<b>The gut microbiome, frailty syndrome, and comorbidities: a complex network in aging</b>

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). Consistent taxonomic patterns were observed: <i>Eggerthella</i>, <i>Parabacteroides,</i> and <i>Erysipelatoclostridium</i> were significantly abundant in FS, while <i>Christensenellaceae R-7 group</i>, <i>Erysipelotrichaceae UCG-003</i> and <i>Hungatella</i> were enriched in NFS.<i> Christensenellaceae R-7 group </i>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 gut microbiota shifts in FS, emphasizing their interaction with metabolic pathways and clinical features. Microbiota-targeted interventions could help improve health outcomes in older populations.