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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↗

PubMed2025

Specificities of chemosensory receptors in the human gut microbiota.

The human gut is rich in metabolites and harbors a complex microbial community, yet surprisingly little is known about the spectrum of chemical signals detected by the large variety of sensory receptors present in the gut microbiome. Here, we systematically mapped the ligand specificities of selected extracytoplasmic sensory domains from twenty members of the human gut microbiota, with a primary focus on the abundant and physiologically important class of Clostridia. Twenty-five metabolites from different chemical classes-including amino acids, nucleobase derivatives, amines, indole, and carboxylates-were identified as specific ligands for fifteen sensory domains from nine bacterial species, which represent all three major functional classes of transmembrane receptors: chemotaxis receptors, histidine kinases, and enzymatic sensors. We have further characterized the specificity and evolution of ligand binding to Cache superfamily sensors specific for lactate, dicarboxylic acids, and for uracil and short-chain fatty acids (SCFAs). Structural and biochemical analysis of the dCache sensor of uracil and SCFAs revealed that its two different ligand types bind at distinct sensory modules. Overall, combining experimental identification with computational analyses, we were able to assign ligands to approximately half of the Cache-type chemotaxis receptors found in the eleven gut commensal genomes from our set, with carboxylic acids representing the largest ligand class. Among these, the most commonly found ligand specificities were for lactate and formate, indicating a particular importance of these metabolites in the human gut microbiota and consistent with their observed growth-promoting effects on selected bacterial commensals.

Humans↗

PubMed2026

Targeting the Microbiota-Gut-Brain Axis: Emerging Nanomedicine Approaches for Neurodegenerative Diseases.

The microbiota-gut-brain axis (MGBA) is a bidirectional relationship between the gut microbiota (GM) and the brain, where the GM affects the gastrointestinal tract (GIT) and the central nervous system (CNS), and vice versa. Microbiotas are important for several vital body processes, including metabolism, immunity, and homeostasis. The MGBA has three main pathways: the vagal nerve mechanism, the immune-related mechanism, and the neuroendocrine mechanism. GM imbalance, known as dysbiosis, affects the GIT, the brain, and the CNS. Furthermore, dysbiosis is linked to several neurological disorders such as Alzheimer's (AD), Parkinson's (PD), depression, autism spectrum disorder (ASD), and multiple sclerosis (MS). Studying MGBA gives researchers new therapeutic ideas using microbiota. Using special diets rich in fiber and probiotics, in addition to fecal microbiota transplantation (FMT), is being studied as a new therapy for MGBA. From the point of view that these therapeutic interventions maintain microbiota imbalance, which in turn will affect the brain and can relieve the neurological disorders caused by dysbiosis and MGBA.

Humans↗

PubMed2026

Two-sample Mendelian randomization study of gut microbiota and inflammatory proteins: Predictive, preventive, and personalized treatment for migraine.

The human gut microbiota is increasingly recognized as a significant factor in the pathogenesis of migraine, potentially via inflammatory pathways. Identifying specific human gut microbiota components associated with migraines, along with the investigation of particular inflammatory proteins, is essential for advancing primary prediction, targeted prevention, and personalized treatment strategies for migraines. We conducted a two-sample Mendelian randomization study using publicly available summary statistics from genome-wide association studies. Data for 473 human gut microbiota taxa were obtained from the Finnish national health survey conducted by the National Institute for Health and Welfare study (FINRISK, n = 5959 European participants). Genome-wide association study data (https://www.ebi.ac.uk/gwas/) for 91 circulating inflammatory proteins were obtained from 14,824 participants across 11 cohorts using the Olink Target 96 Inflammation panel. Migraine outcome data were obtained from the FinnGen R12 release, with cases defined using ICD-10 code G43. All genome-wide association study analyses were adjusted for sex, age, genotyping batch, and 10 genetic principal components to control population stratification (genomic inflation factors: 1.00–1.05). Inverse variance-weighted Mendelian randomization was the primary analysis method, with Mendelian randomization-Egger, weighted median, and mode-based methods as sensitivity analyses. Two-step Mendelian randomization mediation analysis quantified the proportion of the effects of human gut microbiota on migraine that are mediated through inflammatory proteins. Thirty-seven bacterial genera were found to be associated with migraine using the inverse variance-weighted method. Of these, 18 genera exhibited a negative association, while 19 genera demonstrated a positive association with migraine risk. Additionally, eight inflammatory proteins were found to increase the risk of migraine. Among human gut microbiota, four were observed to reduce inflammatory protein levels, whereas another four were associated with increased inflammatory protein levels. Additionally, five gut microbiota were identified to influence migraine through inflammatory proteins in both Mendelian randomization analyses. Specifically, Actinobacteria, Brachyspiraceae, CAG-269 sp001915995, and Paraglaciecola were found to affect migraine outcomes via inflammatory proteins, with mediation proportions of 12%, 19%, 15.5%, and 6.7%, respectively. Lawsonibacter sp002161175 was identified to influence migraine risk through Oncostatin-M and SLAM, with mediation proportions of 15.6% and 11.3%, respectively. Our study elucidated the role of specific human gut microbiota alterations in the pathogenesis of migraine and highlighted the mediating effects of inflammatory proteins. Targeting these particular human gut microbiota alterations offers a promising strategy for predictive, preventive, and personalized medicine in migraine management, resulting in substantial clinical advancements.

causality↗

PubMed2025

Plasma metabolites mediate the causal relationship between gut microbiota and erectile dysfunction: insights from Mendelian randomization study.

BACKGROUND: While the relationship between gut microbiota and erectile dysfunction (ED) has been reported, the specific pathways involved remain unclear. AIM: This study aims to investigate the causal relationship between gut microbiota and ED, and to identify the potential role of plasma metabolites as mediators. METHODS: Utilizing aggregated genome-wide association study (GWAS) data, a comprehensive two-sample Mendelian randomization (MR) analysis was performed involving 196 gut microbiota taxa, 1400 plasma metabolites and ED. Causal relationships between gut microbiota, plasma metabolites and ED were explored. In addition, mediation analysis was applied to identify the pathway from gut microbiota to ED mediated by plasma metabolites. OUTCOMES: This study reveals that plasma metabolites act as mediators regulating the influence of gut microbiota on ED. RESULTS: MR analysis identified causal relationships between six gut microbial taxa and ED, with Butyrivibrio increasing the risk of ED, while Alistipes, Prevotella 9, Dialister, Marvinbryantia, and LachnospiraceaeUCG010 exhibited protective effects. Additionally, 45 plasma metabolites demonstrated causal associations with ED. Finally, mediation analysis revealed four mediation relationships. Sensitivity analysis indicated no heterogeneity or pleiotropy in this study. CLINICAL IMPLICATIONS: Modulating gut microbiota or targeting specific metabolites may offer new therapeutic approaches for ED, highlighting the potential for microbiome-based interventions. STRENGTHS AND LIMITATIONS: The MR approach and large-scale GWAS data provide robust causal evidence, but the findings are limited by their focus on European populations and lack of experimental validation. Further studies are needed to confirm these mechanisms in diverse cohorts and functional models. CONCLUSION: This study establishes a causal link between gut microbiota, plasma metabolites, and ED, identifying specific microbial taxa and metabolites as key contributors to ED risk. The mediating role of plasma metabolites highlights potential therapeutic strategies, such as probiotics or dietary interventions targeting harmful metabolites.

Mendelian randomization↗

PubMed2026

The Mediating Role of Immune Cells in the Genetically Predicted Relationship between Gut Microbiota and Puerperal Sepsis: A Mendelian Randomization Study.

INTRODUCTION: The causal relationship between gut microbiota and puerperal sepsis (PS) remains unclear, and there is a lack of in-depth research regarding the potential mediating role of immune cells in this context. OBJECTIVE: This study aims to investigate the causal relationship between gut microbiota and PS using Mendelian randomization (MR) analysis and to assess the mediating effects of immune cells on the risk of PS onset through mediation analysis. MATERIALS AND METHODS: We selected data from large-scale genome-wide association studies (GWAS) involving 473 gut microbiota species, 731 immune cell phenotypes, and PS datasets. Univariate MR (UVMR) analysis was employed to explore the causal relationship between gut microbiota and PS, with the primary statistical method being inverse variance weighting (IVW). Multiple statistical models were applied for sensitivity analysis to minimize the confounding effects of horizontal pleiotropy and heterogeneity. Subsequently, a two-step mediation MR analysis was conducted to evaluate whether immune cells mediate the relationship between gut microbiota and PS. RESULTS AND DISCUSSION: Analysis using various statistical models indicated that 11 gut microbiota species (e.g., Azorhizobium, Bacillus velezensis, CAG-245 sp000435175, Lentimicrobiaceae, and Providencia) exhibited a causal relationship with PS. Further reverse causal analysis between PS and gut microbiota ruled out the possibility of reverse causality. The two-step mediation MR analysis demonstrated that the percentage of IgD-CD27- B cells (10.26%) and CD62L- monocytes (17.29%) partially mediated the effect of CAG-245 sp000435175 on PS risk. CONCLUSION: This study provides evidence of a causal relationship between the abundance of certain gut microbiota species and PS, while also revealing a potential mediating role of immune cells. These findings offer valuable theoretical insights into personalized treatment strategies and the development of novel diagnostic biomarkers for PS.

Humans↗

PubMed2026

Brucellar spondylitis is associated with disturbance in gut microbiota and histamine metabolism associated inflammation.

BACKGROUND: The pathogenesis of brucellar spondylitis (BLS) has traditionally been considered to be primarily limited to local osteoarticular lesions. With the proposal of the "gut-spine axis" concept, the role of intestinal microecological dysbiosis in inflammatory spinal diseases has attracted in an increase of attention. The overactivated inflammatory cytokine network not only mediates bone destruction and intervertebral disc damage, but also forms a bidirectional interaction with gut microbiota dysbiosis through the "gut-spine axis," collectively driving disease progression. However, the inflammatory mechanism by which gut microbiota participates in the pathological process of BLS remains largely unclear. METHODS: This study recruited 20 BLS patients and 20 healthy donors. Multi-omics analysis including metagenomics, untargeted metabolomics, and targeted short-chain fatty acids (SCFAs) analysis, were used to compare the structural differences in gut microbiota between the two groups and screen for signature differential bacterial species. Plasma levels of histamine and histidine decarboxylase were measured by ELISA to clarify the role of differential histidine metabolic pathway in the disease. Additionally, plasma levels of lipopolysaccharide (LPS) and inflammatory cytokines (IL-1β, IL-6, IL-10, IL-17A, TNF-α) were detected by ELISA. The correlation between gut microbiota and inflammatory indicators was further analyzed. RESULTS: Compared to the healthy control group, the α-diversity of the gut microbiota in BLS patients was significantly reduced, with the microbial community structure exhibiting increased homogeneity. Beta diversity analysis revealed significant differences, suggesting that disease progression is associated with an overall imbalance in the gut microbiota and the deterioration of its specific structural composition. At the phylum level, the abundances of Actinomycetota, unclassified_d_Viruses, and Fusobacteriota were significantly increased in the gut microbiota of BLS patients compared to the control group, while the abundances of Bacillota and Pseudomonadota were significantly decreased. Further analysis revealed that, compared to the control group, the generic abundance of Enterococcus was significantly increased, while the proportions of Blautia, Faecalibacterium, Ruminococcus, Agathobacter, Roseburia, Clostridium, Eubacterium, Alistipes and Anaerobutyricum were significantly decreased. At the species level, the abundances of Enterococcus sp and Enterococcus-faecium were increased, whereas Blautia sp, Ruminococcus sp, Faecalibacterium sp, Faecalibacterium prausnitzii, Agathobacter rectalis, Eubacterium sp, Agathobacter sp, and Roseburia sp were decreased. Furthermore, untargeted metabolomics revealed that metabolites were enriched in the histidine metabolic pathway, and the levels of SCFAs including butyrate, isobutyrate, valerate, and 4-methylvalerate in the intestinal contents were reduced in BLS. Functional KEGG profiling revealed that key KOs involved in butyrate synthesis (e.g., K00074, K00172, K01640) and transport were globally downregulated in the patient group, whereas histidine decarboxylase KOs (K01693, K11755, K19787) that convert histidine to pro-inflammatory histamine were significantly enriched. The loss of butyrate-producing symbionts led to SCFAs deficiency and mucosal barrier disruption, creating ecological niches for facultatively anaerobic Enterococcus, which further exacerbated local inflammation via proteolytic fermentation and histamine production. Compared with the control group, BLS patients showed decreased plasma levels of IL-10, while levels of IL-1β, IL-6, IL-17A, and TNF-α were increased, and LPS levels were elevated. In addition, significantly elevated plasma pro-inflammatory LPS levels in patients with BLS suggest disruption of intestinal integrity and permeability. Correlation analysis indicated a close relationship between gut microbiota and inflammation. CONCLUSION: BLS is associated with gut microbiota dysbiosis and alterations in microbial metabolites, which may be linked to inflammatory responses and histamine metabolism. The differential microbial taxa identified in this study could be developed into a stool-based non-invasive diagnostic panel to facilitate early differentiation of BLS from other spinal disorders. Furthermore, restoring gut microbial balance through probiotic supplementation or dietary modulation may represent a promising adjunctive strategy to enhance the efficacy of standard antibiotic therapy and reduce disease recurrence.

Humans↗

PubMed2026

Toxoplasma gondii infection disrupts secondary bile acid transformation in feline gut microbiota.

UNLABELLED: Bile acid (BA) transformation relies on gut microbiota and is vulnerable to Toxoplasma gondii infection, yet feline microbial BA-transforming capacity upon toxoplasmosis remains unclear. Here, we constructed a catalog of 2,474 nonredundant feline gut microbial genomes and integrated serum metabolomic data to verify BA transformation alterations. The results revealed that the feline gut microbiome harbored widespread genetic potential for BA transformation but lacked a complete 7α-dehydroxylation pathway due to the absence of the key gene baiE. The BA transformation-related genomes (2,045 in total) were predominantly from the phyla Bacillota_A and Actinomycetota, among which only 37 encoded baiB, all belonging to Bacillota_A. The distribution of BA transformation-related genes varied across intestinal regions: genes encoding 7α-HSDH were primarily enriched in the small intestine, whereas genes encoding 3α-HSDH, baiCD, and baiH were more abundant in the large intestine. Additionally, the abundance of genes encoding BSH and 3α-HSDH increased significantly in the small intestine on day 3 post-infection, accompanied by increases in the phylum Bacillota_C and genera such as Blautia_A, Enterococcus_E, and Ligilactobacillus. Serum metabolomics revealed a significant increase in cholesterol levels post-infection, supporting the impact of T. gondii infection on intestinal BA transformation. These findings illustrated that the feline gut microbiota played an important role in BA transformation and that T. gondii infection disrupted the microbial potential for secondary BA transformation. This study provided new insights into gut microbiota-associated metabolic perturbations during feline toxoplasmosis. IMPORTANCE: Bile acid (BA) transformation plays a critical role in host metabolism and immune regulation. Although studies on BA transformation are increasing, the capacity for BA transformation within the feline gut microbiota and the impact of Toxoplasma gondii infection on this capacity remain unclear. To bridge this gap, we constructed a catalog of 2,474 nonredundant feline gut microbial genomes and integrated serum metabolomic data to verify BA transformation alterations. Our findings revealed that the feline gut microbiome lacked a complete 7α-dehydroxylation pathway, and the specific functions involved in BA transformation may differ between the small and large intestines. Furthermore, integrated metagenomic and serum metabolomic analyses suggested that T. gondii infection disrupted BA transformation capacity in the small intestine. This study provided new insights into gut microbiota-associated metabolic perturbations during feline toxoplasmosis.

Toxoplasma gondii↗

PubMed2002

Molecular biological methods for studying the gut microbiota: the EU human gut flora project.

Seven European laboratories co-operated in a joint project (FAIR CT97-3035) to develop, refine and apply molecular methods towards facilitating elucidation of the complex composition of the human intestinal microflora and to devise robust methodologies for monitoring the gut flora in response to diet. An extensive database of 16S rRNA sequences for tracking intestinal bacteria was generated by sequencing the 16S rRNA genes of new faecal isolates and of clones obtained by amplification with polymerase chain reaction (PCR) on faecal DNA from subjects belonging to different age groups. The analyses indicated that the number of different species (diversity) present in the human gut increased with age. The sequence information generated, provided the basis for design of 16S rRNA-directed oligonucleotide probes to specifically detect bacteria at various levels of phylogenetic hierarchy. The probes were tested for their specificity and used in whole-cell and dot-blot hybridisations. The applicability of the developed methods was demonstrated in several studies and the major outcomes are described.

Adult↗

PubMed2025

Immune-mediated indirect interaction between gut microbiota and bacterial pathogens.

BACKGROUND: In many animals, survival during infection depends on the ability to coordinate interactions between the host immune system and gut microbiota. These tripartite interactions, in turn, potentially shape pathogen virulence evolution. A key regulator of the immune system and, hence, bipartite interactions in insects is the immune deficiency (Imd) pathway, which modulates gut microbiota and pathogens by synthesizing antimicrobial peptides (AMPs) through the NF-κB transcription factor Relish. However, whether Imd-dependent AMPs mediate indirect interactions between gut microbiota and pathogens in a tripartite context remains unclear. Using RNAi-mediated knockdown of Tenebrio molitor Relish (TmRelish), we hypothesized that Imd-dependent AMPs influence indirect interaction between Providencia burhodogranariea_B (P. b_B) infection and the gut microbiota. RESULTS: TmRelish knockdown altered bipartite interactions by disrupting gut microbiota load and composition, increasing pathogen load, and ultimately leading to higher host mortality during infection. However, we did not find support for our tripartite hypothesis that Imd-dependent AMPs mediate indirect interactions between the gut microbiota and P. b_B infection, suggesting the involvement of alternative regulatory pathways or Imd-independent mechanisms. Nevertheless, our investigations of tripartite interactions showed a positive effect of P. b_B infection on gut microbiota load, which in turn stimulated the expression of a subset of AMPs. However, this upregulation of AMPs did not result in reduced P. b_B load. Notably, the gut microbiota did not affect pathogen load but promoted host survival during P. b_B infection, indicating a role in increasing host tolerance rather than resistance. CONCLUSIONS: These findings suggest that while Imd-dependent AMPs may not mediate tripartite interactions in our system, microbiota-host interactions, such as microbiota-mediated immune priming and changes in microbiota load, can shape infection outcomes. These effects on infection outcomes almost certainly exert important selective pressures on the evolution of bacterial virulence.

Animals↗

PubMed2026

Causal Effects of Gut Microbiota on Morning Chronotype, Insomnia and Sleep Duration: A Two-Sample Mendelian Randomization Study.

BACKGROUND: The gut microbiota has been shown to be closely associated with brain function; however, whether it exerts a causal influence on sleep traits remains to be further explored. Mendelian randomization (MR) is an emerging epidemiological approach that uses whole-genome sequencing data to infer causal relationships. In this study, we conducted a two-sample MR analysis to investigate the causal effects of gut microbiota on three domains of sleep traits: morning chronotype, insomnia, and sleep duration. METHODS: Single nucleotide polymorphisms strongly associated with 196 gut microbiota taxa were selected as instrumental variables. Morning chronotype, insomnia, and sleep duration were used as outcomes. MR and sensitivity analyses were performed to assess the causal relationships between gut microbiota and sleep traits. RESULTS: Three taxa (Bifidobacteriales, Bifidobacteriaceae, and Bifidobacterium) were negatively associated with morning chronotype, while Tyzzerella 3 showed a positive causal effect on morning chronotype. Oscillibacter was negatively associated with insomnia, whereas four taxa (Negativicutes, Selenomonadales, the Clostridium innocuum group, and Lachnoclostridium) were identified as risk-increasing factors for insomnia. Lentisphaerae and Victivallaceae were positively associated with sleep duration. Actinobacteria and Alistipes had negative effects on long sleep duration, whereas Ruminiclostridium 6 was positively associated with long sleep duration. Four taxa (Victivallales, Anaerofilum, Lentisphaerae, and Lentisphaeria) were negatively associated with short sleep duration. CONCLUSIONS: Our findings suggest that specific gut microbiota taxa may be positively or negatively associated with sleep traits. These results offer new insights into the potential role of gut microbiota in sleep regulation and provide a basis for future studies aimed at understanding whether modulating microbial composition could influence sleep health.

Mendelian randomization↗

PubMed2025

The mouse gut microbiota responds to predator odor and predicts host behavior.

Chronic stressors can alter the mammalian gut microbiota in ways that mediate host stress responses, but the impacts of acute stressors on these interactions are less well understood. Here, we show that brief exposure of wild-derived mice to predator odor altered gut-microbiota composition, which in turn predicted host behavior. We investigated the individual and combined effects of 15-minute exposures to synthetic fox fecal odor and 30 days of chronic social isolation, an established chronic stressor. Using ethological assays, visceral adipose tissue transcriptomics, and genome-resolved metagenomics, we found that predator-odor exposure significantly affected mouse behavior, gene expression, and gut microbiota. Predator odor-responsive bacteria were associated with the expression of genes involved in anti-microbial defense, and host behavioral responses were predicted by random forest models trained on gut-microbiota profiles. These findings indicate interactions between the gut microbiota and wild-mouse responses to the threat of predation, an ecologically relevant acute stressor.

Journal Article↗

PubMed2026

Effects of dietary interventions on gut microbiota and related cardiometabolic changes in pediatric obesity: a systematic review and meta-analysis.

BACKGROUND: Gut microbiota imbalances may contribute to obesity, yet whether dietary interventions can modulate the microbiota and improve metabolic health in pediatrics has not been thoroughly reviewed. This systematic review and meta-analysis explores the impact of dietary interventions on the gut microbiota of children and adolescents with overweight or obesity, and its association with cardiometabolic improvements. METHODS: A systematic search of clinical trials in Pubmed, Cochrane and EMBASE was conducted following PRISMA guidelines (PROSPERO n°CRD42024505494). Risk of bias was assessed with RoB2 and ROBINS, for randomized and non-randomized intervention studies. RESULTS: Overall, 60 articles were assessed for full-text eligibility, 8 were included, and 4 provided alpha-diversity data for meta-analysis. A total of 200 participants were included (6-16 years). Six studies implemented calorie-restricted diets, one a low free-sugar diet, and one CHILD-1 diet. The meta-analysis revealed a significant increase in Chao1 (48.76 [95%CI 1.81; 95.70]; I2 = 86.8%, p < 0.001) following a balanced calorie-restricted dietary intervention. Although there was heterogeneity in taxa-level changes, several butyrate-producing genera (Clostridium XVIa, Coprococcus, Roseburia, Faecalibacterium, Blautia, Butyricimonas) increased following dietary intervention. CONCLUSIONS: Balanced dietary interventions with calorie-restriction adequate for pediatric age could increase gut microbiota richness and butyrate-producing bacteria abundance. Future trials should clarify diet-driven gut microbiota changes in childhood obesity and related metabolic changes. IMPACT: Balanced calorie restriction diet may increase gut microbiota richness in childhood obesity Butyrate-producer expansion needs long-term dietary intervention Gaps in linking microbiota-metabolism interplay in pediatric obesity.

Journal Article↗

PubMed2026

Integrated analysis of gut microbiota, serum metabolomics, and proteomics reveals novel associations with clinical symptoms in patients with cerebral infarction.

BACKGROUND: Cerebral infarction (CI) is a major cause of adult disability and mortality worldwide. Mounting evidence supports the critical role of the gut-brain axis in cerebrovascular disease progression. This study aimed to characterize the alterations in gut microbiota, serum metabolome, and serum proteome in patients with CI, and to identify multi-omics signatures associated with clinical symptoms. METHODS: A total of 20 CI patients and 20 healthy controls (HC) were enrolled. Fecal microbiota was profiled using 16 S rRNA gene high-throughput sequencing. Serum metabolomics and proteomics were analyzed using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and data-independent acquisition (DIA) proteomics, respectively. Spearman correlation and multi-omics integration were applied to explore the associations among microbiota, metabolites, proteins, and clinical indicators. RESULTS: CI patients displayed significant gut microbiota dysbiosis, with a markedly lower gut microbiota health index (GMHI) and higher microbiota disorder index (MDI) compared with HC (P < 0.001). The genera g_norank_o_RF39 and Oxalobacter were significantly enriched in CI patients, whereas Clostridium_sensu_stricto_1 and Agathobacter were enriched in HC. Metabolomic analysis identified 445 differential metabolites, mainly involved in glycerophospholipid metabolism, phenylalanine metabolism, and caffeine metabolism. Proteomic analysis revealed 140 differentially expressed proteins linked to inflammatory responses, calcium signaling, and NF-κB signaling. Multi-omics integration showed that signature gut microbiota was strongly correlated (P < 0.005) with key serum metabolites and proteins implicated in CI pathogenesis. CONCLUSIONS: This integrated multi-omics study revealed distinct gut microbiota, serum metabolomic, and proteomic alterations in CI patients. The microbiota-metabolite-protein regulatory axes provide novel insights into the gut-brain axis in CI and may serve as potential diagnostic biomarkers or therapeutic targets.

Humans↗

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

Novel Insights into Immune Cell Function in Type 2 Diabetes Mediated by Gut Microbiota: A Two-Sample Mendelian Randomization Study.

INTRODUCTION: The role of immune cells in type 2 diabetes mellitus (T2DM) development is well-studied, but their interactions with the gut microbiota and the mediating role in this process remain unclear. METHODS: We analyzed 731 immune cell phenotypes (3,757 Europeans), 473 gut microbiota traits (5,959 Finns), and T2DM data (over 400,000 Finns). Mendelian randomization (MR) was based on three assumptions: the instrumental variable (IV) is associated with exposure, IV is not influenced by confounding, and IV affects the outcome only through exposure. We selected single-nucleotide polymorphisms (SNPs) from genome-wide association studies as instrumental variables (IVs) to infer causal effects in two-sample MR analysis. RESULTS: We identified 36 immune cell phenotypes associated with T2DM, including 29 protective factors and seven risk factors, as well as 10 gut microbiota significantly linked to T2DM, with eight protective factors and two risk factors. MR revealed that five gut microbiota mediated the relationship between immune cells and T2DM. For example, the effects of CD3 on resting Treg (OR: 1.0136), CD3 on CM CD4+ (OR: 1.0180), and CD3 on naive CD4+ cells (OR: 1.0150) in T2DM were found to be partially mediated by the species Bacillus. AYThe corresponding mediation effect proportions were 8.99%, 11.8%, and 11.4%. DISCUSSION: MR analysis identified multiple gut microbiota mediators in the relationship between immune cells and T2DM, addressing previous observational evidence. Limitations included the European ancestry bias, among others. CONCLUSION: This study has highlighted the gut microbiota as a mediator between immune cells and T2DM, offering new insights for its early prevention and intervention.

Diabetes Mellitus, Type 2↗

PubMed2026

Natural products alleviate exercise-induced fatigue by modulating gut microbiota: a systematic review.

BACKGROUND: Exercise-induced fatigue critically impairs athletic performance and training quality. The gut microbiota, as a key regulator of the "gut-muscle axis," has emerged as a promising anti-fatigue target. Natural products - owing to their diverse sources, structural complexity, and favorable safety profiles - have attracted growing research interest. However, a systematic synthesis comparing their anti-fatigue effects via gut microbiota modulation across different sources is lacking. SCOPE AND APPROACH: We systematically searched PubMed, Web of Science, the Cochrane Library, and CNKI for original studies that administered natural products and concurrently assessed gut microbiota changes and anti-fatigue outcomes. Twenty-six studies (25 animal experiments and 1 human trial) were included and categorized into seven groups by source and chemical characteristics. A descriptive systematic review was conducted to identify common mechanisms and source-specific differentiations. KEY FINDINGS AND CONCLUSIONS: The enrichment of short-chain fatty acid (SCFA)-producing bacteria and the activation of the SCFA-AMPK/PGC-1α axis were shared core events across all product categories. However, source-dependent mechanistic divergences emerged: polysaccharides acted primarily as fermentable substrates with an optimal dose window; polyphenols and saponins exerted dual modulation on both microbiota and host signaling pathways; compound extracts achieved systemic synergy through functional complementation; marine- and animal-derived products exhibited unique targeting profiles and rapid action. Intestinal barrier maintenance and brain-gut axis regulation further extended the anti-fatigue repertoire. Collectively, natural products possess a solid mechanistic basis for alleviating exercise-induced fatigue via gut microbiota remodeling. The differentiated characteristics of these methods in targeting precision and pathway engagement provide a theoretical foundation for designing precision intervention strategies tailored to specific fatigue contexts.

Humans↗

PubMed2006

Optimization of terminal restriction fragment polymorphism (TRFLP) analysis of human gut microbiota.

Some compounds originating from the human gut microbial metabolism of exogenous and endogenous substrates may have properties that profoundly affect the host's physiological processes. The influence of these metabolites on differences in disease risk among individuals could be mediated by metabolism specific to the gut microbial community composition. In this study, we evaluated the effectiveness of terminal restriction fragment polymorphism (TRFLP) as a biomarker of the fecal microbial community (as a surrogate of gut microbiota) for application in human population-based studies. We tested the effects of experimental conditions on DNA quality, DNA quantity, and TRFLP patterns derived from gut bacterial communities. Genomic DNA was extracted from fecal slurries and the bacterial 16S rDNA genes were amplified and analyzed by TRFLP. We found that the composition of the TRFLP fingerprints varied by different extraction procedure. The best quality and quantity of community DNA extracted from fecal material was obtained by using the QIAamp DNA stool minikit (Qiagen, Valencia, CA) with 95 degrees C incubation and moderate bead beating treatment during the cell-lysis step. Homogenization of fecal samples reduced variation among replicates. Once the TRFLP procedure was optimized, we assessed the methodological and inter-individual variation in gut microbial community fingerprints. The methodological variation ranged from 4.5-8.1% and inter-individual variation was 50.3% for common peaks. In conclusion, standardized TRFLP is a robust, reproducible, and high-throughput method that will provide a useful biomarker for characterizing gut microbiota in human fecal samples.

Adult↗