Gut microbial signature for frailty discrimination: a metagenomic meta-analysis of 28 independent cohorts.

Frailty, a clinical syndrome of multisystem decline and homeostatic vulnerability, is a critical public health priority. While the gut microbiome regulates immune and metabolic signaling, current evidence remains fragmented. We performed a metagenomic meta-analysis of 955 individuals from 28 independent cohorts across 24 countries to identify universal microbial signatures and develop a generalizable discriminative model. Frailty was determined using a Proxy Frailty Index based on the deficit accumulation model. Following refinement to isolate signatures from disease-specific dysbiosis, we used Firth's penalized regression for biomarker discovery and validated a Random Forest (RF) model via leave-one-study-out cross-validation. Shannon diversity exhibited a significant and sharp decline during the transition from robust to pre-frail states (p = 0.0006), manifesting at the earliest stages of physiological decline. We identified 16 microbial biomarkers characterized by the progressive attrition of core symbionts, such as Coprococcus eutactus, and the opportunistic expansion of pathobionts, including Enterococcus gallinarum. Sensitivity analysis in a healthy sub-cohort (n = 499) confirmed that these shifts occur independently of chronic clinical diagnoses and their associated confounding effects (p = 0.036). The 16-species RF model, predominantly driven by Collinsella massiliensis, achieved a corrected mean area under the receiver operating characteristic curve of 0.7572 across 5 eligible cohorts. Gut microbial restructuring is a sentinel biological hallmark of frailty that occurs independently of aging-related diseases. This study establishes a microbial signature broadly applicable across European and East Asian populations that serves as a high-fidelity, non-invasive metric for precision geriatric assessment.