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ObjectiveDysbiosis of the intestinal fungal community has been observed in inflammatory bowel disease (IBD); however, its potential role in IBD development and prevention remains unclear. Here, we explored the biological effects and molecular mechanisms of intestinal fungi isolated from human faeces on colitis in mice.DesignIntestinal fungal strains with differential abundance in IBD were cultivated in human faeces and their effects on various mouse models of experimental colitis were evaluated. In addition, the bioactive metabolites secreted by the target fungus were accurately identified and their pharmacological effects and potential molecular targets were investigated in vitro and in vivo.ResultsThe abundance of Candida spp was significantly higher in patients with IBD. After large-scale human intestinal fungal cultivation and functional analysis, Candida metapsilosis M2006B significantly attenuated various models of experimental colitis in wild-type, antibiotic-treated, germ-free, and IL10-/- mice by activating farnesoid X receptor (FXR). Among the seven acyclic sesquiterpenoids (F1–F7) identified as major secondary metabolites of M2006B, F4 and F5 attenuated colitis in mice by acting as novel FXR agonists. The therapeutic effects of M2006B and its metabolites on colitis via specific FXR activation were confirmed in Fxr -/- mice.ConclusionThis study revealed that C. metapsilosis M2006B significantly attenuated colitis in mice and identified two acyclic sesquiterpenoids (F4 and F5) as major active metabolites of M2006B. Notably, these metabolites were able to effectively treat experimental colitis by selectively activating FXR. Together, this study demonstrates that M2006B could be a beneficial intestinal fungus for treating and preventing IBD.

Background Akkermansia muciniphila is one of the most dominant bacteria that resides on the mucus layer of intestinal tract and plays key role in human health, however, little is known about its genomic content. Results Herein, we for the first time characterized the genomic architecture of A. muciniphila based on whole-genome sequencing, assembling, and annotating of 39 isolates derived from human and mouse feces. We revealed a flexible open pangenome of A. muciniphila currently consisting of 5644 unique proteins. Phylogenetic analysis identified three species-level A. muciniphila phylogroups exhibiting distinct metabolic and functional features. Based on the comprehensive genome catalogue, we reconstructed 106 newly A. muciniphila metagenome assembled genomes (MAGs) from available metagenomic datasets of human, mouse and pig gut microbiomes, revealing a transcontinental distribution of A. muciniphila phylogroups across mammalian gut microbiotas. Accurate quantitative analysis of A. muciniphila phylogroups in human subjects further demonstrated its strong correlation with body mass index and anti-diabetic drug usage. Furthermore, we found that, during their mammalian gut evolution history, A. muciniphila acquired extra genes, especially antibiotic resistance genes, from symbiotic microbes via recent lateral gene transfer. Conclusions The genome repertoire of A. muciniphila provided insights into population structure, evolutionary and functional specificity of this significant bacterium.

Human gut microbiota is believed to be directly or indirectly involved in cardiovascular diseases and hypertension. However, the identification and functional status of the hypertension-related gut microbe(s) have not yet been surveyed in a comprehensive manner. Here we characterized the gut microbiome in hypertension status by comparing fecal samples of 60 patients with primary hypertension and 60 gender-, age-, and body weight-matched healthy controls based on whole-metagenome shotgun sequencing. Hypertension implicated a remarkable gut dysbiosis with significant reduction in within-sample diversity and shift in microbial composition. Metagenome-wide association study (MGWAS) revealed 53,953 microbial genes that differ in distribution between the patients and healthy controls (false discovery rate, 0.05) and can be grouped into 68 clusters representing bacterial species. Opportunistic pathogenic taxa, such as, spp., spp., and were frequently distributed in hypertensive gut microbiome, whereas the short-chain fatty acid producer, such as, spp. and , were higher in controls. The number of hypertension-associated species also showed stronger correlation to the severity of disease. Functionally, the hypertensive gut microbiome exhibited higher membrane transport, lipopolysaccharide biosynthesis and steroid degradation, while in controls the metabolism of amino acid, cofactors and vitamins was found to be higher. We further provided the microbial markers for disease discrimination and achieved an area under the receiver operator characteristic curve (AUC) of 0.78, demonstrating the potential of gut microbiota in prediction of hypertension. These findings represent specific alterations in microbial diversity, genes, species and functions of the hypertensive gut microbiome. Further studies on the causality relationship between hypertension and gut microbiota will offer new prospects for treating and preventing the hypertension and its associated diseases.

The symbiotic gut microbiota is pivotal for human health, with its composition linked to various diseases and metabolic disorders. Despite its significance, there remains a gap in systematically evaluating how host phenotypes, such as gender, age, and body mass index (BMI), influence gut microbiota. We conducted an analysis of the gut microbiota of 185 Chinese adults based on whole-metagenome shotgun sequencing of fecal samples. Our investigation focused on assessing the effects of gender, age, and BMI on gut microbiota across three levels: diversity, gene/phylogenetic composition, and functional composition. Our findings suggest that these phenotypes have a minor impact on shaping the gut microbiome compared to enterotypes, they do not correlate significantly within- or between-sample diversity. We identified a substantial number of phenotype-associated genes and metagenomic linkage groups (MLGs), indicating variations in gut microflora composition. Specifically, we observed a decline in beneficial Firmicutes microbes, such as , , and spp., in both older individuals and those with higher BMI, while potentially harmful microbes like , and spp. increased with age. Additionally, and spp. were found to increase with BMI, aligning with prior research. Surprisingly, individuals who were older or overweight exhibited a lack of Bacteroidetes, a dominant phylum in the human gut microbiota that includes opportunistic pathogens, while certain species of the well-known probiotics were enriched in these groups, suggesting a complex interplay of these bacteria warranting further investigation. Regarding gender, several gender-associated MLGs from , , and were enriched in females. Functional analysis revealed a multitude of phenotype-associated KEGG orthologs (KOs). Our study underscores the influence of gender, age, and BMI on gut metagenomes, affecting both phylogenetic and functional composition. However, further investigation is needed to elucidate the precise roles of these bacteria, including both pathogens and probiotics.

Colorectal cancer (CRC) is the third most common cancer globally and the second leading cause of cancer-related deaths. While intestinal microbiota dysbiosis is linked to CRC, the direct role of intratumoral bacteria in metastasis remains poorly understood. In this study, we isolated pathogenic bacteria from CRC tumor tissues, identified as Hungatella hathewayi (H. hathewayi), through the 16S rRNA gene and whole-genome sequencing. We developed specific primers (P48/P52) and polyclonal antibodies for detecting H. hathewayi in samples. Using quantitative real-time PCR (qPCR), we found significant enrichment of H. hathewayi in fecal samples from CRC patients compared to healthy controls, with mean fold changes of 137-fold and 142-fold for primers P48 and P52, respectively. Analysis of tissue samples revealed that H. hathewayi abundance was higher in CRC tumor tissues compared to normal tissues, with mean fold changes of 2.90 for P48 and 3.97 for P52. Fluorescence in situ hybridization (FISH), immunofluorescence (IF), and immunohistochemistry (IHC) confirmed its spatial distribution within tumor tissues. In vitro assays using CRC cell lines demonstrated that H. hathewayi-derived succinate upregulates HIF-1α and SUCNR1 expression and promotes cell metastasis by inducing epithelial–mesenchymal transition (EMT). Collectively, these findings identify H. hathewayi as a novel pro-metastatic bacterium and a potential non-invasive biomarker for CRC diagnosis, providing direct evidence for the role of intratumoral bacteria in CRC progression.

Background The gut virome has been implicated in inflammatory bowel disease (IBD), yet a full understanding of the gut virome in IBD patients, especially across diverse geographic populations, is lacking. Results In this study, we conducted a comprehensive gut virome-wide association study in a Chinese cohort of 71 IBD patients (15 with Crohn’s disease and 56 with ulcerative colitis) and 77 healthy controls via viral-like particle (VLP) and bulk virome sequencing of their feces. By utilizing an integrated gut virus catalog tailored to the IBD virome, we revealed fundamental alterations in the gut virome in IBD patients. These characterized 139 differentially abundant viral signatures, including elevated phages predicted to infect Escherichia , Klebsiella , Enterococcus_B , Streptococcus , and Veillonella species , as well as IBD-depleted phages targeting Prevotella , Ruminococcus_E , Bifidobacterium , and Blautia species . Remarkably, these viral signatures demonstrated high consistency across diverse populations such as those in Europe and the USA, emphasizing their significance and broad relevance in the disease context. Furthermore, fecal virome transplantation experiments verified that the colonization of these IBD-characterized viruses can modulate experimental colitis in mouse models. Conclusions Building upon these insights into the IBD gut virome, we identified potential biomarkers for prognosis and therapy in IBD patients, laying the foundation for further exploration of viromes in related conditions. -rW5fkHC-UvmYPog5oPfKK Video Abstract

This study provides novel evidence for the critical role of maternal milk protein glycosylation in shaping early-life gut microbiota and promoting B cell activation of neonates. The special core-fucosylated oligosaccharides might be promising prebiotics for the personalized nutrition of infants. The maternal milk glycobiome is crucial for shaping the gut microbiota of infants. Although high core fucosylation catalyzed by fucosyltransferase 8 (Fut8) is a general feature of human milk glycoproteins, its role in the formation of a healthy microbiota has not been evaluated. In this study, we found that the core-fucosylated N-glycans in milk of Chinese mothers selectively promoted the colonization of specific gut microbial groups, such as Bifidobacterium spp. and Lactobacillus spp. in their breast-fed infants during lactation. Compared with Fut8 +/+ (WT) mouse-fed neonates, the offspring fed by Fut8 +/− maternal mice had a distinct gut microbial profile, which was featured by a significant reduction of Lactobacillus spp., Bacteroides spp., and Bifidobacterium spp. and increased abundance of members of the Lachnospiraceae NK4A136 group and Akkermansia spp. Moreover, these offspring mice showed a lower proportion of splenic CD19 + CD69 + B lymphocytes and attenuated humoral immune responses upon ovalbumin (OVA) immunization. In vitro studies demonstrated that the chemically synthesized core-fucosylated oligosaccharides possessed the ability to promote the growth of tested Bifidobacterium and Lactobacillus strains in minimal medium. The resulting L- fucose metabolites, lactate and 1,2-propanediol, could promote the activation of B cells via the B cell receptor (BCR)-mediated signaling pathway. IMPORTANCE This study provides novel evidence for the critical role of maternal milk protein glycosylation in shaping early-life gut microbiota and promoting B cell activation of neonates. The special core-fucosylated oligosaccharides might be promising prebiotics for the personalized nutrition of infants.

Background: The rapid emergence of antibiotic resistance in Acinetobacter baumannii has led the World Health Organization (WHO) to designate it as a “high priority” pathogen. The emergence of multidrug-resistant (MDR) and pandrug-resistant (PDR) strains poses considerable treatment challenges. As antimicrobial resistance (AMR) escalates toward a post-antibiotic era, innovative therapeutic solutions are urgently needed. Objectives: To clone, over-express, and characterize a novel endolysin, LysTAC1, from Acinetobacter phage TAC1 for its antibacterial efficacy against multidrug-resistant bacteria. Methods: A 24 kDa endolysin featuring a glycoside hydrolase Family 19 chitinase domain was tested against carbapenem-resistant Acinetobacter baumannii clinical isolates and various Escherichia coli strains following outer membrane permeabilization with Ethylenediaminetetraacetic acid (EDTA). Stability assays and molecular docking studies were performed. Results: LysTAC1 demonstrated potent lytic activity against Gram-negative bacteria but showed no activity against Gram-positive bacteria (Staphylococcus aureus ATCC 29213 and Enterococcus gallinarum HCD 28-1). LysTAC1 maintained activity across pH 6–9 and temperatures 4–65 °C, with differential sensitivity to metal ions where K+ showed no inhibitory effect at any concentration (0.1–100 mM), and Fe2+ was non-inhibitory at lower concentrations (0.1–1 mM), while Mg2+ and Ca2+ demonstrated concentration-dependent inhibition across the tested range (0.1–100 mM). Molecular docking revealed LysTAC1 interactions with chitinase substrates 4-nitrophenyl N-acetyl-β-D-glucosaminide and 4-nitrophenyl N, N-Diacetyl-β-D-chitobioside, with binding energies of −5.82 and −6.85 kcal/mol, respectively. Conclusions: LysTAC1 shows significant potential as a targeted therapeutic agent against A. baumannii with robust stability under physiological conditions.

Ankylosing spondylitis (AS), a chronic autoimmune disease, has been linked to the gut bacteriome. To investigate the characteristics of the gut virome in AS, we profiled the gut viral community of 193 AS patients and 59 healthy subjects based on a metagenome-wide analysis of fecal metagenomes from two publicly available datasets. AS patients revealed a significant decrease in gut viral richness and a considerable alteration of the overall viral structure. At the family level, AS patients had an increased abundance of and and a decreased abundance of and . We identified 1,004 differentially abundant viral operational taxonomic units (vOTUs) between patients and controls, including a higher proportion of AS-enriched viruses and control-enriched viruses. Moreover, the AS-enriched vOTUs were more likely to infect bacteria such as , , and , whereas the control-enriched vOTUs were more likely to be , , , , and bacteriophages. Additionally, some viral functional orthologs differed significantly in frequency between the AS-enriched and control-enriched vOTUs, suggesting the functional role of these AS-associated viruses. Moreover, we trained classification models based on gut viral signatures to discriminate AS patients from healthy controls, with an optimal area under the receiver operator characteristic curve (AUC) up to 0.936, suggesting the clinical potential of the gut virome for diagnosing AS. This work provides novel insight into the AS gut virome, and the findings may guide future mechanistic and therapeutic studies for other autoimmune diseases.

Idiopathic inflammatory myopathies (IIMs) are systemic autoimmune disorders with unknown etiology. Despite the established link between gut microbes and immunity, the roles of gut bacteriome, mycobiome, and virome in IIM are unexplored. We performed shotgun metagenomic sequencing on fecal samples from 34 IIM patients and 37 healthy controls to profile gut microbiota. Taxonomic, functional, network, and machine-learning analyses revealed microbial dysbiosis and its potential for discriminating IIM. All three microbial kingdoms were significantly altered in IIM. Several inflammation-associated bacterial taxa (e.g., Rothia mucilaginosa , Streptococcus parasanguinis , Trueperella pyogenes ) and opportunistic fungi (e.g., Aspergillus spp.) were enriched in IIM, while SCFA-producing bacteria and fungi were depleted. Virome analysis revealed substantial shifts, with higher abundance of Siphoviridae in IIM. Altered viral functional gene profiles suggesting enhanced phage-mediated genome integration, recombination, and bacterial stress adaptation. Multi-kingdom network analysis showed extensive rewiring in IIM, characterized by increased network connectivity and a shift toward fungi-centered ecological hubs, contrasting with bacteria/virus-dominated networks in controls. In machine-learning models, the virome demonstrated the strongest discriminatory power, and viral signatures dominated the combined multi-kingdom classifier (AUC = 0.997). This first comprehensive multi-kingdom gut microbiota analysis in IIM provides a foundation for developing diagnostic and therapeutic strategies.