Gut microbiota mediates the relationship between smoking and fall risk: A 2-step Mendelian randomization study

Falls represent a critical public health challenge for the global elderly population, leading to severe health consequences such as fractures, strokes, and even death, while imposing a substantial burden on the healthcare system. While previous studies have identified lifestyle factors (e.g., smoking, alcohol consumption, sleep, and physical activity) as contributors to fall risk, the causal role of the gut microbiota and its mediating mechanisms remain unclear. Mendelian randomization (MR) was employed to analyze the potential mediating effects of 131 gut microbial taxa (genus level) on the associations between smoking, alcohol consumption, sleep, vigorous exercise, and fall risk. First, a 2-sample MR analysis using genome-wide association study summary data was conducted to establish causal links between gut microbiota and fall risk. Subsequently, a 2-step MR approach was applied to investigate the mediating role of gut microbiota in the smoking-fall risk relationship. Smoking significantly increased fall risk (OR = 1.11, P = 8.99 × 10-4), while alcohol consumption, sleep, and vigorous exercise showed no significant causal associations. Notably, the Ruminococcus gnavus group (OR = 1.04, P = 2.20 × 10-3) was identified as a risk-enhancing gut microbiota, while Allisonella (OR = 0.97, P = 5.00 × 10-4) exhibited protective effects. Further analysis confirmed that the R gnavus group mediated 8.63% of the smoking-fall risk association. This study provides the first genetic evidence supporting the mediating role of the gut microbiota, particularly the R gnavus group, in the relationship between smoking and fall risk. These findings offer novel scientific insights for the development of gut microbiota-targeted strategies to prevent falls.