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PubMed2026

In vivo porcine multi-omics integration identifies microbiome-driven histamine elevation and lasting gut perturbations following Ascaris suum infection and fenbendazole treatment.

Ascaris roundworms impair human and swine health. While treatments using anthelmintic drugs are generally effective in eliminating worms, their effects on the gut microenvironment remain poorly understood. Here we applied integrated multi-omics to characterize infection- and treatment-associated alterations in the pig-Ascaris system. In vitro anaerobic cultures were conducted as supportive validation of selected observations. Ascaris suum infection altered microbial composition and dysregulated 182 serum and fecal metabolites, including histamine and p-cresol sulfate. Compared with time-matched uninfected controls, infected pigs treated with fenbendazole showed marked differences in gut microbial composition 13 days after confirmed worm clearance. Eleven microbial pathways were enriched in successfully treated pigs, including peptidoglycan biosynthesis and histidine metabolism, indicating that infection-associated alterations may persist after treatment. In vitro co-exposure of Lactobacillus reuteri to fenbendazole and A. suum proteins increased histamine production by approximately 79% at 48 h (p < 0.05), serving as supportive evidence of a microbiome contribution. Collectively, our in vivo findings support that host-microbiota-parasite interactions are multifaceted. Microbiota-derived metabolites were associated with regulation of host gene expression, such as TFF2 and IL8. Microbiota plasticity allows the exploitation of the niche differentiated upon infection, resulting in the proliferation of certain Lactobacillus strains in treated animals. Nevertheless, interpretations of treatment effects are made cautiously given the absence of an uninfected drug-only group and the cross-sectional design. Understanding these complex interactions will be important for the design of next-generation functional anthelmintics.

Animals↗

PubMed2026

Impacts of host genetics on gut microbiome composition in Alzheimer's disease.

BACKGROUND: Host-microbiome interactions play essential roles in the development of Alzheimer's disease (AD), yet the host genetic impacts on gut microbial alterations in AD remain poorly understood. RESULTS: Here, we simultaneously profiled host genotype and gut microbiome in 252 Chinese individuals with varying degrees of cognitive disability. Using the latent Dirichlet allocation topic model, we identified the Anaerostipes-enriched enterosignature (ES-Ana) at the microbial subgroup level as significantly negatively associated with cognitive disability, which could be recapitulated in external cohorts. With the whole-genome sequencing data, we performed microbiome genome-wide association studies for the ES-Ana relative abundance. We prioritized 41 lead genetic variants and confirmed that the high ES-Ana relative abundance showed a negative correlation with the polygenic risk score of AD, indicating its protective effect against AD. Furthermore, we identified 174 ES-Ana-associated genes, which are enriched in AD-related biological functions and phenotypes, and exhibite pervasive underexpression in glial cells during brain aging. CONCLUSIONS: In summary, our study reveals the complex genetic effects on the gut microbiota in AD, and provides novel evidence for the roles of the gut-brain axis in AD. Video Abstract.

Alzheimer Disease↗

PubMed2025

Large Quantities of Bacterial DNA and Protein in Common Dietary Protein Source Used in Microbiome Studies.

Diet has been shown to greatly impact the intestinal microbiota. To understand the role of individual dietary components, defined diets with purified components are frequently used in diet-microbiota studies. Defined diets frequently use purified casein as the protein source. Previous work indicated that casein contains microbial DNA potentially impacting results of microbiome studies. Other diet-based microbially derived molecules that may impact microbiome measurements, such as proteins detected by metaproteomics, have not been determined for casein. Additionally, other protein sources used in microbiome studies have not been characterized for their microbial content. We used metagenomics and metaproteomics to identify and quantify microbial DNA and protein in a casein-based defined diet to better understand potential impacts on metagenomic and metaproteomic microbiome studies. We further tested six additional defined diets with purified protein sources with an integrated metagenomic-metaproteomic approach and found that contaminating microbial protein is unique to casein within the tested set as microbial protein was not identified in diets with other protein sources. We also illustrate the contribution of diet-derived microbial protein in diet-microbiota studies by metaproteomic analysis of stool samples from germ-free mice (GF) and mice with a conventional microbiota (CV) following consumption of diets with casein and non-casein protein. This study highlights a potentially confounding factor in diet-microbiota studies that must be considered through evaluation of the diet itself within a given study.

Animals↗

PubMed2025

Systematically investigating and identifying bacteriocins in the human gut microbiome.

Human gut microbiota produces unmodified bacteriocins, natural antimicrobial peptides that protect against pathogens and regulate host physiology. However, current bioinformatic tools limit the comprehensive investigation of bacteriocins' biosynthesis, obstructing research into their biological functions. Here, we introduce IIBacFinder, a superior analysis pipeline for identifying unmodified class II bacteriocins. Through large-scale bioinformatic analysis and experimental validation, we demonstrate their widespread distribution across the bacterial kingdom, with most being habitat specific. Analyzing over 280,000 bacterial genomes, we reveal the diverse potential of human gut bacteria to produce these bacteriocins. Guided by meta-omics analysis, we synthesized 26 hypothetical bacteriocins from gut commensal species, with 16 showing antibacterial activities. Further ex vivo tests show minimal impact of narrow-spectrum bacteriocins on human fecal microbiota. Our study highlights the huge biosynthetic potential of unmodified bacteriocins in the human gut, paving the way for understanding their biological functions and health implications.

Humans↗

PubMed2026

Host-independent metagenomics reveal gut bacteria contribution to Delia antiqua growth by vitamin B6 provision.

Insect guts host a diverse and abundant array of microorganisms. These microbes improve host fitness by extensively involving in a range of crucial physiological processes, which have mainly been revealed by high-throughput sequencing, particularly metagenomics. However, it is almost impossible to make an accurate and complete distinction between the genetic functions of microbial symbionts and insect hosts without host genome data. By comparing metagenomic data from gut germ-free and nonaxenic larvae, we accurately identified the data belonging to the gut microbiome of the onion maggot Delia antiqua (Diptera: Anthomyiidae). Besides, a correlation between bacteria of the genus Wohlfahrtiimonas (Gammaproteobacteria: Pseudomonadaceae) and vitamin B6 metabolism was detected through collinearity analysis. Furthermore, in vitro tests confirmed that the gut bacterium Wohlfahrtiimonas larvae contributed to the growth of D. antiqua larvae via the independent synthesis of vitamin B6. This study provides a comprehensive view of the gut bacterial diversity in D. antiqua and reveals a functional profile that is strictly specific to the gut microbiota of this species. It has preliminarily revealed the functional differentiation between insect hosts and their symbiotic microorganisms. This study also offers a technical reference for the study of microbial symbiotic functions in other insect-microbe symbioses without host genomic data.

Animals↗

PubMed2025

Microbiota and kidney disease: the road ahead.

More than 850 million individuals worldwide, accounting for 10-15% of the adult population, are estimated to have chronic kidney disease. Each of these individuals is host to tens of trillions of microorganisms that are collectively referred to as microbiota - a dynamic ecosystem that both influences host health and is itself influenced by changes in the host. Available evidence supports the existence of functional connections between resident microorganisms and kidney health that are altered in the context of specific kidney diseases, including acute kidney injury, chronic kidney disease and renal stone disease. Moreover, promising data from preclinical studies suggest that targeting of gut microbial pathways may provide new therapeutic opportunities for the treatment of kidney disease. This Roadmap describes current understanding of the mechanisms by which microorganisms regulate host organ function, the effects of kidney disease on the gut microbiome, and how these insights may contribute to the development of microbe-targeted therapeutics. We highlight key knowledge gaps that remain to be addressed and strategies for addressing these, outlining both the promise and the potential pitfalls of leveraging our understanding of the gut microbiota to better understand and treat kidney disease.

Humans↗

PubMed2026

Effects of Lactiplantibacillus plantarum KABP051 Probiotic on Body Composition, Microbiome and Mood in Healthy Overweight Adults.

Obesity and mental health disorders are among the greatest public health challenges of the 21st century. Interestingly, an altered microbiome profile has been associated with both conditions. The aim of this randomized, double-blind, placebo-controlled clinical trial was to evaluate the effects of dietary supplementation with a specific probiotic strain (Lactiplantibacillus plantarum KABP051) on body composition and gut microbiome balance, together with measures of mood state, in a population of healthy overweight subjects. Sixty healthy, moderately stressed, nondepressed and overweight or obese volunteers were supplemented for 12 weeks with probiotic (L. plantarum KABP051; 1 billion colony forming units/day) or placebo (microcrystalline cellulose). The KABP051 group experienced significantly greater improvements compared with placebo on body composition measurements, including a reduction in body weight and waist circumference, which decreased in 1.97 ± 0.77 (mean ± SE) kg and 2.15 ± 0.81 (mean ± SE) cm versus placebo at the end of the intervention (both P < .05, mixed model for repeated measures [MMRM] and post-hoc analysis). Microbiome composition improved in KABP051 group, with significant increase in the relative abundance of Lactiplantibacillus spp. versus placebo. Body fat percentage, profile of mood states fatigue, and confusion sub-scores showed a global trend toward improvement compared with placebo, with the change at 12 weeks being significant in the three measurements in post-hoc analysis (P = .015, P = .014, and P = .016, respectively). No serious adverse events were registered during the intervention period. These results suggest that a specific strain of probiotic bacteria (L. plantarum KABP051) may have both metabolic and psychobiotic effects and may be beneficial for enhancing weight loss and body composition, improving energy (less fatigue) and mood levels while embarking on a healthy lifestyle regimen. ClinicalTrials.gov identifier: NCT06808061.

Humans↗

PubMed2025

Understanding disease-associated metabolic changes in human colonic epithelial cells using the iColonEpithelium metabolic reconstruction.

The colonic epithelium plays a key role in the host-microbiome interactions, allowing uptake of various nutrients and driving important metabolic processes. To unravel detailed metabolic activities in the human colonic epithelium, our present study focuses on the generation of the first cell-type-specific genome-scale metabolic model (GEM) of human colonic epithelial cells, named iColonEpithelium. GEMs are powerful tools for exploring reactions and metabolites at the systems level and predicting the flux distributions at steady state. Our cell-type-specific iColonEpithelium metabolic reconstruction captures genes specifically expressed in the human colonic epithelial cells. iColonEpithelium is also capable of performing metabolic tasks specific to the colonic epithelium. A unique transport reaction compartment has been included to allow for the simulation of metabolic interactions with the gut microbiome. We used iColonEpithelium to identify metabolic signatures associated with inflammatory bowel disease. We used single-cell RNA sequencing data from Crohn's Diseases (CD) and ulcerative colitis (UC) samples to build disease-specific iColonEpithelium metabolic networks in order to predict metabolic signatures of colonocytes in both healthy and disease states. We identified reactions in nucleotide interconversion, fatty acid synthesis and tryptophan metabolism were differentially regulated in CD and UC conditions, relative to healthy control, which were in accordance with experimental results. The iColonEpithelium metabolic network can be used to identify mechanisms at the cellular level, and we show an initial proof-of-concept for how our tool can be leveraged to explore the metabolic interactions between host and gut microbiota.

Humans↗

PubMed2026

Microbiome features associated with persistent intestinal carriages of Escherichia coli ST131 in a Southeast Asian cohort study.

Escherichia coli sequence-type 131 (ST131) is the dominant global extraintestinal pathogen capable of asymptomatic intestinal carriage and sustained household transmission, challenging infection control. Despite its clinical significance, the ecological determinants of gut persistence remain poorly understood. We performed shotgun metagenomics on fecal samples to investigate gut microbiome features associated with ST131-positive samples, distinct host carrier statuses (persistent, intermittent and non-carriers) and household risks in a study of a Southeast Asian cohort. Here, we show that ST131 carriage was associated with compositional shifts without reducing species alpha-diversity. Regression analyses identified depletion of commensal taxa and the 1,5-anhydrofructose degradation pathway in ST131-positive samples. Persistent carriers exhibited highly perturbed microbiome enriched with pathobionts, aerobactin- and lipopolysaccharide (LPS)-biosynthesis pathways. Comparing household risk groups to control, revealed that biotin biosynthesis and 1,5-anhydrofructose degradation may influence ST131 co-colonization through both direct and indirect mechanisms. Machine learning analyses identified metabolic pathways as stronger discriminators of persistent carriage than taxonomic features. Genomic-resolved analysis of clinical ST131 isolates revealed conserved genes for iron-acquisition, LPS and antibiotic resistance determinants. Overall, while commensals and metabolism may influence initial ST131 colonization, persistent carriage is associated with specific microbial and metabolic adaptations, providing potential targets to limit intestinal ST131 persistence.

Humans↗

PubMed2026

Microbiota-gut-muscle axis shapes fish muscle texture by regulating collagen synthesis.

BACKGROUND: Increasing studies have emphasized the communication network between the gut microbiome and host organs, revealing that such interactions significantly influence host physiological performances. However, whether a gut-muscle axis exists to regulate muscle quality in animal production is unknown. RESULTS: In two independent cohorts, the muscle hardness of tilapia subjected to a long-term faba bean diet exhibited significant inter-individual variation. RNA-Seq analyses of the high-hardness (H) and low-hardness (L) groups pointed to collagen-based extracellular matrix as a possible factor driving muscle hardness development. Transplantation of gut microbiota from the H donor resulted in enhanced collagen synthesis in gnotobiotic zebrafish. Muscular collagen deposition was featured with an increased abundance of gut Cetobacterium. Gnotobiotic models colonized with live C. somerae exhibited enhanced collagen synthesis. Integrated analyses of microbiome function, bacterial genome, and metabolic profiles identified acetate as a key effector of C. somerae. Acetate incubation upregulated collagen I expression in TGF-β-activated fibroblasts in an acetylation-dependent manner. Mechanistically, acetate promoted the acetylation of SMAD2/3, enhancing its nuclear transport and stability, which ultimately increased collagen expression. An acetate-supplemented feeding experiment corroborated these findings. CONCLUSION: The comprehensive results provided evidences that gut microbes regulated tilapia muscle texture through SMAD2/3 acetylation-driven collagen synthesis. This study expands our understanding of the multifaceted role of the gut-muscle axis in muscle physiology. Furthermore, our findings highlight that targeting gut microbiota and the downstream collagen synthesis pathway could be promising for manipulating muscle quality in animal production. Video Abstract.

Animals↗

PubMed2026

Identification and Classification of Expressed Orphan Genes, Spurious Orphan Genes, and Conserved Genes in the Human Gut Microbiome.

Orphan genes (OGs)-genes lacking detectable homologs outside a species-are widespread in microbial genomes and are thought to contribute to their adaptation and molecular innovation. However, not all predicted OGs may represent novel functional coding sequences. False positive OGs, also called spurious OGs, can arise from gene prediction errors. We reason that OGs lacking detectable expression are more likely to be spurious. To test this, we combined large-scale metatranscriptomic profiling of the human gut microbiome with machine learning to distinguish expressed OGs from spurious ones and compare them with conserved genes (CGs) found in multiple species. Using nearly 5,000 metatranscriptome libraries, we identified ∼218,000 OGs supported by expression evidence, while ∼330,000 predicted OGs lacked detectable expression and were classified as spurious. We extracted 154 features for sequence, structural, and evolutionary properties for each gene and trained XGBoost classifiers while accounting for genomic representation. The models achieved an area under the receiver operating characteristic curve (AUC) of 0.82 in distinguishing expressed OGs from spurious OGs and an AUC of 0.93 in distinguishing expressed OGs from CGs. Interpretation based on SHAP (SHapley Additive exPlanations) revealed clear biological signals. Particularly, expressed orphans were present in more genomes than spurious ones, and expressed OGs were shorter than CGs. This work improves OG discovery and suggests that expressed OGs differ systematically from CGs and spurious OGs in sequence composition, structural constraints, and evolutionary signals.

Humans↗

PubMed2025

Metabolism and gene expression models for the microbiome reveal how diet and metabolic dysbiosis impact disease.

The gut microbiome plays a critical role in human health, spurring extensive research using multi-omic technologies. Although these tools offer valuable insights, they often fall short in capturing the complexity of microbial interactions that associate with disease onset, progression, and treatment. Thus, integration of multi-omics datasets with metabolic models is needed to predict associations between microbial activity and disease. Here, we automated the reconstruction of 495 metabolic and gene expression models (ME-models), overcoming the main limitation preventing the wide use of this approach. We integrated them with multi-omics data from patients with inflammatory bowel disease (IBD), identifying taxa associated with variations in amino acids, short-chain fatty acids, and pH in the gut of IBD patients. In general, this approach provides testable hypotheses of the metabolic activity of the gut microbiota, and the automated pipeline opens the opportunity to study microbial interactions in other biologically relevant settings using ME-models.

Humans↗

PubMed2024

Metagenomic Analysis of Gut Microbiome of Persistent Pulmonary Hypertension of the Newborn.

Persistent pulmonary hypertension of the newborn (PPHN) is one of the most common diseases in the neonatal intensive care unit which severely affects neonatal survival. Gut microbes play an increasingly important role in human health, but there are rarely reported how gut microbiota contribute to PPHN. In our study, the metagenomic sequencing of feces from 12 PPHN's neonates and 8 controls were performed to expose the relation between neonatal gut microbes and PPHN disease. Firstly, we found that the abundance of Actinobacteria, Proteobacteria, Bacteroidetes were significantly increased in PPHN compared with controls, but the Firmicutes components was reduced. And some pathogenic strains (like Vibrio metschnikovii) were significantly enriched in the PPHN compared with controls. Secondly, functional annotation of genes found that PPHN up-regulated transmembrane transport, but down-regulated ribosome and ATP binding. Lastly, microbial metabolic pathway enrichment analysis indicated that some metabolic pathway in PPHN were conflicting and contradictory, showed that an abnormally increased metabolism, disturbed protein synthesis and genomic instability in the PPHN neonate. Our results contribute to understanding the changes in the species and function of gut microbiota in PPHN, thus providing a theoretical basis for the explanation and treatment of PPHN.

Gastrointestinal Microbiome↗

PubMed2024

Characterizing the gut microbiome of diarrheal mink under farmed conditions: A metagenomic analysis.

This study aimed to comprehensively characterize the gut microbiota in diarrheal mink. We conducted Shotgun metagenomic sequencing on samples from five groups of diarrheal mink and five groups of healthy mink. The microbiota α-diversity and Kyoto Encyclopedia of Genes and Genomes (KEGG) orthology did not show significant differences between the groups. However, significant differences were observed in microbiota β-diversity and the function of carbohydrate-active enzymes (CAZymes) between diarrheal and healthy mink. Specifically, The relative abundance of Firmicutes was lower, whereas that of Bacteroidetes was higher in diarrheal mink. Fusobacteria were enriched as invasive bacteria in the gut of diarrheal mink compared with healthy mink. In addition, Escherichia albertii was identified as a new bacterium in diarrheal mink. Regarding functions, nicotinate and nicotinamide metabolism and glycoside hydrolases 2 (GH2) family were the enhanced KEGG orthology and CAZymes in diarrheal mink. Furthermore, the diversity and number of antibiotic-resistant genes were significantly higher in the diarrheal mink group than in the healthy group. These findings enhance our understanding of the gut microbiota of adult mink and may lead to new approaches to the diagnosis and treatment of mink diarrhea.

Animals↗

PubMed2025

Diverse defense systems and prophages in human-associated Bifidobacterium species reveal coevolutionary "arms race" dynamics.

Bacteria of the genus Bifidobacterium are pivotal for human health, especially in early life, where they dominate the gut microbiome in healthy infants. Bacteriophages, as drivers of gut bacterial composition, can affect bifidobacterial abundance. Here, we use a bioinformatics approach to explore direct interactions between human-associated Bifidobacterium spp. and prophages, as evidenced by their genomes. Analysis of 1,086 bifidobacterial genomes reveals the presence of complex systems that prevent viral invasion, with 34 defense systems and 56 subtypes detected, including several different CRISPR-Cas systems. CRISPR spacers target almost three-quarters of bifidobacteria-derived prophages, indicating dynamic interactions. At least one prophage is present in ∼67% of strains, with phages exhibiting high genomic diversity and evidence of historical recombination. These prophages encode various defense and anti-defense systems, such as anti-CRISPR genes and restriction-modification mechanisms. Overall, this investigation reveals that coevolutionary "arms race" dynamics drive genomic diversity in both bifidobacteria and their phages.

Prophages↗

PubMed2025

Human xenobiotic metabolism proteins have full-length and split homologs in the gut microbiome.

Xenobiotics, including pharmaceutical drugs, can be metabolized by both host and microbiota, in some cases by homologous enzymes. We conducted a systematic search for all known human proteins with gut microbial homologs. Because gene fusion and fission can obscure homology detection, we built a pipeline to identify not only full-length homologs, but also cases where microbial homologs were split across multiple adjacent genes in the same neighborhood or operon ("split homologs"). We found that human proteins with full-length gut microbial homologs disproportionately participate in xenobiotic metabolism. While this included many different enzyme classes, short-chain and aldo-keto reductases were the most frequently detected, especially in prevalent gut microbes, while cytochrome P450 homologs were largely restricted to lower-prevalence facultative anaerobes. In contrast, human proteins with split homologs tended to play roles in central metabolism, especially of nucleobase-containing compounds. We identify twelve specific drugs that gut microbial split homologs may metabolize; 2 of these, 6-mercaptopurine by xanthine dehydrogenase and 5-fluorouracil by dihydropyrimidine dehydrogenase, have been recently confirmed in mouse models. This work provides a comprehensive map of homology between the human and gut microbial proteomes, indicates which human xenobiotic enzyme classes are most likely to be shared by gut microorganisms, and finally demonstrates that split homology may be an underappreciated explanation for microbial contributions to drug metabolism.

Humans↗

PubMed2026

The gut microbiota-obesity axis in the pathogenesis and prognosis of breast cancer.

BACKGROUND: Breast cancer (BC) remains a major global health concern, accounting for 11.7% of all cancer cases and ranking as the second leading cause of female cancer-related deaths worldwide. Increasing evidence highlights the interplay between gut microbiota (GM) dysbiosis and obesity-associated metabolic dysfunction in BC progression. This review aims to elucidate the role of GM in obese patients with BC. METHODS: A systematic literature search was conducted in PubMed and Web of Science databases for publications from July 2015 to January 2025. Search terms combined BC, GM, obesity, dysbiosis, immunity, and microbiome. Article selection prioritized studies investigating microbial alterations in BC patients, mechanistic links between obesity and cancer progression, and GM-targeted interventions. Both original studies and authoritative reviews were included, supplemented by manual reference screening. DISCUSSION: Obesity may trigger systemic inflammation, altered adipokine secretion, and disrupted steroid hormone metabolism via gut-derived β-glucuronidase activity, thereby exacerbating BC occurrence and recurrence. GM dysbiosis-driven metabolites such as branched-chain amino acids (BCAAs) and short-chain fatty acids (SCFAs) can activate oncogenic signaling pathways and immunosuppressive myeloid-derived suppressor cells (MDSCs), fostering tumor immune evasion. Conversely, dietary interventions, probiotics, and fecal microbiota transplantation (FMT) can alleviate dysbiosis, strengthen gut barriers, and restore anti-tumor immunity, improving chemotherapy response and reducing recurrence. However, challenges persist in deciphering BC subtype-related microbial signatures and optimizing microbiota-targeted therapies. CONCLUSION: Future longitudinal studies are needed to clarify causal relationships, validate microbial biomarkers, and translate preclinical findings into clinical applications. Addressing the gut-breast axis may offer transformative potential for precision oncology in obesity-driven BC.

Humans↗

PubMed2026

Metagenome-scale modeling to assess microbiome metabolic complementarity for precision microbiota transplantation therapies.

Fecal microbiota transplantation (FMT) holds therapeutic promise beyond recurrent Clostridioides difficile infection, but clinical outcomes remain unpredictable and donor-selection strategies remain limited, in part because the role of donor‒recipient metabolic interactions in shaping the post-FMT community remains poorly understood. Here, we leverage metagenome-scale metabolic modeling to quantify metabolic niche complementarity between donor and recipient microbiomes and predict post-FMT community composition. Using MICOM-derived metabolic models, we show that donor genomes whose metabolic flux profiles are more dissimilar from the recipient community colonize at significantly higher rates in a murine FMT model. In a human IBS trial, the same metric predicted post-FMT community composition via leave-one-out cross-validation and captured known disease-associated alterations in short-chain fatty acid, sulfur, and gas metabolism. We then performed 2,548 in silico FMT simulations between IBS-D/M patients and donors from the OpenBiome biobank to evaluate personalized donor screening, identifying super-donors characterized by high taxonomic diversity, broad metabolic niche coverage, and community interaction networks dominated by cross-feeding rather than competition. Together, these results support metabolic niche complementarity as a potential determinant of post-FMT community composition and provide a mechanistic basis for evaluating donor-recipient metabolic compatibility. This framework offers a scalable approach for generating testable hypotheses for personalized donor selection.

Fecal Microbiota Transplantation↗