The Role of the Gut Microbiome in the Complex Network of Frailty Syndrome and Associated Comorbidities in Aging

The gut microbiota changes throughout life, potentially influencing health and triggering physiological disorders. Frailty syndrome (FS) is an age-related condition that reduces quality of life and increases hospitalization and mortality risks, making early detection and prevention essential in older populations. This study analyzed 16S rRNA gene and metagenomics sequencing of fecal samples from 203 older adults (FS: n = 64, non-FS (NFS): n = 139) to assess the role of gut microbiota in FS and related comorbidities, such as sarcopenia and impaired lower extremity function (ILEF) or anthropometric variables. Consistent taxonomic patterns were observed: Eggerthella, Parabacteroides, and Erysipelatoclostridium were significantly abundant in FS, while Christensenellaceae R-7 group, Erysipelotrichaceae UCG-003, and Hungatella were enriched in NFS. Christensenellaceae R-7 group was also associated with better mobility. Metagenomics analysis identified 680 KEGG functions differing between groups, categorized into 28 metabolic pathways. FS individuals had overrepresented biotin metabolism, antimicrobial resistance, and energy production, but underrepresented ribosomal and protein synthesis and sporulation pathways. Resistome analysis found the tetM/tetO (K18220) gene most abundant, alongside tetracycline, β-lactam, and macrolide resistance, primarily mediated by antibiotic efflux and transporters. These findings highlight distinct microbial and functional signatures associated with FS, underscoring the complex interplay between the gut microbiota and host physiology in aging. Adjusting for covariates, age and diabetes acted as confounding factors in FS for both 16S gene and metagenomics sequencing. This study offers new insights into fundamental questions in the biology of aging and opens avenues for microbiota-targeted strategies to improve the quality of life in older adults.