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PubMed2025

ITIH4 alleviates OVA-induced asthma by regulating lung-gut microbiota.

BACKGROUND: Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4), a Type 2 acute phase protein, is critical for resolving inflammation and promoting tissue repair. While its role in chronic respiratory diseases is recognized, its effects on asthma remain unclear. This study investigated the effects of ITIH4 on the modulation of lung and gut microbiota, the attenuation of allergic inflammation, and the improvement of respiratory outcomes in an asthma mouse model. METHODS: Six-week-old male Balb/c mice were divided into five groups: control, ITIH4, ovalbumin (OVA), and two OVA + ITIH4 treatment groups at different doses. Lung function and oxygen saturation were measured, and bronchoalveolar lavage fluid (BALF) was analyzed for white blood cell counts and cytokines. Lung and gut microbiota were profiled using 16 S rRNA gene sequencing, and short-chain fatty acids (SCFAs) were measured using gas chromatography-mass spectrometry (GC-MS). Proteomic profiling of intestinal tissues was conducted to identify ITIH4-associated signaling pathways. RESULTS: ITIH4 administration significantly mitigated OVA-induced asthma symptoms by reducing weight loss, airway resistance, and tissue damping (p < 0.05). Histological analysis showed decreased airway wall thickening and lung injury scores (p < 0.05). ITIH4 also lowered BALF eosinophils and lymphocytes, IgE, and Th2 cytokines (IL-4, IL-5, and IL-13) (p < 0.05). ITIH4 treatment modulated microbiome composition, enriching Gram-positive taxa (Nocardioidaceae and Acholeplasmataceae) and depleting Gram-negative Helicobacteraceae (p < 0.05). SCFAs correlated with microbiome alterations, notably reduced 4-methylpentanoic acid levels (p < 0.05). Proteomic analysis revealed a dose-dependent activation of granzyme A signaling and suppression of metabolic and solute transport pathways. CONCLUSIONS: ITIH4 ameliorates asthma symptoms by modulating lung and gut microbiota, dampening Th2-driven inflammation, and restoring mucosal immune balance. These findings support ITIH4 as a potential candidate for microbiome-targeted asthma therapy.

Animals↗

PubMed2026

Human DNA levels in feces reflect gut inflammation and associate with presence of gut species in IBD patients across the age spectrum.

BACKGROUND: Feces represent a complex biological matrix that provides valuable information about intestinal physiology and gut microbial activity. Comprehensive fecal DNA sequencing is mostly utilized as a non-invasive way to profile the gut microbiome, and both clinical practice and research on inflammatory bowel diseases (IBD) would greatly benefit from accurate and non-invasive methods to monitor gut inflammation in IBD patients. In IBD, excessive immune cell recruitment and epithelial cell shedding in the gut increase the amount of human DNA in feces, making fecal DNA profiling a desirable approach to monitor gut inflammation dynamics. METHODS: We used a combination of sequencing techniques to comprehensively characterize the fecal DNA diversity in a newly established cohort of pediatric IBD patients and controls (Pediatric cohort, N = 134 children, Israel). We performed methylation-based human cell-specific profiling together with shotgun metagenomics to characterize the human and the microbial DNA content in feces, respectively. Moreover, we included a large complementary external cohort including adult IBD patients and controls (Adult cohort, N = 689 adults, the Netherlands), not only to compare microbial patterns across the age spectrum, but also to extend our findings from the methylation-based profiling to the more broadly-available quantification of human DNA in metagenomic sequencing. RESULTS: We found that neutrophil DNA dominates fecal human DNA content in IBD patients, and our measurements were highly correlated with fecal calprotectin levels. Combining neutrophil and other cell type DNA fractions in one metric was able to distinguish between remissive and active cases of IBD. Human reads percentage by metagenomics was well correlated with disease severity and species richness, which had distinct trends in CD and UC over time. We used a combination of species richness, human DNA percentage, and microbiome composition data to predict IBD and distinguish CD from UC in both adult and pediatric IBD cohorts. CONCLUSIONS: The comprehensive characterization of human and microbiome fecal DNA is a useful approach to track immune response level and investigate the interaction that the immune system has with gut microbiome richness and composition over time, enriching opportunities for better disease monitoring and thus better treatment of IBD patients. Video Abstract.

Humans↗

PubMed2026

Comparative analysis of rumen metagenomes with dietary supplementation of 3-nitrooxypropanol revealed divergent modes of action in hydrogen metabolism and reductant pathways between beef and dairy cattle.

BACKGROUND: The compound 3-nitrooxypropanol (3-NOP), an inhibitor of methyl-coenzyme M reductase (MCR), reduces enteric methane production in both beef and dairy cattle. Although the proposed mechanisms of 3-NOP involve on inhibiting the activity of MCR in vivo, it is unknown how this process could affect rumen microbiome as a whole and if it differs between beef and dairy cattle. This study conducted a comparative analysis of the rumen microbiome and its functional shifts in four different cattle studies (two beef and two dairy cattle studies) that evaluated 3-NOP supplementation using metataxonomics and metagenomics. RESULTS: Comparative analysis of 281 rumen metataxonomic datasets (143 beef and 138 dairy cattle) revealed that dietary supplementation with 3-NOP affected rumen bacteria and methanogens. Further, comparative analysis of 54 metagenomic datasets (24 beef and 30 dairy cattle) revealed that 3-NOP inhibited mcrA, decreased the abundances of Methanobrevibacter gottschalkii and the protozoal species Isotricha prostoma, while increased the abundances of Methanobrevibacter ruminantium and Methanosphaera sp., Prevotella sp. was a significant bacterial taxon in both beef and dairy cattle, contributing to various pathways such as propionate and butyrate production. Its increased abundance after 3-NOP supplementation may also be linked to the decrease in Isotricha prostoma. Hydrogenotrophic methanogenesis decreased after 3-NOP supplementation with the abundance of genes involved in methylenetetrahydromethanopterin dehydrogenase decreased in beef cattle, while that of 4Fe-4S ferredoxin gene decreased in dairy cattle. The abundance of protozoal Polyplastron multivesiculatum increased after long-term 3-NOP supplementation in beef cattle, potentially due to changes in hydrogen (H2) partial pressure. During 3-NOP-mediated methanogenesis reduction, abundance of genes encoding methanogenic hydrogenase and H2 producing hydrogenase were decreased, while those encoding H2 sensory hydrogenase increased. Acyl-CoA dehydrogenase gene involved in propionate and butyrate production pathways increased in both beef and dairy cattle, while nitrite reductase increased specifically in beef cattle, indicating a rise in alternative H2 sinks. Video Abstract CONCLUSION: Our findings revealed broad effects of 3-NOP on rumen microbiome and functions in vivo, with varied effects in beef and dairy cattle, which provide mechanistic insights into the supplementation of 3-NOP in both beef and dairy cattle, supporting its more sustainable and effective use in the future.

Metagenome↗

PubMed2025

Gut microbial and functional alterations lead to metagenomic signatures for midgut neuroendocrine tumor patients and for carcinoid syndrome.

Midgut neuroendocrine tumors (NET) derive from enterochromaffin cells, which have a close interrelationship with intestinal microbiota. Recently, we have utilized 16S rRNA sequencing to uncover that midgut NET patients have a depleted gut microbiome and a specific fecal microbial signature. This study aims to validate these findings and to further characterize the role of microbes and microbial metabolic pathways in midgut NET patients with and without carcinoid syndrome (CS). Fecal samples from 60 midgut NET patients and 20 household-matched controls were subjected to whole metagenome sequencing. The gut microbial community composition of midgut NET patients differed from that of controls, with 2 genera, 17 species and 9 microbial pathways showing differential abundance (P < 0.001). No differences in the microbial composition were observed between midgut NET patients with and without CS (P > 0.05). However, we did observe changes in inter-genus correlations of Bacteroides, Odoribacter, Parasutterella, Klebsiella, Ruminococcus and Proteobacteria when comparing these two patient groups. A signature of 16 microbial species (area under the receiver operating characteristics (AUROC) curve 0.892) or 18 microbial pathways (AUROC 0.909) accurately predicted the presence of a midgut NET. Furthermore, a microbial signature consisting of 14 functional microbial pathways distinguished CS patients from non-CS patients (AUROC 0.807). Thus, this study confirms that the gut microbiome of midgut NET patients is altered at the metagenomic level, which is not related to the presence of CS. A fecal microbial signature could constitute a novel biomarker for the diagnosis of midgut NET or CS.

Aged↗

PubMed2026

Oral and gut microbiota profiles in patients with locally advanced rectal cancer with varying responses to neoadjuvant chemoradiotherapy.

Recent research has focused on gut bacteria in colorectal cancer, but the influence of other microbiota, including oral and nonbacterial gut microbiota, on treatment efficacy remains insufficiently explored. This study aimed to investigate their relationship with the efficacy of neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC). Saliva and fecal samples were collected from patients with LARC before treatment. Shotgun metagenomic sequencing was used to profile bacterial, archaeal, eukaryotic, and viral taxonomic groups and to examine oral and gut microbial functions. An artificial intelligence-based prediction model was developed by integrating oral and gut microbiome data with clinical information. Statistical analyses compared diversity and response-associated microbial features between responders and non-responders to nCRT. Response-associated differences were observed in bacterial and nonbacterial taxonomic profiles and in oral and gut microbial functional profiles. In the internal test subset, the integrated analysis yielded an observed AUC of 0.917. Given the small cohort and the exploratory comparison of candidate classifiers, this estimate requires confirmation in larger, independent cohorts. Baseline oral and gut microbiome profiles were associated with response to nCRT. Integrating microbiome and clinical features showed potential for response prediction, but the model remains exploratory and requires validation in larger, independent cohorts before clinical application. Retrospectively registered on 01/08/2026, NCT07346729.

Aged↗

PubMed2025

Impact of the maternal microbiome on neonatal immune development.

Historically, multigenerational health and disease transmission have primarily focused on genetic inheritance. However, the discovery that beneficial microorganisms known as commensal microbiota outnumber human genes tenfold has reshaped this perspective, highlighting their critical role in maintaining homeostasis and protecting against pathogens. Unlike the human genome, commensal microbiota is not genetically inherited but is acquired anew with each generation. with initial gut colonization playing a pivotal role in shaping an infant's immune system, neurodevelopment, and long-term health, all heavily influenced by maternal factors. In this review, we examine emerging research on maternal microbial influences on the fetus beginning in utero. We provide an updated overview of the current insights into the impact of the vaginal microbiome during parturition on offspring immunity and discuss the potential long-term health implications for infants born via cesarean section. We explore the advantages and limitations of techniques designed to mitigate these effects, such as vaginal seeding and emphasize that the development of the neonatal immune system is a dynamic process influenced by maternal factors beyond birth, including the transfer of microbiota through breast milk and skin contact. Finally, we present gaps in current research and propose future research directions to deepen our understanding of the impacts of the maternal microbiome on her child. Together, these insights demonstrate how maternal influence on offspring health and immunity extends beyond genetic factors, encompassing the transmission of microbiota, which, in turn, has profound long-term implications for health and disease resilience, offering a novel perspective on intergenerational health dynamics.

Humans↗

PubMed2026

Farming reshapes the gut resistome, virulome, and mobilome of Cervidae.

The rapid expansion of cervid farming raises concerns about antimicrobial resistance (AMR) dissemination, yet its impact on the Cervidae gut microbiome remains poorly characterized. We integrated 89 newly sequenced fecal metagenomes with 599 publicly available datasets, comprising 285 metagenomes from farmed cervids and 370 from wild cervids, to construct a catalog of 15,494 non-redundant metagenome-assembled genomes (MAGs) representing 2,401 species. Our analysis demonstrates that farming profoundly reshapes the gut microbiome's functional composition. Specifically, farmed cervids exhibited significantly higher relative abundance, diversity, and heterogeneity of antimicrobial resistance genes (ARGs) compared to wild counterparts. We observed a robust synergistic relationship between ARGs, virulence factor genes, and mobile genetic element (MGE)-associated genes, identifying 70 ARG-MGE combinations as evidence of potential horizontal gene transfer. Plasmid profiling further suggested that a subset of ARGs may be associated with conjugative plasmids, with plasmid-associated ARGs being significantly more abundant in farmed than in wild cervids. Virome analyses indicated that bacteriophages, particularly Siphoviridae, may serve as mobile reservoirs for ARGs. Notably, Cervidae shared 268 ARG types with humans, including 23 high-risk genes associated with resistance to clinically important antibiotics (e.g. tetX1, vanRD, and bla-CTX-M-178), with Escherichia coli as a key cross-host carrier. These findings highlight that human-impacted cervid gut microbiomes are significant environmental reservoirs of clinically relevant AMR, underscoring the necessity for enhanced antibiotic stewardship and resistance surveillance in managed wildlife within a One Health framework.

Animals↗

PubMed2025

Expansion of a bacterial operon during cancer treatment ameliorates fluoropyrimidine toxicity.

Dose-limiting toxicities remain a major barrier to drug development and therapy, revealing the limited predictive power of human genetics. Here, we demonstrate the utility of a more comprehensive approach to studying drug toxicity through longitudinal profiling of the human gut microbiome during colorectal cancer (CRC) treatment (NCT04054908) coupled to cell culture and mouse experiments. Substantial shifts in gut microbial community structure during oral fluoropyrimidine treatment across multiple patient cohorts, in mouse small and large intestinal contents, and in patient-derived ex vivo communities were revealed by 16S rRNA gene sequencing. Metagenomic sequencing revealed marked shifts in pyrimidine-related gene abundance during oral fluoropyrimidine treatment, including enrichment of the preTA operon, which was sufficient for the inactivation of active metabolite 5-fluorouracil (5-FU). preTA+ bacteria depleted 5-FU in gut microbiota grown ex vivo and in the mouse distal gut. Germ-free and antibiotic-treated mice experienced increased fluoropyrimidine toxicity, which was rescued by colonization with the mouse gut microbiota, preTA+ Escherichia coli, or preTA-high stool from patients with CRC. Last, preTA abundance was negatively associated with fluoropyrimidine toxicity in patients. Together, these data support a causal, clinically relevant interaction between a human gut bacterial operon and the dose-limiting side effects of cancer treatment. Our approach may be generalizable to other drugs, including cancer immunotherapies, and provides valuable insights into host-microbiome interactions in the context of disease.

Animals↗

PubMed2023

Strain-specific alterations in gut microbiome and host immune responses elicited by tolerogenic Bifidobacterium pseudolongum.

The beneficial effects attributed to Bifidobacterium are largely attributed to their immunomodulatory capabilities, which are likely to be species- and even strain-specific. However, their strain-specificity in direct and indirect immune modulation remain largely uncharacterized. We have shown that B. pseudolongum UMB-MBP-01, a murine isolate strain, is capable of suppressing inflammation and reducing fibrosis in vivo. To ascertain the mechanism driving this activity and to determine if it is specific to UMB-MBP-01, we compared it to a porcine tropic strain B. pseudolongum ATCC25526 using a combination of cell culture and in vivo experimentation and comparative genomics approaches. Despite many shared features, we demonstrate that these two strains possess distinct genetic repertoires in carbohydrate assimilation, differential activation signatures and cytokine responses signatures in innate immune cells, and differential effects on lymph node morphology with unique local and systemic leukocyte distribution. Importantly, the administration of each B. pseudolongum strain resulted in major divergence in the structure, composition, and function of gut microbiota. This was accompanied by markedly different changes in intestinal transcriptional activities, suggesting strain-specific modulation of the endogenous gut microbiota as a key to immune modulatory host responses. Our study demonstrated a single probiotic strain can influence local, regional, and systemic immunity through both innate and adaptive pathways in a strain-specific manner. It highlights the importance to investigate both the endogenous gut microbiome and the intestinal responses in response to probiotic supplementation, which underpins the mechanisms through which the probiotic strains drive the strain-specific effect to impact health outcomes.

Mice↗

PubMed2026

Targeting microbial bile salt hydrolase reprograms bile acid metabolism and ameliorates metabolic dysfunction-associated steatohepatitis in mice.

Microbial bile salt hydrolase (BSH) plays a central role in shaping bile acid composition and gut-liver metabolic signaling, yet its therapeutic potential in metabolic dysfunction-associated steatohepatitis (MASH) remains incompletely defined. Here, we evaluated the efficacy of the non-absorbable BSH inhibitor GR-7 in a diet-induced mouse model of steatohepatitis using early and late intervention strategies with different dosing regimens. GR-7 reduced food intake and exerted stage- and dose-dependent therapeutic effects, with early intervention robustly suppressing hepatic fibrosis even at a low dose, whereas late-stage administration of high-dose GR-7 markedly reduced hepatic steatosis and inflammation, as evidenced by decreased liver weight, hepatic triglyceride and cholesterol levels, and plasma ALT. Although late intervention did not result in statistically significant histological reversal of fibrosis, a trend toward improvement was observed, together with suppression of fibrogenic gene expression, suggesting that prolonged treatment may further enhance antifibrotic efficacy. Mechanistically, GR-7 effectively inhibited microbial BSH activity in vivo, leading to reduced cecal unconjugated primary and secondary bile acids-including deoxycholic acid and lithocholic acid, which was associated with improved gut barrier integrity and reduced hepatic inflammation. In parallel, BSH inhibition reprogrammed hepatic bile acid metabolism toward activation of the alternative CYP27A1-mediated synthesis pathway, accompanied by reduced food intake, thereby contributing to reduced hepatic lipid accumulation. Furthermore, late-stage high-dose treatment selectively remodeled the hepatic immune landscape rather than fully restoring homeostasis, highlighting immune recalibration as a key component of therapeutic response. Together, these findings identify microbial BSH inhibition as a promising microbiome-targeted therapeutic strategy for MASH.

Animals↗

PubMed2025

Influence of creatine pyruvate on newly received cattle: insights from metagenomics and metabolomics.

Transport stress is a critical factor affecting the health and growth performance of beef cattle, potentially leading to oxidative stress, inflammation, and metabolic disorders. Creatine pyruvate (CrPyr), as a potential stress alleviator, has unclear mechanisms of action. We monitored the growth of 17 Simmental calves (control, n = 8; CrPyr, n = 9) over 30 days post-transportation, collecting rumen and blood samples on days 1/4, and 30. This study aims to investigate the effects of CrPyr on the growth performance, rumen microbiome, and metabolome of calves subjected to transport stress. Results showed that CrPyr increased average daily gain and antioxidant capacity, while reducing the level of stress hormones and inflammation. In the 4 days post-transport, CrPyr mainly increases Ruminococcus abundance to boost ruminal nitrogen metabolism, providing substrates for microbial protein synthesis. CrPyr also provides energy for the proliferation of Ruminococcus by regulating ATP synthesis genes (ATPVC) and enriching purine metabolism products. Meanwhile, it strengthens the host's amino acid metabolism, especially aspartate, to enhance antioxidative capacity. By day 30, CrPyr primarily boosts Prevotella abundance to regulate VFA synthesis, supplying host energy. It regulates the ATP synthesis gene ATPF0A and enriches purine metabolism products, supporting Prevotella growth. Increased citric acid and ATP levels further aid host growth. The findings distinctly demonstrate that the mechanisms by which CrPyr alleviates transport stress through the regulation of the rumen microbiome and metabolome, and confirms that its effects are time-dependent. These findings provide a theoretical basis for the development of stress-alleviation strategies based on CrPyr and hold significant implications for enhancing the health and production performance of beef cattle.

Animals↗

PubMed2026

Resistant starch types 2 and 4 induce distinct and reversible changes in the human gut microbiome.

Resistant starch (RS) can confer benefits for the gut microbiome and host cardiometabolic health. However, different types of resistant starch can differentially affect gut microbiome composition and functional capacity, especially given interindividual variability in responses, thus limiting the application of resistant starch in dietary strategies. We used shotgun metagenomics to perform a secondary analysis of samples collected during a previously reported randomized clinical trial to determine the effects of dietary supplementation with two types of resistant starch (RS2 and RS4) and a digestible starch (control) on the gut microbiome. Both resistant starch types induced distinct but transient alterations in the gut microbial community. RS2 enriched the keystone degrader, Ruminococcus bromii, and Blautia glucerasea, whereas RS4 favored Parabacteroides distasonis and known but uncharacterized microbial species such as a Lachnospiraceae bacterium. Moreover, we detected strain-level differences in the response of Bifidobacterium adolescentis to resistant starch. Microbial functional profiling revealed an enhanced capacity for complex carbohydrate utilization following resistant starch intake, including increased abundance of specific α-amylases, glycoside hydrolases, starch utilization systems, and other currently uncharacterized genes. Identifying the bacterial strains and genes that respond to different RS types will help to more accurately predict who will benefit from a given RS type. Our findings demonstrate that RS2 and RS4 differentially shape microbial ecology and metabolic capacity and provide a foundation for microbiome-informed personalization of resistant starch-based dietary interventions.IMPORTANCEDietary intake influences human health by modulating metabolism, partly by shaping the microbiota inhabiting the gut. Resistant starch (RS), a dietary fiber, is associated with metabolic improvements. While previous research has explored how RS alters the gut microbiome, RS comprises five types with differing physical and chemical characteristics, and the distinct impacts of each type on the microbiome and host health have not been fully characterized, particularly using high-resolution approaches such as shotgun metagenomics. In this secondary analysis of samples from a longitudinal crossover intervention study, we link dietary supplementation with RS2 and RS4 with distinct and transient changes in the composition and functional potential of the human gut microbiome. Specifically, we identify species that increase in abundance with each RS type, accompanied by increases in genes and pathways involved in complex carbohydrate utilization. The findings support the development of precision nutrition strategies utilizing RS supplementation to improve metabolic health.This study is registered with ClinicalTrials.gov as NCT05743790.

Humans↗

PubMed2026

Commensal Dysbiosis Alters Primary Bile Acid Signaling to Drive Mammary Gland Inflammation and Breast Tumor Dissemination.

UNLABELLED: Breast cancer is the most commonly diagnosed malignancy and a leading cause of cancer-related mortality. Hormone receptor-positive (HR+) tumors represent the most prevalent metastatic subtype, and early dissemination remains a major clinical challenge. Commensal dysbiosis, defined as an inflammatory gut microbiome with low biodiversity, promotes metastasis by inducing mammary gland inflammation. In this study, we investigated systemic mechanisms governing dysbiosis-induced metastasis. Metabolomic profiling revealed elevated primary bile acids (BA) in the dysbiotic fecal microbiome. Sequestration and supplementation approaches demonstrated that beyond driving metabolic disease and mammary gland inflammation, primary BAs orchestrated enhanced HR+ tumor dissemination via a prostaglandin E2 (PGE2)-dependent pathway. Analysis of The Cancer Genome Atlas showed that BA, insulin resistance, and PGE2 gene signatures are associated with reduced survival in patients with HR+ tumors. In complementary analyses using the Epic Cosmos electronic health record database, BA sequestrant use was associated with longer restricted mean survival time among patients with metastatic disease. Together, these findings reveal that commensal dysbiosis-associated loss of microbial BA metabolism elevates primary BAs and promotes HR+ metastatic progression through PGE2 signaling. SIGNIFICANCE: Dysbiosis-induced bile acids drive systemic and mammary tissue-specific inflammation that promotes HR+ breast tumor metastasis, supporting the development of strategies targeting microbiome-derived metabolites to reduce metastatic risk in vulnerable populations.

Female↗

PubMed2026

Fecal immunochemical tests from population-based colorectal cancer screening programs support prospective microbiome cohorts.

BACKGROUND: Large, prospective cohorts are needed to research the gut microbiome's role in colorectal cancer (CRC) risk. We evaluated the gut microbiome leveraging residual fecal immunochemical tests (FIT) from a CRC screening program in Turin, Italy, and conducted one of the largest population-based case-control studies across the adenoma-carcinoma sequence to date. METHODS: We extracted DNA from residual FIT stool, used whole-genome shotgun sequencing, and included those with CRC (N = 44), advanced adenomas (N = 269), early adenomas (N = 134), and FIT-negative controls (N = 478). Alpha diversity, beta diversity, and species, gene, and pathway relative abundances were estimated. Multivariable logistic regression models were used to estimate associations of these metrics with colorectal neoplasms. RESULTS: Alpha diversity was mostly inversely associated with colorectal neoplasms, particularly early adenomas (OR: 0.45, 95% CI: 0.25-0.80; P = 0.01). Presence of oral pathogens, including Parvimonas micra, was associated with higher odds of CRC. Furthermore, Escherichia coli and Bacteroides fragilis were strongly associated with higher odds of all colorectal neoplasms. Several genes and pathways were associated with colorectal neoplasms. CONCLUSIONS: Our findings align with smaller studies of the gut microbiome and colorectal neoplasms, supporting that CRC screening programs provide opportunities to prospectively study the gut microbiome's association with cancer risk in large populations.

Humans↗

PubMed2026

A geroprotective probiotic and its functional metabolite counteract inflammaging to extend healthspan.

The gut microbiome profoundly influences host aging, yet the specific microbes and mechanisms governing divergent aging trajectories remain elusive. In this study, we delineated enterotype-specific gut microbial remodeling during aging and developed a microbiome-based aging clock (MicroAge) to track biological aging trajectories. We identified Bifidobacterium pseudocatenulatum (B. pseudocatenulatum) as a candidate geroprotective species consistently depleted during aging across both sexes and multiple Chinese cohorts. In naturally aged mice, oral B. pseudocatenulatum monotherapy rescued intestinal homeostasis, mitigated multiorgan inflammaging, enhanced cognitive-motor performance and extended healthspan. Mechanistically, we characterized 5-aminovaleric acid betaine (5-AVAB) as a key B. pseudocatenulatum-derived metabolite whose levels decline physiologically in aging humans. 5-AVAB supplementation partially recapitulated a broad spectrum of the systemic benefits observed with B. pseudocatenulatum treatment, including improved cognitive and motor function and suppressed multiorgan inflammaging. Our findings identify the B. pseudocatenulatum-5-AVAB axis as a promising target for microbiome-based interventions to promote healthy aging.

Animals↗

PubMed2026

Ruminosignatures associated with methane emissions and feed efficiency across geographies and cattle breeds.

The cattle rumen microbiota represents a complex and dynamic ecosystem whose organization and relationship to host phenotypes are important for food security and environmental sustainability. We analyzed rumen microbiota profiles from 2496 cattle representing five breeds and production systems across five countries, identifying microbial co-abundance groups termed Ruminosignatures. We detected 14 distinct Ruminosignatures, including 2 observed across all populations dominated by Prevotella and UBA2810. Additional Ruminosignatures showed breed- and diet-specific patterns and collectively explained 96%-99% of variance in rumen microbial composition. Integrative cross-country analysis confirmed 10 out of 14 Ruminosignatures identified in cohort-specific analyses. Several Ruminosignatures were associated with methane emissions and feed efficiency traits and were partially under host genetic control, with heritability estimates ranging from 0.09 to 0.58. Structural equation modeling revealed consistent negative genetic and phenotypic correlations between the UBA2810-dominated Ruminosignature (RS_UBA2) and methane emissions across cohorts (rg = -0.40 to -0.65), with structural coefficients concordant in sign across all populations, supporting the expected direction of phenotypic response to selection on RS_UBA2. Meta-analysis confirmed positive associations of RS_UBA2 with average daily gain and negative associations with methane-related traits and feed conversion ratio. Functional genome-based predictions suggested RS_UBA2 may reduce methanogenesis through alternative hydrogen utilization pathways competing with methanogenic archaea. Production system type influenced both Ruminosignature occurrence and relationships with host phenotypes, emphasizing the relevance of context-specific strategies for microbiome modulation. Our findings highlight the potential of the Ruminosignatures framework for microbiome-informed breeding programs aimed at improving feed efficiency while reducing the environmental impact of cattle production.

Animals↗

PubMed2025

A randomized controlled trial to unveil the influence of an exercise intervention on brain integrity and gut microbiome structure in individuals with HIV.

OBJECTIVE: Exercise intervention programs enhance physical fitness, cognition, neuroimaging measures, and alter the structure of the gut microbiome in individuals without HIV. However, interventional studies exploring the effects of exercise in persons with HIV (PWH) have not included neuroimaging or gut microbiome analyses. DESIGN: A randomized controlled trial conducted at Washington University in St. Louis, MO, USA. METHODS: 65 PWH (aged ≥40 years, self-reported sedentary lifestyle) were randomly assigned to a 6-month cardiorespiratory and resistance training (EXS) or stretching control (SIS) intervention in a 2 : 1 ratio. Longitudinal change in cognition, cerebral blood flow (CBF), physical and cardiorespiratory fitness, and gut microbiome diversity and composition were examined among participants ( n  = 62) who completed any portion of the intervention (ClinicalTrials.gov: NCT02663934). RESULTS: Better fitness and better cognitive performance were associated with greater phylogenetic diversity in gut microbiome composition at baseline. Longitudinal findings indicated slight but significant improvements in psychomotor speed and executive function, reductions in body mass index, improvements in physical fitness, and increased gut microbiome diversity. These changes were observed regardless of assigned intervention group. There were no observed changes in CBF for either group. CONCLUSIONS: These findings highlight physical fitness as a modifiable factor in PWH that may improve cognitive performance and change gut microbiome composition. Both interventions were beneficial, suggesting light stretching exercise or study participation alone could have been sufficient to introduce positive cognitive shifts in previously sedentary PWH. Longer interventions with more participants are needed to identify changes in neuroimaging metrics related to brain integrity.

Humans↗

PubMed2026

Integrated metagenomic and metabolomic analysis identifies severity-specific inflammatory and metabolic signatures in post-stroke depression.

Post-stroke depression (PSD) is a common complication that significantly impacts patient prognosis. This study aimed to systematically characterize the associations among gut microbial ecology, metabolic profiles, and inflammatory responses across different severities of PSD. We conducted metagenomic sequencing, non-targeted metabolomics, and serum cytokine analysis (IL-1β, IL-6, IL-10, IL-18, TNF-α, IFN-γ, and CRP) in 91 patients with varying degrees of PSD and non-PSD controls. Bioinformatics analyzes were employed to construct multi-omics association networks and machine learning models. Results indicated that PSD patients exhibited significantly increased gut microbiota alpha-diversity, suggesting dysbiosis. Mild depression was characterized by compensatory neural signaling activation, whereas the moderate depression group exhibited abnormalities in tryptophan/indole metabolism, oxidative stress-related metabolic imbalances, and functional decompensation. Further analyzes suggested that Alistipes, Blautia_A, Evtepia gabavorous, and Lachnospira were associated with inflammatory features, GABA-related metabolic alterations, aromatic amino acid/indole metabolism, and lipid-amino acid metabolism, respectively. Under a more rigorous 10-fold cross-validation framework, the performance of different multi-omics combination models showed heterogeneity; however, some combinations still demonstrated superior discriminatory ability compared to single-omics approaches. This study provides multi-omics clues suggesting associations between different PSD severity levels and features such as increased Alistipes abundance, reduced antioxidant capacity, and altered tryptophan metabolism. It provides candidate biomarker combinations that may be useful for PSD stratification and suggests that the gut microbiome may represent a potential target for future PSD intervention. In summary, PSD may be associated with dynamic alterations along the "gut-brain-inflammation-metabolism" axis. These findings provide integrated evidence for microbial, metabolic, and inflammatory abnormalities across different PSD severity levels, but still require validation in larger samples, longitudinal cohorts, and mechanistic studies.

Humans↗