Inactivity during HDBR led to changes in gut and oral microbiome composition.

Inactivity-associated changes in the gut may be linked to early frailty development.

Participants who engaged in exercise did not exhibit inactivity-associated changes.

Both gut and oral microbiome β-diversity exhibited associations with frailty.

Results may inform strategies to preserve the health of older adults and astronauts.

The physiological effects of spaceflight resemble those of ageing and prolonged inactivity, and ground-based microgravity analogs have emerged as promising models for studying frailty. The human microbiome is increasingly recognised for its role in age-associated decline, although precise mechanisms remain unclear. Here, we evaluate the gut and oral microbiomes of twenty-two participants, aged 55–65, who were enrolled in a head-down tilt bedrest (HDBR) study, the first Canadian HDBR study conducted in an older cohort. Participants were randomly assigned to an inactivity or multi-modality exercise intervention group for fourteen days of HDBR, followed by seven days of rehabilitation and additional follow-up appointments. Gut (n = 343) and oral (n = 344) taxonomic profiles were generated using V4-V5 16S rRNA gene sequencing from fecal and salivary samples collected throughout the study. Gut functional profiles were generated using metagenomic (n = 86) data, used for pathway inference, and metabolomic (n = 83) data. Frailty was measured using a 36-item frailty index. Inactivity-associated changes to the gut microbiome during HDBR included decreasing α-diversity, decreasing Akkermansia and Lactobacillus, and increasing Bacteroides. Exercise-associated changes included increasing gut Roseburia. Both gut and oral β-diversity were associated with frailty scores and individual frailty components. We conclude that inactivity-associated changes to the human microbiome are associated with the early stages of frailty development, and that exercise may serve as an effective countermeasure against these effects. These results may inform strategies to preserve the health of both older adults facing prolonged periods of inactivity, as well as astronauts during longer space exploration missions.

Microbiome

Gut

Oral

Ageing

Frailty

Microgravity

HDBR

© 2026 The Authors. Published by Elsevier Inc.