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PubMed2024

Pangenomes of human gut microbiota uncover links between genetic diversity and stress response.

The genetic diversity of the gut microbiota has a central role in host health. Here, we created pangenomes for 728 human gut prokaryotic species, quadrupling the genes of strain-specific genomes. Each of these species has a core set of a thousand genes, differing even between closely related species, and an accessory set of genes unique to the different strains. Functional analysis shows high strain variability associates with sporulation, whereas low variability is linked with antibiotic resistance. We further map the antibiotic resistome across the human gut population and find 237 cases of extreme resistance even to last-resort antibiotics, with a predominance among Enterobacteriaceae. Lastly, the presence of specific genes in the microbiota relates to host age and sex. Our study underscores the genetic complexity of the human gut microbiota, emphasizing its significant implications for host health. The pangenomes and antibiotic resistance map constitute a valuable resource for further research.

Humans↗

PubMed2026

Microbial Interactions with Protein Intake and Preterm Infant Body Composition: Secondary Analysis of a Randomized Trial.

BACKGROUND: Enteral protein supplementation improves preterm infant growth and may impact body composition and the gut microbiota. OBJECTIVES: This study aimed to identify the effects of additional enteral protein supplementation on the gut microbiota and microbial and clinical drivers of body composition. METHODS: Secondary analysis of a masked randomized trial of additional enteral protein vs. standard fortification in preterm infants born at 25 to 28 weeks of gestation (NCT03586102) was conducted. Stool samples at weeks 4 and 8 underwent 16S rRNA sequencing; functional potential was predicted by Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt2). Body composition was measured by air-displacement plethysmography at 36 wk postmenstrual age (PMA). Least absolute shrinkage and selection operator (LASSO) regression with multivariable linear regression identified body composition predictors. RESULTS: Among 46 infants, gestational age (P = 0.16) and sex (P = 0.55) did not differ between groups. The protein group had higher week 4 Shannon diversity than standard fortification (median 1.2 vs. 0.87, P = 0.049). Week 4 Shannon diversity was positively correlated with fat-free mass z-score at 36 wk PMA (r2 = 0.34, P = 0.02). Adjusting for covariates, the protein group had higher Peptoniphilus (β = 1.6, Padj = 0.10) and lower Vibrio centered log-ratio abundance (β = -0.98, Padj = 0.10); 62 predicted metabolic pathways were lower in the protein group (false discovery rate < 0.20). In combined LASSO models, Bacillus abundance at week 4 was the strongest predictor of fat-free mass z-score (β = -0.17, P < 0.001; R2 = 0.80) and fat mass z-score (β = -0.31, P < 0.001; R2 = 0.66). CONCLUSIONS: Additional protein supplementation is associated with fat-free mass z-score and alterations to the gut microbiota. Clinical variables and microbial variables are key predictors of body composition, suggesting that nutrition, clinical factors, and the gut microbiota jointly contribute to body composition in extremely preterm infants. This study was registered at clinicaltrials.gov as NCT03586102 https://clinicaltrials.gov/study/NCT03586102 (registered in March 2020).

Humans↗

PubMed2026

Faecalibacterium prausnitzii-derived L-arginine ameliorates insomnia by inhibiting POMC-ACTH-cortisol axis.

Insomnia is associated with gut microbial dysbiosis, but the specific microbial metabolites mediating gut-brain communication remain elusive. Here, we integrate metagenomic sequencing from 171 individuals (primary insomnia, post-COVID insomnia, and controls) with functional pathway analysis and preclinical validation. We identify Faecalibacterium prausnitzii depletion and reduced L-arginine biosynthesis as consistent features in both insomnia subtypes, accompanied by elevated cortisol levels. Genomic and in vitro analyses confirm that F. prausnitzii is a key microbial contributor to L-arginine production. In a chronic mild stress mouse model, administration of either F. prausnitzii or L-arginine restores sleep duration, normalizes corticosterone levels, and reverses stress-induced gut dysbiosis. Mechanistically, L-arginine suppresses POMC gene expression and dampens adrenocorticotropic hormone (ACTH)-stimulated corticosterone release, implicating the POMC-ACTH-cortisol axis as a key target. These findings uncover a gut-brain axis driven by F. prausnitzii-derived L-arginine that modulates sleep through endocrine signaling, positioning this metabolite as a potential therapeutic avenue for insomnia.

Arginine↗

PubMed2026

Maternal secretor status and human milk oligosaccharides influence the infant gut resistome.

The infant gut resistome is established early in life and is shaped by perinatal exposures, yet the mechanisms underlying its modulation remain unclear. We combined shotgun metagenomics of fecal samples from 57 one-month-old infants and paired milk samples from 50 mothers in the MAMI cohort to investigate the influence of maternal secretor status on early-life resistome development. Longitudinal follow-up at 6 and 12 months, and also further validation in the independent Lifelines NEXT (LLNEXT) cohort, support our findings. Cesarean section (C-section) was associated with increased antibiotic resistance gene (ARG) diversity, whereas exclusive breastfeeding reduced ARG abundance and diversity. Maternal secretor status further modified resistome composition among exclusively breastfed infants. Human milk oligosaccharide profiling identified specific glycans underlying these associations, with 2'-fucosyllactose and 6'-sialyllactose showing negative correlations with distinct ARG classes. These findings identify human milk composition as a key determinant of early-life resistome assembly and a potential target for modulating antimicrobial resistance.

Humans↗

PubMed2025

Clostridium scindens: history and current outlook for a keystone species in the mammalian gut involved in bile acid and steroid metabolism.

Clostridium scindens is a keystone bacterial species in the mammalian gut that, while low in abundance, has a significant impact on bile acid and steroid metabolism. Numerous studies indicate that the two most studied strains of C. scindens (i.e. ATCC 35704 and VPI 12708) are important for a myriad of physiological processes in the host. We focus on both historical and current microbiological and molecular biology work on the Hylemon-Björkhem pathway and the steroid-17,20-desmolase pathway that were first discovered in C. scindens. Our most recent analysis now calls into question whether strains currently defined as C. scindens represent two separate taxonomic groups. Future directions include developing genetic tools to further explore the physiological role of bile acid and steroid metabolism by strains of C. scindens and the causal role of these pathways in host physiology and disease.

Bile Acids and Salts↗

PubMed2026

Increasing gut short-chain fatty acids protects intestinal barrier function but does not spare muscle glycogen or impact aerobic performance.

Animal studies suggest gut microbiota-derived short-chain fatty acids (SCFA) provide an intestinal barrier-protecting, glycogen-sparing energy source that increases aerobic endurance performance, but confirmation in humans is needed. This study aimed to determine whether increasing colonic SCFA availability impacts intestinal barrier function, substrate metabolism, muscle glycogen and aerobic performance in healthy adults. Using a randomized, double-blind, crossover design 12 active men (age 18-30 years;40.0 ± 7.1 mL/kg/min) performed prescribed exercise and consumed a provided diet supplemented with acetylated and butyrylated high-amylose maize starch engineered to deliver SCFA to the colon (HAMS-A/B) or low-amylose maize starch (LAMS) for 7 days, separated by a 2 week washout. Indirect calorimetry, stable isotopes and blood, muscle and urine biomarkers were measured on intervention day 8 while participants completed 90 min of steady-state cycle ergometry (ExSS; 60 ± 5%) followed by a 5 km treadmill time trial. HAMS-A/B, relative to LAMS, increased faecal and serum SCFA. Multiple markers of intestinal barrier damage and permeability were lower, and the respiratory exchange ratio during ExSS was higher (0.02 [95% confidence interval (CI): 0.01, 0.03], Ptreatment < 0.001) following HAMS-A/B versus LAMS. However no between-treatment difference in glucose turnover, muscle glycogen depletion (14 µmol/kg/g dry wt. [95% CI: -116, 143], Pinteractio n = 0.613) or TT performance (5 s [95%CI: -44, 54], Ptreatment = 0.816) was observed. Increasing colonic and circulating SCFA modestly altered substrate oxidation and preserved intestinal barrier function during endurance exercise. However effects were not sufficient to spare muscle glycogen or increase aerobic endurance performance, leaving the practical relevance unclear and underscoring challenges inherent in translating promising preclinical findings to humans. KEY POINTS: Animal studies suggest gut microbiota-derived short-chain fatty acids (SCFA) provide an intestinal barrier-protecting, glycogen-sparing energy source that increases aerobic endurance performance, but confirmation in humans is lacking. A gut microbiota-targeted dietary supplementation strategy was used to deliver SCFA to the colon and successfully increased colonic and systemic SCFA concentrations in healthy, physically active adults before and during an endurance exercise bout and aerobic performance test. Increasing colonic and systemic SCFA availability preserved intestinal barrier function but did not impact glucose turnover, alter protein expression in muscle or spare muscle glycogen during endurance exercise. Increasing colonic and systemic SCFA availability did not impact aerobic endurance performance.

Humans↗

PubMed2026

Novelty, diversity, and genetic dark matter in enterococci of invertebrates.

Enterococci appear to have originated in the guts of early terrestrializing arthropods and invertebrates over 425 million years ago-hosts that are now highly diverse and widespread in nature today. Yet most knowledge of the genus comes from human infection-associated lineages with genomes swollen by the recent accretion of foreign DNA conveyed by mobile elements. Because invertebrates dominate terrestrial animal diversity and biomass, they would be predicted to constitute a major but little-explored reservoir of enterococcal diversity. We therefore systematically examined Enterococcus association and species diversification in invertebrate hosts of the comparatively natural, isolated, but well-characterized environment of the Azorean island of Terceira. Over 100 invertebrate specimens were examined for associated enterococci, which were taxonomically classified by whole-genome sequencing. Supporting the existence of a large pool of uncharacterized enterococci and Enterococcus-adapted genes, 40% (eight of 20) of the Enterococcus species identified were either undescribed, including four candidate new species described here, or very recently discovered. In contrast, control isolates from vertebrates were exclusively of known species typical of sampling elsewhere, discounting geographic isolation as a main driver of the novelty observed. Further, because of the abundance of E. casseliflavus and E. flavescens in this collection, we obtained the resolution necessary to quantify the divergence and decipher the drivers of speciation in the controversial division between these naturally vancomycin-resistant species. These findings provide robust support for the existence of a large pool of new species and unexplored adaptive traits in invertebrate-associated enterococci-diverse environmental survival traits optimized for expression in an enterococcal background, and well positioned for transmission into human-associated enterococcal strains.IMPORTANCEEnterococci are auxotrophic gut-associated bacteria that co-evolved with their terrestrial hosts over many eons. In the last 75 years-the "antibiotic era"-E. faecalis and E. faecium gained genes for antibiotic resistance and enhanced virulence, emerging as leading causes of multidrug-resistant infection. Little is known about the source of those genes or the pathway by which they entered human-associated strains. A recent global survey suggested a potentially large repository of uncharacterized genetic diversity in the enterococci of invertebrates. We directly tested this prospect by examining enterococci of invertebrate hosts in a largely natural and pastoral environment. Our findings provide clear evidence that invertebrates naturally harbor vast unexplored enterococcal diversity. Moreover, associations are likely driven by intrinsic host selection factors rather than geographic isolation. This expands our knowledge of Enterococcus biodiversity, including the identification of four novel species, identifying a vast reservoir of enterococcal genes available to species that colonize and infect humans.

Animals↗

PubMed2025

The selective culture and enrichment of major rumen bacteria on three distinct anaerobic culture media.

Ruminants play an important part in global food security, but also emit methane, which contributes to global warming. Rumen microbes strongly influence the energy retention efficiency from the host's plant-based diet and produce methane as a by-product. While thousands of novel microbial genomes have been assembled from metagenomic sequence data, their culturability is ill-defined. Here, different media (Med10, Med2, and MedTC) were used to isolate co-cultures of microbes from rumen fluid. Thirty-four OTUs were identified belonging to the phyla Bacillota (75.28 ± 6.34%), Bacteroidota (19.99 ± 4.85%), Pseudomonadota (2.46 ± 2.01%), and Actinomycetota (2.09 ± 1.07%). The most abundant genera were Selenomonas (28.08 ± 11.71%), Streptococcus (22.67 ± 6.06%), Prevotella (18.71 ± 4.02%), and unclassified Lachnospiraceae (11.50 ± 2.54%), and 31 significantly enriched on at least one medium, with each medium successfully culturing a distinct range of microbes. The composition of the source rumen fluid was vastly different from those cultured. Bacteroidota (52.53 ± 5.10%) predominated, with Bacillota (41.00 ± 3.96%), Methanobacteriota (5.12 ± 1.94%), Pseudomonadota (1.22 ± 0.78%), and Actinomycetota (0.12 ± 0.08%) comprising the rest. The most abundant genera were Prevotella (29.13 ± 4.16%), Butyrivibrio (18.21 ± 2.08%), Succiniclasticum (15.57 ± 5.03%), unclassified Bacteroidetes (13.91 ± 1.67%), and unclassified Prevotellaceae (9.50 ± 2.01%). These data further emphasize the importance of using defined media to select for different microbial taxa. This is essential to understand the complex workings of the rumen microbes to enhance digestion efficiency and reduce the loss of energy that could potentially be utilized by the host.IMPORTANCEThis research demonstrates that using a range of culture media, containing a wide variety of substrates, can lead to the culture of key rumen microbes. The knowledge of which of these microbes is selectively enriched on each medium is essential to understand how to grow these microbes in co-culture and isolate them in pure culture for further investigation. In addition, this research shows the stark disparity between the population of rumen microbes grown in co-culture and those found in the rumen itself. This further demonstrates the need for a targeted approach to growing and isolating these microbes. Learning how these microbes respond to culture media with different nutritional compositions will lead to a better understanding of the rumen microbiota, and this research provides a valuable insight into how selective media can target the enrichment of different microbes. This knowledge will contribute to increasing ruminant digestion efficiency and reducing methane production.

Rumen↗

PubMed2026

Diet change reveals asymmetric response in gene expression and microbial composition across the digestive tract of two closely related herbivores.

BACKGROUND: Understanding what shapes variation in organisms' capacity to utilize novel resources is essential to predicting how species will respond to environmental change. For herbivores, exposure to toxic phytochemicals in novel plants may limit persistence in new habitats. We investigated the behavioral, physiological, genetic, and microbial consequences of diet switching in two closely related species of rodent herbivores that each consume differentially toxic plants in their native habitat, and that maintain different dietary strategies (i.e., relative dietary specialist versus relative generalist). RESULTS: In reciprocal laboratory feeding trials, we exposed wild-caught woodrats (genus Neotoma) to toxins characteristic of either familiar or novel plant secondary compounds. We measured changes in food and water intake, locomotor activity, gut microbial composition, and gene expression across the digestive tract following feeding trials. The dietary generalist responded minimally, but the specialist responded strongly when exposed to the novel diet. This response included behavioral and genetic components including increased water intake, reduction in locomotor activity, increased differential expression of detoxification genes, and a greater shift in gut microbial composition. CONCLUSIONS: The dietary specialist exhibited a strong response to diet switching that corresponded with ecologically relevant shifts in behavior and physiology that would have negative fitness consequences. Although the dietary specialist had a strong genetic and microbial response to novel plant secondary compounds, this response would likely be insufficient to overcome the immediate challenge of exposure to novel dietary toxins in the wild. Our results underscore the link between feeding strategy and the capacity to shift to novel dietary resources in response to environmental change.

Animals↗

PubMed2026

Gut microbiota dysbiosis and host metabolite-immune crosstalk drives the pathogenesis of neonatal lupus erythematosus: a multi-omics analysis.

BACKGROUND: Neonatal lupus erythematosus (NLE) is a rare autoimmune condition triggered by the transplacental transfer of maternal antibodies. Despite its recognized clinical manifestations, the underlying pathogenesis remains incompletely understood. This study seeks to explore the disruption of the gut microbiota-host metabolism-immune axis in anti-Ro/La-positive neonates, and to assess its potential role in the development of NLE. METHODS: This multicenter, cross-sectional study included 90 neonates, divided into three groups: 30 with neonatal lupus erythematosus (NLE), 30 with positive antibodies but without clinical manifestations (No-NLE), and 30 healthy controls. We performed 16 S rRNA sequencing to analyze gut microbiota composition, untargeted plasma metabolomic profiling, and proteomic analysis to identify alterations associated with the pathogenesis of NLE. RESULTS: We identified significant alterations in the gut microbiota, plasma metabolome, and proteome profiles of anti-Ro/La-positive neonates. NLE infants exhibited marked enrichment of Enterobacteriaceae and depletion of Bifidobacterium and Clostridium butyricum. Metabolomic analysis revealed hyperactivation of β-alanine and purine metabolism, along with impaired α-linolenic acid metabolism and endocannabinoid signaling. Proteomic profiling indicated aberrant protein expression that modulated IFN signaling, particularly within the C-type lectin receptor pathway. Dysregulation of the spleen tyrosine kinase (SYK) and high-affinity immunoglobulin epsilon receptor subunit gamma (FCER1G) decoupling was observed, correlating with elevated IFN-α and NF-κB p65 levels. Integrated correlation analysis revealed significant associations among differential microbial taxa, plasma metabolites, and proteins. Notably, E. coli-associated metabolites and proteins displayed inverse relationships with those associated with C. butyricum. CONCLUSIONS: These findings represent comprehensive evidence of dysregulation along the "gut microbiota-host metabolism-immune" axis in neonatal lupus erythematosus (NLE), providing novel insights into the disease's underlying heterogeneity.

Humans↗

PubMed2026

Impact of Tilapinevirus tilapiae (TiLV) infection on the composition and functional dynamics of gut microbiota in Nile Tilapia (Oreochromis niloticus) (Linnaeus, 1758).

Tilapinevirus tilapiae (TiLV) (formerly Tilapia Lake Virus) is a highly prevalent pathogen capable of inducing significant mortality rates in Nile tilapia (Oreochromis niloticus). The alterations induced by Tilapia Lake Virus (TiLV) in the gut microbiota composition, diversity and functional prediction of Nile tilapia have not been thoroughly investigated. This study investigated the gut microbiota of a healthy control group and a TiLV-infected group of Nile tilapia of size 30 ± 2.45g. The alpha diversity of microbiota was hardly affected by TiLV infection, whereas species richness and beta diversity patterns explained the significant differences between control and TiLV-infected groups. The study highlighted a decline in Cetobacterium and an increase in Mycobacterium in the TiLV-infected group. The phyla, including Firmicutes, Actinobacteriota and Proteobacteria, exhibited a significant increase in the TiLV-infected group, while Bacteroidota and Fusobacteriota decreased substantially. The PICRUSt-based functional gene prediction revealed that TiLV infection had considerably changed the KEGG (Kyoto Encyclopaedia of Genes and Genomes) pathways associated with membrane transport, amino acid metabolism, transcription, carbohydrate metabolism, cellular process and signalling in the gut microbiota of Nile tilapia. The results suggest that the infection by TiLV altered the composition and functional pathways in the gut microbiota of Nile tilapia.

Animals↗

PubMed2026

Metagenomic Insights Into Microbial Diversity of Tea Rhizosphere of the Kangra Valley.

This study provides the first metagenomic assessment of microbial diversity from the tea rhizosphere of the Kangra valley. Tea rhizosphere soil samples were collected from 4 locations (Dharamshala, Baijnath, Palampur, and Joginder Nagar) of the Kangra valley. DNA extracts of rhizosphere samples were analysed for bacterial and Archaeal diversity using amplicon sequencing (V3-V4) region of the 16S rRNA gene and Fungal diversity using ITS1 and ITS2 regions. Baijnath and Palampur samples showed the highest bacterial richness, while Dharamshala and Palampur had the highest fungal richness. Proteobacteria was a dominant phylum in all the rhizosphere samples, followed by Firmicutes, Actinobacteria, Acidobacteria, and Bacteroidetes. A total of 11 fungal phyla were identified among all the locations, with abundance of Ascomycota and Basidiomycota. For the Archaea domain, uncultured archaeon and Aeropyrum camini were the most common found among all the locations. A small fraction (< 0.5%) of Bacillus and Pseudomonas species were observed among all the locations. Alpha and beta diversity indices displayed notable differences within and between microbial diversities. Soil factors were variably associated with microbial diversity, with nitrogen positively aligned with fungal diversity, while EC and K were associated with Archaeal diversity. Soil pH and OM% showed moderate associations with bacterial diversity. These findings provided valuable and comprehensive insights into tea rhizosphere microbial ecology and could be used to better understand microbial functions and their role in plant health.

Rhizosphere↗

PubMed2026

Multi-Omic Insights Into Mediterranean Diet-Associated Microbiota.

This study aimed to evaluate the gut microbiota and mycobiota composition, depending on the Mediterranean diet (MD) adherence, using metataxonomics. Combining metagenomics and metatranscriptomics, we also investigate the gene expression level in the bacterial community. Two groups of healthy subjects greatly differing in adherence were selected. Significant differences in microbiota composition were observed between individuals with high adherence (HAMD; mean 10.5 +/- 0.9 points) and low adherence (LAMD; 5.23 +/- 83 points). Notably, the olive oil, vegetable, and fruit consumption presented an important discriminant power between groups. Saccharomyces, Penicillium, and Candida were the most abundant genera. Mycobiota richness was higher in LAMD than in HAMD. Aspergillus was identified as a biomarker for LAMD, whereas Yarrowia, a potential probiotic, was a biomarker for HAMD. Metatranscriptomics indicated that Bacillota was the most metabolically active phylum in the gut microbiota. The low-abundant genus, Methanobrevibacter, showed high transcriptional activity, contributing to the crucial methanogenesis process. Gene expression analyses further highlighted functional differences. Overall, HAMD microbiota presented increased metabolic activity, protein synthesis, and cellular mobility. Overexpression of flagellin and urease genes may enhance immune response in HAMD. Further metatranscriptomic studies are necessary to deepen our understanding of intestinal microbiota transcriptional programs and their interactions with the diet and human health.

Humans↗

PubMed2026

Lipidomic Profiling Reveals Differential Behaviors of Individual Free Fatty Acids During Altered Metabolic States in Rats.

We used lipidomic analyses to investigate how individual free fatty acids (FFAs) behave differently in metabolic states altered by diet and by antibiotic treatment (ABX) that depletes gut bacteria. Wistar rats were fed either a low-fat or high-fat purified diet, or standard chow with or without antibiotics for two weeks (n = 8-10). Blood samples were then collected before and after meals. Individual FFAs were quantified and grouped based on distinct postprandial response patterns across dietary and treatment conditions. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), key ω-3 FFAs, exhibited postprandial shifts suggestive of suppressed adipocyte lipolysis following meals. Fatty acids in the high-fat diet (HFD) elevated postprandial FFA levels, masking the meal-induced suppression of lipolysis observed with chow or low-fat diet (LFD). Some FFAs, including medium-chain saturated species, remained unaffected by meals. We further evaluated the impact of diet and ABX on baseline (pre-meal) concentrations of FFAs. Certain FFAs were altered by purified diets compared to standard chow. Notably, EPA and DHA were selectively depleted under HFD conditions, likely due to enhanced catabolic activity. In conclusion, lipidomic profiling revealed divergent behaviors among individual FFAs, reflecting distinct metabolic processes and regulatory mechanisms under altered metabolic states.

Animals↗

PubMed2025

Exploring the associations between preen oil bacterial, chemical and proteomic profiles of passerines.

Preen gland bacteria are thought to be the key producers of preen oil components such as chemosignalling molecules including volatile organic compounds (VOCs) and antimicrobial compounds including peptides and antimicrobial VOCs. However, data on the preen oil bacteriome and chemical composition are limited to a small subset of bird species, and the presence of antimicrobial peptides is largely unexplored. Here, we performed an exploratory study to characterize, for the first time, the preen oil chemical and proteomic profiles and to explore the possible contribution of the bacteriome to the production of preen oil VOCs and antimicrobial peptides (bacteriocins) in eight passerine species, each represented by a single individual. Preen oil bacteriome, chemical and proteomic profiles varied among birds. The bacterial profiles were dominated by the genera Streptococcus, Lactococcus, Corynebacterium and Cutibacterium. The chemical profiles mainly consisted of alcohols, ketones and carboxylic acids. The biological functions primarily associated with the proteomic profiles were proteolysis and response to oxidative stress. Although we were unable to explore a direct association between the bacteriome and chemical profiles, the preen oil contained bacteriocin- and VOC-producing bacterial genera capable of producing detected microbially-derived VOCs (mVOCs), the relative abundance of which varied between birds. Riparian species showed the highest chemical diversity and high abundances of putative preen oil mVOC-producing bacteria, which could suggest habitat-specific adaptations. This exploratory study may significantly contribute to the formulation of hypotheses on the potential role of host ecological factors in the variation of preen oil bacterial, chemical and proteomic profiles in passerines.

Animals↗

PubMed2025

New evidence for the protective effect of gut microbiota regulation of ferroptosis-related proteins against osteoporosis.

Osteoporosis (OP), characterized by bone degradation and increased fracture susceptibility, constitutes a significant global health burden. Recent findings implicate gut microbiota and ferroptosis in the regulation of bone metabolism; however, causal evidence for the gut microbiota's influence on OP specifically via ferroptosis regulation remains to be established. This study employed two-sample Mendelian randomization (MR) using genome-wide association study (GWAS) summary statistics to investigate these causal relationships and delineate mediating pathways.We assessed causal links between gut microbiota, ferroptosis-related proteins, and OP risk. Associations for gut microbiota abundance and ferroptosis-related proteins were derived from GWAS data and Icelandic blood-derived protein quantitative trait loci, respectively. Outcome data for OP were obtained from the FinnGen Release R12. The primary analysis utilized the inverse variance weighted (IVW) method, supplemented by sensitivity analyses to evaluate heterogeneity and horizontal pleiotropy.  MR analysis identified 33 gut microbial taxa causally associated with OP risk: 13 protective and 20 detrimental. Similarly, 34 ferroptosis-related proteins were categorized as protective (18) or detrimental (16) for OP. Mediation analysis revealed that the protective effect of Terrisporobacter othiniensis on OP is partially mediated by the ferroptosis regulator MDM4 (indirect effect β = -0.020, 95% CI: -0.068 to 0.029), accounting for 6.8% of the total effect. Sensitivity analyses showed no significant evidence of heterogeneity or horizontal pleiotropy. This study provides the first genetically validated evidence supporting a causal relationship between specific gut microbiota, ferroptosis-associated proteins, and OP susceptibility. Specifically, Terrisporobacter othiniensis demonstrates a novel protective mechanism, modulating OP risk partly through the ferroptosis regulator MDM4. These findings broaden understanding of the "gut-bone axis" and highlight the gut microbiota-ferroptosis pathway, particularly the MDM4/p53 axis, as a promising target for novel OP prevention and therapeutic strategies.

Ferroptosis↗

PubMed2026

Assessing the Safety and Probiotic Potential of Bifidobacterium longum subsp. infantis BI45: A Comprehensive Study from Genomic Analysis to Randomized Controlled Clinical Trial in Healthy Adults.

While probiotics are increasingly consumed for health benefits, comprehensive safety assessments, particularly for novel strains, are imperative. This study aimed to conduct a holistic safety and efficacy assessment of Bifidobacterium longum subsp. infantis (B. infantis) BI45, spanning genomic analysis, in vitro tests, In vivo toxicity test, and a clinical trial. The safety of B. infantis BI45 was evaluated through: (1) whole-genome sequencing for antibiotic resistance and virulence genes; (2) in vitro phenotyping (hemolysis, cytotoxicity, gastrointestinal tolerance and antibiotic susceptibility); (3) an acute oral toxicity study in mice; and (4) a randomized, double-blind, placebo-controlled clinical trial. Forty-eight healthy adults were recruited and randomly assigned to receive either B. infantis BI45 or a placebo (n = 24/group) for 8 weeks. Hematological, biochemical, immunological, and gut microbiota parameters were assessed. Genomic analysis identified no transferable antibiotic resistance or virulence genes. In vitro assays confirmed the absence of hemolytic and cytotoxic activity, alongside high gastrointestinal tolerance. Antibiotic susceptibility testing showed that B. infantis BI45 is sensitive to a range of antibiotics. No adverse effects were observed in the murine toxicity study at 2 × 10¹⁰ CFU/kg. Importantly, the clinical intervention revealed no adverse events or significant alterations in hematological, hepatic, or renal function markers in the B. infantis BI45 group, demonstrating an excellent safety profile. Furthermore, B. infantis BI45 supplementation significantly increased serum levels of immunomodulatory markers Immunoglobulin A (IgA) and antimicrobial peptide LL-37 compared to the placebo (p < 0.05) and modulated the gut microbiota by enriching beneficial short-chain fatty acid producers. The multi-tiered evidence demonstrates that B. infantis BI45 is a safe probiotic strain that does not induce adverse reactions in healthy adults. Its consumption positively modulates host immunity and the gut microbiota.Trial Registration Number: NCT06863415 (ClinicalTrials.gov).

Adult↗

PubMed2026

A Risk Score for Polycystic Ovary Syndrome Based on Meta-Analysis and Machine Learning of Gut Microbiota Signatures.

Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine and metabolic disorder among reproductive-age women, in which emerging evidence suggests a substantial role played by the gut microbiota. To comprehensively evaluate gut microbiota alterations in PCOS and identify microbial biomarkers through integrated analysis, a systematic search of PubMed, Web of Science, and Embase was conducted for studies employing 16S rRNA gene sequencing of fecal samples from PCOS cohorts. Ten eligible PCOS cohorts, comprising 858 individuals, were included in the study, from which a risk score was derived using a 20-gene gut microbial signature associated with PCOS. Meta-analysis at the genus level identified that Subdoligranulum, NK4A214_group, and Collinsella significantly decreased, and Bacteroides increased in PCOS across multiple cohorts. Machine learning analysis identified a 20-genus microbial signature using the least absolute shrinkage and selection operator (LASSO) method, which was used to construct a risk score with an AUC of 0.835 in diagnosis prediction. Network analysis further identified Negativibacillus and Lachnospiraceae_UCG_010 as potential driver microbes in PCOS. The analysis in this study highlights key alterations in the gut microbiota across PCOS cohorts. The identified gut microbial signature and derived LASSO-based risk model offer novel insights and a potential tool for PCOS diagnosis.

Polycystic Ovary Syndrome↗