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Background <p>The relationship between gut microbiota and metabolic syndrome (MetS) has attracted significant attention, with MetS comprising components like abdominal obesity, dysglycemia, dyslipidemia, and hypertension. The dietary index for gut microbiota (DI-GM) has also been developed as a standardized tool for assessing a balanced diet for the gut microbiota. Additionally, the interplay between aging and metabolism is important for understanding disease development. Nevertheless, the intrinsic regulatory mechanisms of factors such as aging in the association between the DI-GM and MetS have not been thoroughly investigated.</p> Methods <p>Participants were recruited from multiple cycles of National Health and Nutrition Examination Surveys (NHANES). In this study, weighted logistic regression models, restricted cubic spline (RCS) and subgroup analyses were employed to&#xa0;investigate the association between DI-GM index, categorized as unfavorable or beneficial to gut microbiota, and the prevalence of MetS as well as its components. Mediation analysis models analyzed the mediating roles of biological age advance index (KDM-BAA) and body mass index (BMI). Sensitivity analyses were performed to assess the robustness of the models. Candidate genes related to aging and BMI mediators in this association were retrieved using the GeneCards database (evidence: literature/database annotations). GO and KEGG enrichment was conducted to reveal the potential regulatory mechanisms. Top ten topologically central genes were prioritized as potential regulators by protein–protein interaction (PPI) network and cytoHubba-MCC algorithm. GeneMANIA co-expression network and friends analysis refined the functional annotations of these genes, thereby providing clear hypotheses for subsequent experimental validation.</p> Results <p>A total of 6086 participants was enrolled. The DI-GM score was significantly negatively correlated with the prevalence of MetS (odd ratio (OR) = 0.91, 95% confidence interval (CI) 0.87–0.95,<i> P</i> &lt; 0.05). Participants with DI-GM scores of 7 or higher had an adjusted OR of 0.69 (95% CI 0.57–0.84) compared to individuals with scores of 0–3. Additionally, unfavorable to gut microbiota were significantly associated with a lower risk of MetS (OR = 0.84, 95% CI 0.79–0.88,<i> P</i> &lt; 0.05). RCS analysis further revealed the linear relationship between DI-GM and the prevalence of MetS as well as its components. Subgroup analyses indicated that alcohol consumption may influence this relationship (<i>P</i> for interaction &lt; 0.05). Mediation analysis revealed that KDM-BAA (mediation proportion: 36.76%) and BMI (mediation proportion: 48.57%) had more prominent mediating effects. Furthermore, candidate genes were primarily associated with&#xa0;stress response, cellular localization, and molecular regulation, and the Pl3K-AKT pathway was the main enriched pathway. Top ten candidate genes were predominantly linked to DNA repair, with TP53 being the most important.</p> Conclusions <p>Higher DI-GM scores are linearly associated with a lower risk of MetS and its components, with BMI and KDM-BAA index playing prominent mediating roles. Our study demonstrates the important role of DI-GM in potentially preventing the risk of MetS, and we observe the significant influence of unfavorable factors for gut microbiota in this relationship. It also suggests that the improvement of body weight management and modulation of physiological functions during aging may be key mechanisms in this association. Additionally, TP53 may serve as a novel diagnostic biomarker and potential therapeutic target.</p>

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Mediating role of aging and obesity in the relationship between dietary index for gut microbiota and metabolic syndrome and its potential regulatory mechanisms

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月23日

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  • Han Yang,
  • Shuang Zhao,
  • Haijuan Zhao,
  • Zhaojun Pang,
  • Huiqing Yao,
  • Xin Wang

摘要

Background

The relationship between gut microbiota and metabolic syndrome (MetS) has attracted significant attention, with MetS comprising components like abdominal obesity, dysglycemia, dyslipidemia, and hypertension. The dietary index for gut microbiota (DI-GM) has also been developed as a standardized tool for assessing a balanced diet for the gut microbiota. Additionally, the interplay between aging and metabolism is important for understanding disease development. Nevertheless, the intrinsic regulatory mechanisms of factors such as aging in the association between the DI-GM and MetS have not been thoroughly investigated.

Methods

Participants were recruited from multiple cycles of National Health and Nutrition Examination Surveys (NHANES). In this study, weighted logistic regression models, restricted cubic spline (RCS) and subgroup analyses were employed to investigate the association between DI-GM index, categorized as unfavorable or beneficial to gut microbiota, and the prevalence of MetS as well as its components. Mediation analysis models analyzed the mediating roles of biological age advance index (KDM-BAA) and body mass index (BMI). Sensitivity analyses were performed to assess the robustness of the models. Candidate genes related to aging and BMI mediators in this association were retrieved using the GeneCards database (evidence: literature/database annotations). GO and KEGG enrichment was conducted to reveal the potential regulatory mechanisms. Top ten topologically central genes were prioritized as potential regulators by protein–protein interaction (PPI) network and cytoHubba-MCC algorithm. GeneMANIA co-expression network and friends analysis refined the functional annotations of these genes, thereby providing clear hypotheses for subsequent experimental validation.

Results

A total of 6086 participants was enrolled. The DI-GM score was significantly negatively correlated with the prevalence of MetS (odd ratio (OR) = 0.91, 95% confidence interval (CI) 0.87–0.95, P < 0.05). Participants with DI-GM scores of 7 or higher had an adjusted OR of 0.69 (95% CI 0.57–0.84) compared to individuals with scores of 0–3. Additionally, unfavorable to gut microbiota were significantly associated with a lower risk of MetS (OR = 0.84, 95% CI 0.79–0.88, P < 0.05). RCS analysis further revealed the linear relationship between DI-GM and the prevalence of MetS as well as its components. Subgroup analyses indicated that alcohol consumption may influence this relationship (P for interaction < 0.05). Mediation analysis revealed that KDM-BAA (mediation proportion: 36.76%) and BMI (mediation proportion: 48.57%) had more prominent mediating effects. Furthermore, candidate genes were primarily associated with stress response, cellular localization, and molecular regulation, and the Pl3K-AKT pathway was the main enriched pathway. Top ten candidate genes were predominantly linked to DNA repair, with TP53 being the most important.

Conclusions

Higher DI-GM scores are linearly associated with a lower risk of MetS and its components, with BMI and KDM-BAA index playing prominent mediating roles. Our study demonstrates the important role of DI-GM in potentially preventing the risk of MetS, and we observe the significant influence of unfavorable factors for gut microbiota in this relationship. It also suggests that the improvement of body weight management and modulation of physiological functions during aging may be key mechanisms in this association. Additionally, TP53 may serve as a novel diagnostic biomarker and potential therapeutic target.