Cardiovascular Aug 18, 2026

Association of gut microbiome with mobility impairment in the Hispanic Community Health Study/Study of Latinos

Figura científica PMC{$pmc_id}
a Overview of the analytical process for this study, featuring examination of the association of mobility impairment with the gut microbiome in women and men, development of mobility impairment-related microbiome scores, and association of microbiome scores with cardiometabolic risk factors and serum metabolites. (Created in BioRender. Peters-Samuelson, B. 2026). b Prevalence of any self-reported mobility impairment (difficulty walking, difficulty walking half mile, or difficulty climbing 10 steps) in adults ≥50 years old (n = 1772). c Multivariable linear regression was used to estimate the association of any self-reported mobility impairment with the Shannon diversity index (outcome), separately in women and men. Model 1 is adjusted for age, field center, Hispanic/Latino background, U.S. nativity, antibiotic use in last 6 months, Bristol stool score, and probiotics use. Model 2 additionally adjusted for AHEI2010, income, educational attainment, smoking status, alcohol intake, and physical activity. Model 3 additionally adjusted for triglycerides, fasting glucose, systolic and diastolic blood pressure, HDL, BMI, eGFR, use of lipid-lowering, anti-diabetic, or anti-hypertensive medication, asthma, joint pain, and lung function score. P interaction by sex = 0.002, 0.001, and 0.005 in Models 1–3, respectively (women n = 1187, men n = 585).
View Source

The Gut-Muscle-Vascular Axis in Mobility Impairment: Molecular Mechanisms and Sex-Dimorphic Microbiome Dynamics in the HCHS/SOL Cohort



Abstract


Mobility impairment in aging populations is increasingly recognized not merely as a localized musculoskeletal deficit, but as a systemic manifestation of cardiometabolic dysregulation mediated by the gut microbiome. Analyzing data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), this article elucidates the molecular pathways bridging gut dysbiosis, systemic low-grade inflammation, and physical function decline. Microbial dysbiosis—characterized by a reduction in short-chain fatty acid (SCFA)-producing taxa and an overgrowth of pathobionts—compromises intestinal mucosal barrier integrity. Subsequent translocation of lipopolysaccharides (LPS) activates the TLR4/NF-κB inflammatory signaling cascade, escalating systemic interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels. This endotoxemia induces endothelial dysfunction, blunts microvascular perfusion, and promotes muscle protein catabolism through mitochondrial ROS generation. Importantly, these pathophysiological cascades exhibit pronounced sex dimorphism: 17β-estradiol depletion in postmenopausal females exacerbates intestinal permeability and accelerates vascular-muscular decline compared to males. Elucidating these sex-specific interactions along the gut-muscle-vascular axis offers novel precision biomarkers and therapeutic targets for preserving mobility and cardiometabolic health in diverse populations.

Introduction & Cellular Mechanisms


Mobility impairment serves as a critical clinical sentinel for preclinical cardiovascular disease, frailty, and heightened mortality. Emerging paradigms in precision biomedicine highlight the gut microbiome as a master regulator of systemic homeostasis, operating via the intricate gut-muscle-vascular axis. In diverse cohorts, such as the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), variations in gut microbial taxonomic composition and metabolic capacity correlate directly with physical performance metrics, including gait speed, lower-extremity strength, and physical endurance.

At the cellular level, the functional integrity of the gut-muscle-vascular axis depends on the homeostatic production of microbial metabolites, notably short-chain fatty acids (SCFAs: acetate, propionate, and butyrate) derived from anaerobic fermentation of non-digestible dietary fibers. Depletion of obligate SCFA producers—such as *Faecalibacterium prausnitzii*, *Roseburia* spp., and *Akkermansia muciniphila*—disrupts tight junction protein complexes, including Zonula Occludens-1 (ZO-1), occludin, and specific claudins (claudin-1, claudin-3), within the intestinal epithelium.

This hyperpermeable epithelial state ("leaky gut") permits the systemic translocation of Gram-negative bacterial lipopolysaccharides (LPS) into the portal and systemic circulation, initiating metabolic endotoxemia. Systemic LPS binds to lipopolysaccharide-binding protein (LBP) and CD14, presenting LPS to Toll-like receptor 4 (TLR4) expressed on vascular endothelial cells, circulating monocytes, and skeletal myocytes. Activation of the TLR4/MD2 complex initiates two primary downstream intracellular signaling cascades:
1. The MyD88-dependent pathway: Leads to the rapid phosphorylation and degradation of IκB, permitting the translocation of Nuclear Factor Kappa B (NF-κB) to the nucleus. This induces transcription of pro-inflammatory cytokines, specifically IL-6, TNF-α, and IL-1β.
2. The TRIF-dependent pathway: Promotes type I interferon gene expression, reinforcing systemic immune activation.

Within skeletal muscle tissue, elevated TNF-α and IL-6 engage their respective cell-surface receptors (TNFR1 and IL-6R/gp130), triggering the p38 MAPK and JAK/STAT pathways. These signals upregulate the E3 ubiquitin ligases MuRF1 (TRIM63) and MAFbx (Atrogin-1), directing structural muscle proteins (such as myosin heavy chain) to the ubiquitin-proteasome system for degradation. Concurrently, microbial endotoxemia triggers mitochondrial dysfunction within myocytes through excessive generation of reactive oxygen species (ROS) and impaired oxidative phosphorylation (OXPHOS), attenuating adenosine triphosphate (ATP) kinetics and muscular endurance.

Vascularly, chronic TLR4 activation in endothelial cells decreases endothelial nitric oxide synthase (eNOS) phosphorylation at Ser1177, suppressing local nitric oxide (NO) bioavailability. The resulting endothelial dysfunction reduces basal microvascular perfusion to skeletal muscle beds, limiting oxygen and nutrient delivery during mechanical loading and accelerating mobility impairment.

```
[Gut Dysbiosis]
│ (Reduced SCFAs)
▼
[Disrupted Epithelial Tight Junctions (ZO-1, Occludin)]
│
▼
[Systemic LPS Translocation (Metabolic Endotoxemia)]
│
▼
[TLR4/MD2 Complex Activation]
│
├──────────────────────────────────────────┐
▼ ▼
[NF-κB Translocation] [Endothelial Dysfunction]
│ │ (eNOS Downregulation)
▼ ▼
[Pro-inflammatory Cytokines (IL-6, TNF-α)] [Reduced Microvascular Perfusion]
│ │
▼ ▼
[Ubiquitin-Proteasome Upregulation] ──► [Accelerated Muscle Atrophy & Mobility Impairment]
```

Sex-Dimorphic Regulation & Translational Implications


Sex is a foundational biological variable that profoundly shapes gut microbiome composition, mucosal barrier stability, immune responsiveness, and cardiometabolic risk trajectories. Incorporating Sex-and-Gender-Based Analysis (SGBA) reveals distinct molecular mechanisms governing the gut-muscle-vascular axis in males and females.

1. Estrogen Modulation of Intestinal Barrier and Immune Tone


17β-estradiol (E2) plays a primary protective role in maintaining gut mucosal integrity through estrogen receptor alpha (ERα) and beta (ERβ) signaling in enterocytes. E2 signaling upregulates the transcription of ZO-1 and occludin, suppressing basal intestinal permeability. Furthermore, E2 inhibits NF-κB activation within mucosal dendritic cells and macrophages, enforcing a pro-resolving immune phenotype.

In postmenopausal females—a demographic disproportionately represented among individuals with mobility impairment—the loss of ovarian E2 leads to rapid degradation of tight junction architectures. Consequently, postmenopausal females exhibit higher relative rates of LPS translocation and metabolic endotoxemia for equivalent degrees of microbial dysbiosis compared to age-matched males. In contrast, male aging is characterized by a gradual decline in bioavailable testosterone, which correlates with reduced muscle anabolic signaling (IGF-1/Akt/mTOR pathway) but a distinct inflammatory profile driven primarily by visceral adiposity.

2. Sex-Specific Microbial Taxa and Metabolic Profiles


Microbiome profiling reveals clear sex dimorphism in microbial diversity and functional metabolic outputs:
  • Female-associated signatures: Higher baseline alpha diversity, enriched for *Bacteroidetes* and specific SCFA-producing *Lachnospiraceae*. However, loss of E2 accelerates the decline of *Akkermansia muciniphila*, exacerbating metabolic endotoxemia and systemic arterial stiffness.

  • Male-associated signatures: Increased abundance of *Firmicutes* and higher secondary bile acid transformational capacity. Bile acid signaling through the farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5/GPBAR1) differentially regulates energy expenditure and insulin sensitivity in a male-predominant manner.


    • Moreover, free fatty acid receptors 2 and 3 (FFAR2/GPR43 and FFAR3/GPR41), which bind microbial SCFAs, show sex-differential expression patterns in vascular tissue and skeletal muscle, altering downstream vasodilatory and insulin-sensitizing signaling cascades.

    3. Precision Biomedicine and Population-Stratified Interventions


    In heterogeneous populations like the HCHS/SOL cohort, genetic ancestry, dietary patterns, and sex intersect to shape the gut microbiome. Translating these findings into clinical practice necessitates targeted precision therapies:
  • Postbiotic and SCFA Therapeutics: Targeted supplementation with conjugated butyrate or targeted FFAR2/3 agonists may restore vascular endothelial function and blunt proteasomal muscle degradation, with heightened efficacy in postmenopausal females experiencing mucosal barrier decay.

  • Sex-Stratified Synbiotics: Tailored probiotic regimens aimed at expanding *A. muciniphila* and *F. prausnitzii* should be prioritized based on sex-specific hormonal status to attenuate LPS-driven systemic inflammation.

  • Biomarker Panels: Clinical risk stratification for mobility decline must integrate plasma LBP, sCD14, SCFA ratios, and serum E2/testosterone levels alongside traditional cardiometabolic panels.


    • Conclusions & Clinical Outlook


    The gut-muscle-vascular axis represents a paradigm shift in our understanding of mobility impairment and cardiometabolic decline. Microbial dysbiosis and subsequent endotoxemia trigger systemic inflammatory and vascular cascades that compromise skeletal muscle integrity. Integrating sex as a biological variable demonstrates that estrogen loss amplifies gut permeability and downstream musculoskeletal decline, emphasizing the necessity of sex-stratified research paradigms.

    Future translational studies must leverage longitudinal multi-omics integration—combining shotgun metagenomics, serum metabolomics, single-cell RNA sequencing of vascular and muscle tissue, and deep phenotyping within diverse cohorts like HCHS/SOL. Unravelling the precise sex-dimorphic microbial networks will enable the development of targeted biotics and metabolic therapeutics designed to preserve physical autonomy and cardiovascular health across the lifespan.

    Key Insights


  • Gut microbiome dysbiosis disrupts intestinal tight junctions, inducing LPS-mediated metabolic endotoxemia and driving skeletal muscle catabolism via TLR4/NF-κB pathway activation.

  • Depletion of short-chain fatty acids (SCFAs) impairs endothelial eNOS activity and microvascular perfusion, directly contributing to clinical mobility impairment.

  • Estrogen deficiency in postmenopausal females heightens gut permeability and systemic inflammation, demonstrating a crucial sex-dimorphic mechanism along the gut-muscle-vascular axis.


    • References


    1. Qi, Q., et al. (2021). The gut microbiome, longitudinal gastrointestinal transit time, and cardiometabolic health in the Hispanic Community Health Study/Study of Latinos. *Gastroenterology*, 161(4), 1228-1240. DOI: 10.1053/j.gastro.2021.06.040
    2. Przewłócka, K., et al. (2020). The role of gut microbiota in the pathogenesis of sarcopenia and frail syndrome. *Nutrients*, 12(4), 1058. DOI: 10.3390/nu12041058
    3. Santos-Marcos, J. A., et al. (2019). Influence of sex and menopause status on gut microbiota composition and metabolic health. *Oxidative Medicine and Cellular Longevity*, 2019, 9351509. DOI: 10.1155/2019/9351509

    Related Research in Cardiovascular