Effect of bedrest on the human gut and oral microbiome: implications for frailty

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) 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 -diversity, decreasing Akkermansia and Lactobacillus, and increasing Bacteroides. Exercise-associated changes included increasing gut Roseburia. Interestingly, oral microbiome {beta}-diversity was more strongly associated with frailty than the gut. We conclude that inactivity-associated changes to the human microbiome could contribute to the early stages of frailty development, and that exercise can 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. IMPORTANCEHealthy ageing carries significant demographic, economic, and public health implications globally, and both physical activity and human-associated microorganisms play important roles in its trajectory. Using microgravity simulation in older adults as a human frailty model, we show that short periods of inactivity could have significant effects on these microbial communities, particularly in the gut, which could further contribute to multi-system physiological decline and frailty pathogenesis. Participants who completed a daily, multi-modality exercise intervention did not exhibit these changes, which may help protect both older adults facing periods of inactivity and astronauts in the advent of longer space exploration missions. Interestingly, our results suggested that oral bacteria may be a more sensitive indicator of individual frailty levels than gut bacteria. Future research should ensure that functional aspects of human-associated microbial communities are thoroughly investigated, as these may offer deeper insight into their contributions to age-related decline.