Frailty is a prevalent condition in older adults, characterized by a progressive decline in physiological function, diminished resilience, and heightened risks of adverse outcomes, including mortality, falls, hospitalizations, and disabilities (1, 2). The increasing global prevalence of frailty, driven by population aging, imposes substantial burdens on healthcare systems and society (3, 4).

Among modifiable risk factors in aging, the gut microbiota has appeared as a key focus, with evidence highlighting its role as a central mediator of systemic health. Nutritional approaches emphasizing fiber and fermented foods demonstrate cost-effective potential to restore microbial balance (2), counteracting chronic inflammation and metabolic dysregulation underlying frailty (5). Frailty progression is driven by interconnected mechanisms involving intestinal barrier compromise, chronic inflammation, and microbial imbalance (6–9). Targeted dietary modifications that enhance the production of anti-inflammatory metabolites may disrupt this pathological cycle (10, 11).

The development of the Dietary Index for Gut Microbiota (DI-GM) provides a methodological framework to operationalize dietary interventions, specifically designed to evaluate longitudinal relationships between habitual dietary patterns and gut microbial community trajectories (12). Higher DI-GM scores, reflecting diets rich in prebiotics (e.g., whole grains, legumes) and fermented foods (e.g., yogurt, kimchi), have been associated with reduced risks of depression (13), suicide (14), stroke (15), kidney stones (16), infertility (17), and metabolic disorders (18–20). Despite evidence linking DI-GM to chronic diseases, its association with frailty—a multidimensional aging syndrome—remains unexplored.

Therefore, this study leverages data derived from the National Health and Nutrition Examination Survey (NHANES, 2005–2018), to investigate diet-related exposures in frailty prevalence, aiming to develop microbiota-targeted dietary interventions for mitigating frailty in elder adults.

This cross-sectional study examined the associations between DI-GM and frailty in U.S. adults aged 45 years and older. Analyses revealed a significant nonlinear relationship, with a threshold effect at a DI-GM score of 4.082. Higher DI-GM scores were inversely associated with frailty risk, notably among women and individuals with higher educational attainment. BMI demonstrated partial mediation (38.28% of total effect) between DI-GM exposure and frailty phenotypes. Our threshold analysis (DI-GM ≥ 4.082) identifies an actionable dietary benchmark, offering a scalable strategy for healthy aging.

Unlike traditional dietary indices (e.g., Mediterranean Diet Score) that evaluate general dietary quality, DI-GM pioneers a microbiota-centric approach by quantifying foods that directly modulate gut ecosystem functionality, thereby enabling targeted frailty prevention strategies. It emphasizes the intake of dietary fiber and fermented foods, which promote gut microbiota diversity and the production of anti-inflammatory metabolites, such as short-chain fatty acids (SCFAs) (27). Dietary fiber intake classified as beneficial for gut microbiota under DI-GM criteria is associated with the abundance of SCFA-producing bacterial genera, whereas long-term low-fiber diets may lead to intergenerational declines in microbial diversity (28, 29). Conversely, high–fat/high–sugar diets promote the proliferation of conditional pathogens like Proteobacteria while reducing the Firmicutes–to–Bacteroidetes ratio, a dysbiotic state closely linked to gut barrier dysfunction (30, 31). Clinically, the Mediterranean diet—rich in polyphenols and omega-3 fatty acids—has been shown to significantly enhance microbiota diversity indices and foster colonization of anti-inflammatory genera such as Bifidobacterium and Lactobacillus (32).

Frail individuals commonly exhibit marked reductions in gut microbiota alpha diversity (e.g., Shannon index). For instance, species richness in frail older adults decreases by 20–30% compared to healthy controls, and this loss of diversity inversely correlates with elevated systemic inflammatory markers (e.g., Interleukin-6, C-reactive protein) (33, 34). These findings suggest that dietary patterns regulate the “microbiota–gut–frailty” axis by modulating microbial diversity. Sustained intake of prebiotic-rich foods is necessary to maintain anti-inflammatory metabolite levels, thereby mitigating sarcopenia and chronic inflammation (35). This study identified a nonlinear association between improvements in DI-GM score and frailty risk (Figure 3). Notably, frailty risk demonstrated a measurable decline only when DI-GM scores surpassed a critical threshold of 4.082. This threshold-dependent phenomenon delineates a significant dose–response pattern, characterized by minimal risk modulation below the cutoff and a progressive protective effect beyond it. These findings, in conjunction with previous research, provide robust empirical support for the crucial regulatory function of gut microbiota in attenuating frailty progression through metabolic pathway modulation.

To investigate the potential mechanism by which DI-GM score improvement reduces frailty risk, we conducted mediation analyses (Figure 4), identifying BMI as a statistically significant mediator in the DI-GM-frailty association (mediation effect: 38.28%). This finding aligns with established epidemiological evidence demonstrating BMI’s critical role in frailty pathogenesis. Jayanama et al. established that elevated BMI (>25.0 kg/m²) predicts heightened frailty indices in both cross-sectional evaluations and longitudinal observations (36). Sun’s longitudinal BMI trajectory modeling identified sustained high adiposity patterns as conferring greater frailty risk compared to stable normal-weight profiles (37). Yuan’s systematic review and meta-analysis, including community-dwelling older adults aged ≥60 years, further confirmed a strong positive correlation between BMI and frailty risk (38). Chronic low-grade inflammatory responses mediated by adiposity constitute a central pathophysiological mechanism linking elevated BMI to frailty susceptibility (39). Growing evidence indicates gut-microbiota-targeting diets regulate immune function and influence disease pathways, including frailty development (40, 41). These interactions underscore complex links between metabolic status, inflammatory processes, gut health, and frailty progression. The bidirectional interplay between BMI and gut microbiota operates through three principal mechanistic axes: energy homeostasis regulation, inflammatory modulation, and intestinal barrier maintenance. Individuals with elevated BMI (overweight/obese) exhibit gut dysbiosis characterized by reduced alpha-diversity, increased Firmicutes/Bacteroidetes ratio, depletion of SCFA-producing bacteria, and enrichment of pro-inflammatory species (42, 43). Obesity-associated microbial consortia, particularly Firmicutes-dominated clusters, upregulate carbohydrate-active enzyme expression, thereby augmenting energy absorption and adipocyte lipid accumulation (44). Conversely, microbial metabolites orchestrate systemic energy balance through multi-organ crosstalk: (1) butyrate enhances intestinal barrier integrity via tight junction protein upregulation, (2) inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis, and (3) stimulates glucagon-like peptide-1 secretion to regulate glucose-lipid homeostasis (45). Lipopolysaccharide translocation triggered by dysbiosis induces adipose tissue inflammation and suppresses lipolysis through Toll-like receptor 4 signaling pathway activation (46). Our mediation analysis identifies BMI as a critical modulator in the microbiota-frailty axis, suggesting novel therapeutic targets at this metabolic interface. Clinically, managing frail patients requires combining tailored diets to modify gut bacteria, routine BMI checks using body scans, and gut microbiome testing to assess frailty risks.

Subgroup analyses revealed a pronounced association of DI-GM against frailty, particularly evident in female participants and those with advanced educational attainment. The augmented protective association observed in females may arise from dynamic hormone–microbiome interplay. Estrogen-mediated reinforcement of intestinal barrier integrity and promotion of Lactobacillus colonization appear to act synergistically with DI-GM to potentiate SCFAs biosynthesis (47). The postmenopausal estrogen declines precipitate gut dysbiosis, potentially accounting for diminished protective effects (OR = 0.88) in elderly females (>75 years subgroup), despite comparable DI-GM profiles. Notably, dietary analyses demonstrated greater consumption of fiber-rich and fermented foods among females compared to males (48), correlating with their disproportionate representation in the highest DI-GM quartile (Q4: 54.2% vs. 45.8%). These nutritional patterns appear conducive to maintaining keystone commensals such as Bifidobacterium, organisms critically involved in folate biosynthesis and DNA methylation homeostasis. Although current studies confirm significant estrogen-microbiota correlations (49, 50), NHANES database limitations impede mechanistic interpretation of estrogen’s mediation in DI-GM-conferred frailty protection. Key constraints include undocumented menopausal status (natural/surgical), incomplete estrogenic biomarker profiling (cycle-specific estrone/estradiol measurements), and absent hormone replacement therapy records. Thus, longitudinal estrogen dynamics monitoring is essential to delineate precise mechanisms.

The socioeconomic gradient in DI-GM efficacy manifested through enhanced protection against frailty in highly educated individuals (OR = 0.85 vs. 0.93 in lower education strata). Mechanistically, advanced education confers greater protective benefits through multidimensional pathways: Health literacy enables a nuanced understanding of nutritional guidelines, driving preferential selection of prebiotic-rich foods (whole grains, legumes) that optimize DI-GM adherence (51). Educational attainment further correlates with dietary diversity and consistent intake of methyl donors (folate, vitamin B12), serving as critical substrates for DNA methylation processes (52). Recent epidemiological evidence demonstrates education–associated hypomethylation at the IL-10 promoter region, potentiating anti-inflammatory cytokine production—an effect amplified in subjects maintaining microbiota–supportive dietary patterns (53). These findings consist with our observations, suggesting that education may establish an epigenetically “primed state” that facilitates the translation of dietary inputs (e.g., DI-GM) into health benefits, potentially mediated through microbiota–epigenome interaction. This dual-axis interaction demonstrates the convergence of biological determinants (e.g., hormonal regulation, epigenetic modulation) with social determinants (e.g., health literacy), offering pivotal implications for advancing clinically actionable precision nutrition strategies.

Our findings highlight the translational potential of DI-GM as a public health tool. Specifically, the identified threshold (DI-GM ≥ 4.082) could inform national dietary guidelines targeting older adults. For example: (1) Community-level interventions: Subsidizing fiber-rich foods (e.g., whole grains, legumes) in low-income neighborhoods to reduce socioeconomic disparities in DI-GM adherence. (2) Clinical integration: Incorporating DI-GM screening into geriatric assessments to identify high-risk individuals (DI-GM < 4) for tailored nutritional counseling. 3) Policy advocacy: Collaborating with agricultural sectors to increase the production of fermented foods (e.g., yogurt, kimchi), which are key DI-GM components linked to gut health (32, 34). These strategies align with the WHO’s “Decade of Healthy Aging” framework, emphasizing cost-effective dietary interventions to mitigate frailty burden (2).

While our investigation demonstrates methodological rigor, several limitations warrant consideration. First, the cross-sectional design of the NHANES database restricts causal inference between diet-microbiota patterns and frailty development. Future research needs longitudinal cohorts with repeated dietary assessments, microbial monitoring, and frailty tracking to clarify temporal relationships among multifactorial influences. Second, 24-h dietary recalls present inherent constraints: (1) recall bias, particularly in older adults with cognitive decline; (2) inadequate capture of daily/weekly dietary variations, potentially underestimating long-term microbiome impacts on gut microbiota and frailty risk (54, 55); and (3) discrepancies between reported intake and actual microbial nutrient exposure (e.g., lactase activity differences). Combining food biomarkers (plasma carotenoids, urinary nitrogen) with metagenomic metrics (polysaccharide utilization genes) could improve nutritional assessments (55). Third, the ethnogeographic limitations of NHANES data—particularly the absence of validation in Asian/European cohorts—substantially restrict the external validity of these findings. Inadequate gut microbiota sampling frequency (Fecal sample collection was exclusively conducted in 2013–2014 cycle) further restricts understanding of host–microbe interactions. Future DI-GM validation requires: (1) Multi-ethnic replication using UK Biobank’s diverse cohorts; (2) Multi-omics mapping integrating fecal metagenomics, SCFA metabolomics, and single-cell transcriptomics for microbial functional profiling; (3) Germ-free model interventions establishing diet-microbiota dose–response relationships. Fourth, though we adjusted for key confounders, residual confounding from unmeasured covariates (e.g., socioeconomic mobility and environmental exposures) remains plausible.

Our findings reveal a robust inverse association between elevated DI-GM scores and frailty risk, with demographic-specific patterns showing special efficacy in females and individuals with advanced educational attainment. Mediation analyses further demonstrated a significant indirect pathway, with BMI partially explaining the association between DI-GM scores and frailty status. The identification of a clinically relevant threshold effect (DI-GM = 4.082) underscores the public health importance of attaining dietary benchmarks to optimize frailty prevention. These findings collectively highlight the translational potential of microbiota–targeted nutritional frameworks as geroprotective strategies, particularly for modulating gut microbial diversity in aging populations.