Causal Link between Gut Microbiota, Neurophysiological States, and Bone Diseases: A Comprehensive Mendelian Randomization Study

Abstract

Increasing evidence highlights a robust correlation between the gut microbiota and bone diseases; however, the existence of a causal relationship between them remains unclear. In this study, we thoroughly examined the correlation between gut microbiota and skeletal diseases using genome-wide association studies. Linkage disequilibrium score regression and Mendelian randomization were used to probe genetic causality. Furthermore, the potential mediating role of neuropsychological states (i.e., cognition, depression, and insomnia) between the gut microbiota and bone diseases was evaluated using mediation analysis, with genetic colocalization analysis revealing potential targets. These findings suggest a direct causal relationship between Ruminococcaceae and knee osteoarthritis (OA), which appears to be mediated by cognitive performance and insomnia. Similarly, a causal association was observed between Burkholderiales and lumbar pelvic fractures, mediated by cognitive performance. Colocalization analysis identified a shared causal variant (rs2352974) at the TRAF-interacting protein locus for cognitive ability and knee OA. This study provides compelling evidence that alterations in the gut microbiota can enhance cognitive ability, ameliorate insomnia, and potentially reduce the risk of site-specific fractures and OA. Therefore, strategies targeting gut microbiota optimization could serve as novel and effective preventive measures against fractures and OA.

Gut-bone axis research: unveiling the impact of gut microbiota on postmenopausal osteoporosis and osteoclasts through Mendelian randomization

“…By focusing on the gut microbiota, we identified a microbial community that affects both: order Burkholderiales.id.2874. In previous studies, a causal relationship between Burkholderiales and lumbar spine fractures has been identified, corroborating our findings that this genus indeed has an unknown connection with bone (25). Building on prior research, we expanded the related mechanisms by incorporating the impact on osteoclasts and predicting their potential downstream targets.…”

Genus_Ruminococcus and order_Burkholderiales affect osteoporosis by regulating the microbiota-gut-bone axis

“…N, ALP, claudin-1, and occludin. This suggests that Burkholderiales can repair damage to the gut barrier, promote bone formation, and increase bone density, and that Burkholderiales itself has a unique ability to degrade a variety of compounds (including exogenous substances), and its effect on bone may play an indirect osteoprotective role by eliminating potential pathogenic cytokines in the gut, enriching the diversity of the intestinal microbiota in conjunction with other bacterial flora ( Wicaksono et al, 2023 ), and maintaining the integrity of the intestinal tract ( Luo et al, 2023 ). Meanwhile, this study also identified g_Akkermansia, g_Parabacteroides, g_Alistipes, g_Parasutterella, and g_Muribaculum as possible differential genera affecting BMD, among which B. Akkermansia is a potential probiotic located in the mucus layer of the intestine, which produces a variety of mucin-degrading bio-enzymes and ferments to produce SCFAs ( Collado et al, 2007 ).…”