Microbiota protect against frailty and loss of skeletal muscle, and maintain inflammatory tone during aging in mice

Chronic low-level inflammation or "inflammaging" is hypothesized to contribute to sarcopenia and frailty. Resident microbiota are thought to promote inflammaging, frailty, and loss of skeletal muscle mass. We tested immunity and frailty in male C57BL6/N germ-free (GF), specific pathogen-free (SPF) mice, and mice that were born germ-free and colonized (COL) with an SPF microbiota. Male and female GF mice had lower systemic cellular inflammation indicated by lower blood Ly6C(high) monocytes across their lifespan. Male GF mice had lower body mass, but relative to body mass, GF mice had smaller hindlimb muscles and smaller muscle fibers compared with SPF mice across the lifespan. Male and female GF mice had increased frailty at 18 mo or older. Colonization of female GF mice increased blood Ly6C(high) monocytes but did not affect frailty at 18 mo or older. Colonization of male GF mice increased blood Ly6C(high) monocytes, skeletal muscle size, myofiber fiber size, and decreased frailty at 18 mo or older. Transcriptomic analysis of the tibialis anterior muscle revealed a microbiota-muscle axis with over 550 differentially expressed genes in COL male mice at 18 mo or older. Colonized male mice had transcripts indicative of lower tumor necrosis factor (TNF)-alpha signaling via nuclear factor kappa B (NF-kappa B). Our findings show that microbiota can increase systemic cellular immunity while decreasing muscle inflammation, thereby protecting against muscle loss and frailty. We also found sex differences in the role of microbiota regulating frailty. We propose that microbiota components protect against lower muscle mass and frailty across the lifespan in mice.