Enteric hyperoxaluria (EH) results from increased oxalate bioavailability in the gastrointestinal (GI) tract, often affecting patients with inflammatory bowel disease (IBD). We investigated the pathophysiology of EH in an ileitis mouse model, hypothesizing that fat malabsorption, increased gut permeability, and microbial shifts collectively contribute to the hyperoxaluric phenotype in the setting of GI tract inflammation. SAMP1/YitFc (SAMP1) mice and their parental AKR controls were fed one of three diets varying in fat content (10%, 45%, or 60% kcal), each supplemented with 1% oxalate, for 6 weeks. Plasma (P), urine (U), oxalate (Ox), and creatinine (Cr) levels were measured, while stool lipid species were analyzed using mass spectrometry. Intestinal permeability was assessed using sucralose and 13C2 oxalate gastric gavage in SAMP1 and AKR mice. Histology, qPCR, and Western blotting were performed on kidney, liver, and GI tissues. Microbial DNA was analyzed at the community, genus, and functional levels. Changes in bacterial metabolic pathways were investigated in the mice fed the highest fat content. The oxalobiome of SAMP1 and AKR mice was characterized using our bioinformatics pipeline. On high-fat diets, SAMP1 mice had higher UOx, POx, and PCr levels than AKR mice. Increased levels of diacylglycerols and free fatty acids in SAMP1 stool samples suggested fat malabsorption. A decrease in ZO1 and occludin intestinal expression, coupled with significantly increased urinary sucralose and oxalate levels, indicated increased intestinal permeability. Microbiome analysis revealed the enrichment of Lactobacilli and Bacteroides in SAMP1 mice, with bacterial pathways favoring lipid synthesis and glyoxylate metabolism. Ileal SLC26A6 protein expression was significantly reduced in SAMP1 mice. SAMP1 mice also developed progressive kidney injury with interstitial inflammation. These findings highlight fat malabsorption as a central pathophysiologic disturbance in EH that reduces luminal calcium availability for oxalate binding, is associated with enhanced intestinal permeability, and accompanies microbiome and enzymatic pathway alterations.
The gut-brain immune axis integrates microbial, immune, and neural signals to regulate neurodevelopment, homeostasis, and disease susceptibility. Early-life nutrition, particularly human milk oligosaccharides, shapes beneficial microbiota composition, enhances hippocampal plasticity, promotes anti-inflammatory microglia polarization, and fosters immune tolerance. Gut microbiota-derived metabolites, including short-chain fatty acids, tryptophan derivatives and secondary bile acids, regulate microglia maturation, astrocyte function, T cell differentiation, neurotransmitter production, and vagus nerve signaling. These processes influence synaptic pruning, neurogenesis, and neuroinflammation. Adaptive immune cells in the central nervous system, notably meningeal and infiltrating CD4 T cells, further connect peripheral immunity to neuronal responses through cytokines, such as IL-4, IFNγ, and IL-17A. Nutritional imbalances may exacerbate disease-associated microglia and pathogenic T cell activity in Multiple Sclerosis, Alzheimer’s disease, and autism spectrum disorders. In aging, diet helps mitigate “inflammaging” by countering metabolic shifts in microglia and lymphocytes. This review examines how nutrition modulates bidirectional gut-brain immune crosstalk across the lifespan.
Flatulence is closely associated with gut dysbiosis, yet the characteristic microbial signatures, metabolic alterations, and actionable intervention targets remain unclear. This limited mechanistic understanding has hindered the development of precise microbiota-based strategies for managing flatulence. Here, we found that participants with flatulence exhibited marked shifts in gut microbial functions and fecal metabolic profiles compared with healthy controls, characterized by enhanced abnormal fermentation, enrichment of oxidative stress-related functions, elevated low-grade inflammatory signatures, and reduced anti-inflammatory and mucosal-protective metabolic features. Faecalibacterium prausnitzii was significantly negatively associated with the high-gas-producing phenotype. In vitro replenishment experiments further validated the role of F. prausnitzii in reducing gas production, promoting butyrate generation, and remodeling butyrate-associated microbial communities. Based on microbial interaction analysis, we identified Bifidobacterium longum CCFM1319 as a candidate strain for targeting F. prausnitzii. In a double-blind, randomized, placebo-controlled clinical trial, supplementation with B. longum CCFM1319 significantly increased intestinal F. prausnitzii abundance and improved flatulence-related symptoms. Collectively, these findings reveal the microbiota and metabolic dysbiosis underlying flatulence, highlight the key regulatory role of F. prausnitzii, and lays the foundation for targeted microbiota-based intervention strategies for flatulence.
Salmonella enterica serovar Typhimurium (S. Tm) mouse infection models commonly rely on antibiotic pretreatment to disrupt microbiota-mediated colonization resistance and enable reproducible infection. Streptomycin is the primary antibiotic used, but alternative pretreatment regimens like ampicillin are increasingly employed, particularly for infections with attenuated S. Tm mutants. However, the impact of different antibiotic pretreatments on Salmonella infection kinetics and host responses remains poorly characterized. Here, we compared S. Tm infection outcomes in streptomycin- versus ampicillin-pretreated mice. While both antibiotics supported comparable luminal colonization, ampicillin pretreatment induced earlier, stronger, and more sustained intestinal inflammation and histopathology during S. Tm infection. In germ-free mice, these differences were absent, indicating a microbiota-dependent mechanism, further supported by microbiota transfer experiments. The distinct infection outcomes were associated with antibiotic-specific alterations in the microbiota composition, while targeted analysis of luminal metabolites by mass spectrometry revealed no pronounced differences. Strikingly, ampicillin pretreatment coincided with higher early TTSS-1 expression in S. Tm, consistent with increased epithelial invasion. Together, our findings demonstrate that antibiotic pretreatment profoundly shapes the intestinal environment and is associated with differences in Salmonella virulence expression, host responses, and infection kinetics. The choice of antibiotic pretreatment is therefore a crucial variable in murine Salmonella infection models.
Proteolytic imbalance involving host and microbial serine proteases and their inhibitors (serpins) contributes to intestinal barrier disruption and chronic inflammation in inflammatory bowel disease (IBD). However, the interplay among these components remains insufficiently characterized. Here, we survey 13,304 publications over five decades, to map protease-serpin-microbiome literature in IBD. Our analysis reveals a fragmented literature structure, with uneven coverage and limited cross-domain integration among host proteases, microbial proteases, and inhibitory pathways. We synthesize evidence linking these components to intestinal barrier integrity, mucosal immunity, extracellular-matrix remodeling, and microbial ecology. Considering the protease-serpin-microbiome axis may provide an integrative direction for future studies of IBD pathogenesis, including the investigation of mechanisms underlying disease heterogeneity, prioritizing future biomarker and therapeutic studies.
The gut microbiota plays an important role in the occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD), but the specific molecular mechanisms involved have not been fully elucidated. In this study, human cohort studies were performed to identify that the relative abundance of Bacteroides cellulosilyticus (B. cellulosilyticus) was significantly decreased in patients with MASLD. Through the integration of metagenomic and metabolomic analyses, it was confirmed that B. cellulosilyticus and its metabolite 2-hydroxyphenylacetic acid (2HPAA) are key factors regulating the occurrence and development of MASLD. Single-cell sequencing and lipidomic analyses revealed that 2HPAA can enter the liver through the enterohepatic circulation to exert regulatory effects. Specifically, 2HPAA inhibits the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway, thereby suppressing the expression of the fatty acid transporter CD36. Meanwhile, 2HPAA regulates lipid metabolism in hepatocytes by significantly enhancing palmitate conversion efficiency and inhibiting CD36 palmitoylation. This dual regulatory effect on CD36 expression and palmitoylation can reduce lipid accumulation in hepatocytes and ultimately alleviate MASLD progression. These findings reveal the mechanism by which B. cellulosilyticus and 2HPAA alleviate MASLD by targeting the PPARγ-CD36 pathway. This work provides a new perspective for the study of gut microbiota-host interactions in regulating liver diseases.
Drug resistance in inflammatory bowel disease (IBD) precision therapy remains a critical barrier to clinical outcomes, with traditional studies focusing on single molecules or isolated pathways but failing to systematically dissect the bidirectional, context-dependent dynamic crosstalk among gut microbiota, immunity, and epigenetic modifications. This review dissects resistance mechanisms of key biologics (e.g., antitumor necrosis factor-α agents, vedolizumab) and small-molecule drugs (e.g., janus kinase inhibitors), proposing and validating the “triple-loop hierarchical regulation model”—gut microbiota dysbiosis as the initiator, immune dysregulation as the amplifier, and epigenetic maintenance as the stabilizer, with a bidirectional feedback loop sustaining resistance. It identifies the interaction network as the central regulatory axis, outlining a cascade where altered microbiota composition, signature metabolites (e.g., short-chain fatty acids), epigenetic modification (e.g., acetylation), and Th17/Treg imbalance may collectively contribute to the emergence of drug-resistant phenotypes. Four distinct subtypes (immunogenic, metabolic, epigenetic, barrier-deficient) are defined, with targeted strategies: precise microbiota regulation (e.g., fecal microbiota transplantation), immunity-epigenetics intervention (e.g., histone deacetylase inhibitors), and synergistic schemes that could partially rescue resistant clinical presentations. It also discusses multi-omics biomarkers for early prediction and formulation translation challenges, emphasizing cutting-edge technologies (single-cell multi-omics, organoid-microbiota co-cultures) and interdisciplinary collaboration. This review provides a comprehensive framework for overcoming IBD drug resistance and advancing personalized therapies.
Enteropathogenic Escherichia coli (EPEC) causes disease in children, presenting as chronic diarrhea that can impair physical and cognitive development. The attachment of typical EPEC (tEPEC) to the gut epithelium via bundle-forming pili (BFP) is a key factor in its virulence. Yet, infections by atypical EPEC (aEPEC), which lack BFP, have become increasingly common. To investigate how aEPEC recover host-attachment in the absence of BFP, we performed experimental evolution using a non-adherent E. coli, constructed to mimic the ancestor of aEPEC, and selected adherent progeny. Highly adherent variants evolved through phase-variable activation of type I fimbriae (T1F), followed by two alternative trajectories: bacterial filamentation, which increases T1F avidity, or point mutations in the T1F adhesin FimH that enhance ligand affinity. Extending our analysis to the genomes of 327 aEPEC strains isolated from infected patients revealed that similar FimH mutations are common. We further demonstrated experimentally that these naturally occurring variants often increase epithelial-attachment. Our findings implicate T1F in aEPEC pathogenesis and suggest it may be clinically relevant for anti-adhesion therapy. More broadly, these results indicate that impaired host-attachment can be rapidly compensated by upregulating and optimizing an alternative adhesin, and that combining experimental evolution with comparative genomics can reveal evolutionary trajectories occurring in nature.
Beneficial effects of the gut commensal Agathobacter rectalis (Ar) are reported in diseases, yet its role in colorectal cancer (CRC) remains unclear. Here, metagenomic analysis revealed consistent fecal Ar depletion across CRC cohorts. In Apc min/+ mice, Ar inhibited colon tumorigenesis, reducing tumor number and volume versus E. coli and PBS controls. LC-MS/MS metabolomics showed decreased fecal cholesterol and altered lipid/cholesterol pathways after Ar treatment. In vitro, Ar-conditioned medium suppressed CRC cell growth, clonogenicity, migration, and cell cycle progression. LC-MS/MS identified (-)-epigallocatechin (EGC) as an Ar-derived metabolite absent in control bacteria. EGC recapitulated Ar-mediated anti-CRC effects in vitro and in vivo, with metabolic changes linked to lipid/cholesterol pathways. Transcriptomics showed that EGC suppressed SREBP signaling, cholesterol metabolism, and MAPK pathways. Mechanistically, EGC reduced nuclear SREBF2 and its transcriptional activity, downregulated cholesterol synthesis/metabolism genes, including FDPS and PCSK9, and suppressed MAPK signaling. Molecular docking suggested that EGC may bind pSREBF2 or SCAP. Cellular thermal shift assay revealed that EGC interacts with and stabilizes pSREBF2, but not SCAP. Co-immunoprecipitation demonstrated that EGC reduces pSREBF2-SCAP interaction, thereby inhibiting SCAP-mediated SREBF2 cleavage activation. Together, these findings define an Ar-EGC microbe-metabolite axis and support Ar/EGC-based interventions targeting cholesterol metabolism in CRC.
Animals coexist with complex microbial communities that influence their development, immunity, metabolism, and behavior. Evidence shows these effects arise not just from metabolic and immune signaling but also from epigenetic mechanisms that alter host gene expression. Microbial signals can modulate DNA methylation, histone modification, chromatin accessibility, and RNA pathways, reshaping transcription across tissues. This review synthesizes evidence from diverse animal systems to demonstrate how microbial communities influence epigenetic landscapes and contribute to immunity, development, metabolism, and neurobiology. We explore data suggesting that microbial epigenetic interactions extend into the tumor microenvironment, where intratumoral microbes may shape disease progression by remodeling epigenetic states. Comparative studies indicate that microbial regulation of host epigenetics is an evolutionarily conserved mechanism linking environmental signals to phenotype. Despite recent advances, questions remain about causality, cell-type specificity, persistence, and inheritability of these effects. We propose microbial epigenetic regulation as a key interface integrating microbial cues with host physiology and pathology, providing a framework for understanding host-microbe interactions across species.
Major Depressive Disorder (MDD) is a highly prevalent, severe mental health condition that constitutes one of the leading causes of disability worldwide. While recent animal studies suggest a causal role of the gut microbiome in the pathophysiology of MDD models, evidence in humans is still unclear due to small sample sizes, inconsistent clinical assessment of MDD diagnosis, and methodological limitations regarding causal inference in cross-sectional data. Here, we explicitly address these shortcomings to investigate the potential causal link between the gut microbiome and MDD: First, we replicate previously reported microbiome-depression associations using one of the largest multicenter MDD cohorts for which microbiome data and in-depth diagnostic assessment are available (N = 1,269 MDD patients and controls). We find a significant difference between healthy controls and MDD patients for the relative abundance of four taxa: Eggerthella, Hungatella, Coprobacillus, and Lachnospiraceae FCS020. Second, we employ state-of-the-art, fully data-driven causal inference tools within Judea Pearl's framework, allowing us to derive model constraints from the data rather than relying on potentially strong, unrealistic assumptions. Using this approach, we found evidence for Eggerthella and Hungatella as potential causal contributors to MDD. Furthermore, we show that the potential causal effects of Eggerthella and Hungatella on MDD persist beyond the influence of body mass index, revealing two distinct potential causal pathways linking the gut microbiome to MDD. Finally, the difference in relative abundance of these taxa between healthy and MDD patients was independent of antidepressant medication. Our study provides the first data-driven evidence for a potential causal role of gut microbiota in the pathophysiology of depression in humans.
Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality, particularly in under-resourced populations. Although nutritional interventions are important for CVD prevention, their outcomes are commonly evaluated using conventional clinical and behavioral indicators, which may not fully capture early molecular responses. In this study, we developed the BIOCARD framework, an exploratory fecal multi-omics platform integrating bile acids, lipids, and metabolites to evaluate intervention outcomes related to cardiovascular health. Fecal samples were collected from caregiver-child participants enrolled in a 10-week randomized controlled trial comparing a multicomponent garden-based intervention (SHA) with an education-only control group (MSP). Fecal polar metabolites, lipids, and bile acids were analyzed by UHPLC-HRMS-based approaches and integrated with conventional health indicators. Traditional clinical indicators in the present study showed limited sensitivity for detecting intervention-related differences. In contrast, fecal multi-omics analyzes revealed intervention-associated differences in metabolites, lipids, and bile acids, with children showing more apparent molecular variation than parents. Network analysis further revealed associations between selected molecular features and cardiovascular-related indicators, including blood pressure, body fat, skin carotenoids, and Healthy Eating Index scores. Together, these findings suggest that the BIOCARD framework may serve as an exploratory molecular approach to complement traditional outcome measures and improve the evaluation of nutritional interventions for cardiovascular health.
Vitamin B12 is acquired through the consumption of animal-source foods and supplements. In animal models, interventions with B12 and/or methionine influence fecal short-chain fatty acid (SCFA) concentration. Yet the relevance of dietary B12 to microbially produced SCFAs in humans is unknown. This study determined associations between dietary B12 and the gut microbiome in a deeply phenotyped cohort of healthy U.S. adults. Habitual diet and fecal shotgun metagenomes were integrated alongside measurements of fecal SCFAs, plasma SCFAs, and plasma B12 (n = 277). Vitamin B12 intake ranged from 2.4 to 1062 µg/day, and nearly all participants were B12 replete. Stratification of participants into adequate (2.4-8.51 µg/day) and high B12 intake (>8.51 µg/day) groups revealed the association of high intake with a reduction in bacteria capable of anaerobic B12 biosynthesis. High B12 intake was also associated with lower fecal SCFA concentrations even after controlling for fiber and methionine intake. Differences in microbial taxa between dietary groups were limited. However, machine learning models demonstrated the ability to predict fecal propionate and butyrate from microbial pathways in the adequate or no supplement groups, but not in the high intake or supplement groups. Our results indicate that dietary B12 greater than 8.51 µg/day may be associated with reduced microbial synthesis of B12 and lower fecal SCFA production.
Dietary therapy is central to irritable bowel syndrome (IBS) management, yet the long-term durability of the low-FODMAP diet (LFD), and of microbiome-guided personalization, remains unclear. We assessed the long-term clinical and gut-microbiome effects of a microbiome-guided personalized diet (PD) compared with a standard LFD in adults meeting Rome IV criteria for IBS. In this multicenter, open-label randomized controlled trial with blinded outcome assessment, participants who completed a 6-week dietary intervention (PD or LFD) were followed at 6 and 12 months without further dietary intervention. Outcomes included the IBS Severity Scoring System (IBS-SSS), IBS Quality of Life (IBS-QOL), and the Hospital Anxiety and Depression Scale (HADS); gut microbiota were profiled by 16S rRNA sequencing. Longitudinal changes were evaluated using linear mixed-effects models, responder analyses, PERMANOVA, and PERMDISP. Both diets reduced IBS-SSS at 6 weeks. PD maintained symptom improvement at 6 and 12 months (-82.0 and -78.3 points from baseline), whereas LFD benefits regressed by 12 months (+29.3 points; between-group p = 0.001). At 12 months, IBS-SSS responder rates were higher with PD than LFD (62.5% vs 34.5%; absolute risk difference +28.0%, 95% CI 4.2-47.7; Fisher p = 0.029), and IBS-QOL, HADS-anxiety, and HADS-depression showed more favourable trajectories with PD. PD was associated with sustained Shannon alpha-diversity gains (+0.488 at 6 weeks; +0.205 at 12 months; both p < 0.01). A modest between-group beta-diversity difference at 6 months (R2 = 0.035; p = 0.011) was not significant at 12 months. This hypothesis-generating follow-up suggests more durable benefit with PD; larger trials powered for long-term clinical and microbiome outcomes are warranted.
Chronic inflammation fosters cancer development by sustaining redox imbalance, oxidative stress and persistent tissue damage. A key component to this process is the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2), which coordinates antioxidant and detoxification programs to maintain redox homeostasis. While transient Nrf2 activation protects non-malignant tissues by limiting cell and tissue damage, persistent or dysregulated Nrf2 signaling in premalignant tissue and established tumors can promote cancer cell survival, metabolic adaptation and resistance to chemotherapy. Growing evidence identifies gut microbiota-derived metabolites as modulators of Nrf2 signaling, thereby providing a mechanistic link between microbial metabolism and inflammation-driven carcinogenesis. Distinct functional classes of bacterial metabolites, including short-chain fatty acids, tryptophan-derived indoles, secondary bile acids, polyphenol-derived metabolites and electrophilic redox-active compounds, converge on Nrf2 regulation across epithelial, immune and tumor compartments. Importantly, the biological consequences of these interactions are highly context-dependent and shaped by disease stage, cellular metabolic state and tissue microenvironment.This review integrates current evidence on how microbial metabolites regulate Nrf2 signaling and redox homeostasis during chronic inflammation and cancer development or progression. We further discuss how dietary interventions, probiotics or postbiotics, and metabolite-based strategies may be leveraged to modulate the microbiota-Nrf2 axis for cancer prevention or therapy. Overall, we propose that microbial metabolites represent a context-dependent mechanism for modulating Nrf2 activity in inflammation-associated cancers, with important implications for translational and precision medicine approaches.
Previous studies have established that long-term antibiotic (ABX) exposure disrupts gut microbiota, leading to adiposity, insulin resistance, and metabolic dysfunction-associated steatotic liver disease (MASLD). However, the metabolic effects of short-term ABX treatment in early life, along with the underlying mechanism, remain unclear. This study reveals that short-term ABX exposure during early life induces sex-specific metabolic programming in mice. Immature males exhibited reduced gonadal white adipose tissue (gWAT) mass, predisposing them to exacerbated hepatic steatosis under high-fat diet (HFD) challenge. Females displayed protected liver metabolism. We identified dimethylarsinous acid (DMAIII) as a key microbiota-dependent metabolite that inversely correlated with both gWAT mass and specific bacterial abundances, including Muribaculum gordoncarteri and Ligilactobacillus apodemi in male mice. Critically, timely fecal microbiota transplantation (FMT) reversed these metabolic alterations in males. Our findings demonstrate that transient early-life microbiota disruption programs lasting, sex-divergent metabolic outcomes, highlighting the therapeutic potential of microbiota-targeted interventions during developmental windows.
The interaction of pectin, as one of the most complex dietary glycans, with gut microbiota represents a typical pattern for shaping the gut microenvironment and human homeostasis. Pectin has a heterogeneous structure, characterized by homogalacturonan (HG), rhamnogalacturonan I (RG-I), and rhamnogalacturonan II (RG-II) domains, which dictate its fermentability and functional outcomes. This review systematically examines the pathways through which pectin is degraded by the gut microbial consortia, with a central focus on the role of carbohydrate-active enzymes (CAZymes). These enzymes, including glycoside hydrolases (GHs), polysaccharide lyases (PLs), and carbohydrate esterases (CEs), act synergistically to depolymerize pectin into oligosaccharides and monosaccharides. Specific microbial groups, notably Bacteroides and Bifidobacterium, utilize these breakdown products via specialized transport systems. Intracellular fermentation leads to the synthesis of a series of degradation products, such as acetate, propionate, and butyrate, which are crucial for maintaining gut barrier integrity, modulating immune responses, and regulating systemic metabolism. Finally, we summarize the multifaceted health effects of pectin-derived short-chain fatty acids (SCFAs) and propose that future efforts should focus on achieving a more comprehensive understanding of microbial and enzymatic mechanisms of pectin degradation, as well as complex cross-feeding networks, to inform the development of targeted nutritional interventions.
BACKGROUND:Long COVID (LC) manifests in 10%-30% of non-hospitalized individuals post-SARS-CoV-2 infection, leading to significant morbidity. The predictive role of gut microbiome composition during acute infection in the development of LC is not well understood, partly because of the heterogeneous nature of the disease. OBJECTIVES:To determine whether the gut microbiome composition in the acute phase of SARS-CoV-2 infection predicts subsequent LC and to investigate the role of microbiome signatures in disease subphenotypes. DESIGN:We conducted a longitudinal cohort study involving 799 outpatient participants tested for SARS-CoV-2 due to similar symptom presentation, including 380 SARS-CoV-2 positive and 419 negative individuals. Stool samples were collected at two time points for metagenomic sequencing. Logistic regression with L1 regularization was employed to predict LC based on the microbiome and clinical metadata. RESULTS:The individuals who developed LC harbored a distinct gut microbiome during acute infection compared to those who recovered fully and uninfected controls with similar symptomatology. However, the temporal changes in the gut microbiome between the acute (0-1 month) and post-acute (1-2 months) phases were similar across the three cohorts. Using machine learning, we showed that the gut microbiome carried a modest signal for subsequent LC, but model performance was insufficient for clinical prediction, likely reflecting the heterogeneous nature of LC. Finally, we identified four LC symptom clusters, with gastrointestinal and fatigue-only groups strongly linked to gut microbiome alterations. CONCLUSION:The gut microbiome can potentially offer solutions for understanding the heterogeneous nature of LC. Larger cohorts and phenotype-aware computational algorithms may help overcome current model performance limitations and support the development of targeted diagnostic and therapeutic strategies.
Atherosclerotic cardiovascular disease remains the leading cause of mortality worldwide, and a substantial residual risk persists despite optimal management of traditional risk factors. Increasing evidence implicates the gut microbiome as a mechanistic contributor to atherogenesis, not merely through taxonomic shifts but via the production of bioactive microbial metabolites that link diet, microbial metabolism, and host vascular biology. These metabolites have emerged as central effectors of the gut-artery axis, influencing intestinal barrier integrity, systemic immunity, lipid handling, and thrombosis. Among the best-characterized pathways, trimethylamine N-oxide and phenylacetylglutamine have been robustly linked to macrophage lipid accumulation, platelet hyperreactivity, and adverse cardiovascular outcomes. More recently, imidazole propionate, a histidine-derived microbial metabolite, has emerged as a candidate mediator of vascular inflammation and plaque development through imidazoline-1 receptor-dependent activation of mTORC1 signaling, supported by mechanistic and experimental evidence. Advances in metagenomics, metabolomics, and proteomics now enable systems-level interrogation of microbiome-host interactions, facilitating causal inference through integrative metabolite-protein and pathway-level analyses. These approaches have revealed reproducible molecular networks associated with subclinical and clinical atherosclerosis, providing a framework for biomarker discovery and therapeutic targeting. People with HIV represent a particularly informative human model, in which persistent gut barrier disruption and dysbiosis sustain immune activation and confer excess cardiovascular risk, with distinct microbial and metabolite signatures linked to vascular inflammation and plaque progression. This review synthesizes current evidence linking gut microbial function to atherosclerosis, with a specific focus on metabolite-driven mechanisms, multi-omic integration, and translational relevance. We highlight emerging biomarkers and therapeutic strategies targeting microbial metabolic pathways and discuss methodological challenges that must be addressed to advance the gut-artery axis toward precision cardiovascular medicine.
Chronic liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), frequently progress to liver fibrosis, yet effective antifibrotic therapies remain limited. Here, we investigated the therapeutic potential of the commensal bacterium Phocaeicola coprocola using Western diet (WD)-induced MASLD and DDC + TAA-induced fibrosis murine models. In the WD model, P. coprocola administration attenuated hepatic steatosis, reduced lipogenic gene expression, and improved metabolic and histological parameters. In contrast, in the DDC + TAA model of advanced fibrosis, P. coprocola significantly reduced cholestatic markers and fibrosis severity. Mechanistically, these antifibrotic effects occurred independently of broad suppression of inflammatory mediators or upstream TGF-β-Smad signaling, and were instead associated with selective downregulation of extracellular matrix (ECM)-related fibrogenic programs, including Col1a1, Col3a1, and Mmp2. Notably, these effects were observed even in the absence of detectable gut colonization, suggesting that stable engraftment is not required for therapeutic activity. P. coprocola also enhanced colonic epithelial barrier-related gene expression and host-microbial metabolic signaling. In humans, circulating ECM remodeling markers (PIIINP, MMP2, and TIMP1) were associated with fibrosis severity, supporting the translational relevance of ECM-targeted mechanisms. Collectively, these findings identify P. coprocola as a selective modulator of ECM remodeling that uncouples fibrotic output from upstream inflammatory signaling, highlighting its potential as a microbiome-based therapeutic strategy for liver fibrosis across multiple disease etiologies.
