) isolates from 62 countries spanning 1932–2024. Our findings reveal that CC23-K1, the dominant hypervirulent sublineage, emerged approximately 170 years ago and diversified into seven major clades with distinct regional dominance. We observe that carbapenem resistance in CC23-K1 exhibits notable instability, with at least 130 independent acquisitions and 20 losses of resistance genes, suggesting an evolutionary trade-off between hypervirulence and antimicrobial resistance. Experimental validation demonstrates that capsule production physically impedes plasmid conjugation, while isolates carrying blaKPC-2, blaNDM-1, or blaNDM-5 frequently exhibit substantial deletion of virulence determinants. Conversely, blaOXA-48-carrying isolates maintain virulence gene integrity, potentially due to their lower hydrolytic activity and reduced fitness costs. The geographic distribution of these resistance mechanisms correlates with regional antimicrobial usage patterns, with European countries with moderate carbapenem use favoring blaOXA-48 in CC23, while Asian countries with higher consumption show patterns favoring high-efficiency carbapenemases incompatible with complete virulence determinants. We also identified core genomic regions with significantly higher mutation rates in resistant isolates, particularly affecting pathways involved in oxidative phosphorylation and reactive oxygen species production. These findings provide additional insights into CC23 evolution and geographical spread, complementing existing knowledge of carbapenemase distribution patterns observed across K. pneumoniae lineages.
Fastp has been recognized as one of the most popular FASTQ file preprocessors because of its powerful functions and extreme performance. As its first major update, fastp 1.0 will be formally presented in this paper, including its new features and the implementation principles behind it. Two other popular FASTQ preprocessors, Trimmomatic and Cutadapt, will be compared to demonstrate the great advantages of fastp in terms of simplicity, efficiency, and versatility. Some modules, such as the batch processing scripts, will be introduced on how to apply fastp to process FASTQ files efficiently. Additionally, some software design principles will be highlighted to showcase how to develop a successful bioinformatics software.
Early identification of patients at risk of acute coronary syndrome (ACS) remains a major unmet need, particularly among those with stable coronary artery disease (sCAD), where timely intervention could markedly improve outcomes. The gut microbiota has been implicated in coronary artery disease (CAD), but its ability to distinguish ACS from sCAD is not well defined. Here, we performed cross-sectional multi-omics profiling of fecal microbiota and plasma metabolites in 548 individuals, including participants with normal coronary arteries (N = 175), primary sCAD (N = 161), and ACS (N = 212). To assess whether disease-associated changes resolve with treatment, we further analyzed an independent cohort of ACS patients (N = 52) who transitioned to sCAD following standard therapy. We identified profound ACS-associated alterations in gut microbial composition and systemic metabolism, marked by enrichment of pro-inflammatory taxa such as Streptococcus spp. and elevated circulating levels of 3-hydroxybutyrate (3-HB). Strikingly, many of these ACS-specific microbial and metabolic signatures, including 3-HB and related microbial functional pathways, were restored toward sCAD-like levels after clinical recovery. Integrative models combining microbial taxa, metabolites, and clinical biomarkers robustly discriminated ACS from healthy controls (AUC = 0.91) and from sCAD (AUC = 0.83), significantly outperforming clinical markers alone (AUC = 0.69 for NCA vs. ACS; 0.59 for sCAD vs. ACS). These findings establish the gut microbiome and its metabolic outputs as key discriminators of ACS, reveal their dynamic resolution during disease recovery, and highlight their potential as biomarkers and therapeutic targets for cardiovascular risk stratification and management.