Just 14 days of head-down tilt bedrest in adults aged 55-65 significantly decreased beneficial gut bacteria including Akkermansia and Lactobacillus while increasing Bacteroides and reducing overall microbial diversity. Participants assigned to exercise interventions showed increases in Roseburia, a beneficial butyrate-producing bacterium. Both gut and oral microbiome changes correlated directly with frailty index scores across 36 measured parameters. This represents the first direct evidence that short-term inactivity rapidly reshapes the microbiome in ways that mirror aging-associated decline. The speed of these changes is remarkable—previous research suggested such microbiome shifts required months or years of inactivity. The findings bridge two critical areas: the emerging understanding that Akkermansia supports metabolic health and longevity, and the recognition that frailty represents a measurable precursor to age-related decline. For healthy adults, this suggests that even brief periods of inactivity—whether from illness, injury, or lifestyle—may trigger cascading microbiome changes that accelerate frailty. The protective effect of exercise on Roseburia levels offers a actionable countermeasure, potentially explaining why resistance to inactivity varies so dramatically between individuals based on their exercise habits.