The predictive, preventive, and personalized medicine of insomnia: Gut microbiota and inflammation

Abstract

Abstract Background The human gut microbiota (GM) has been recognized as a significant factor in the development of insomnia, primarily through inflammatory pathways, making it a promising target for therapeutic interventions. In light of the principles of primary prediction, targeted prevention, and personalized treatment medicine (PPPM), identifying of specific gut microbiota associated with insomnia and exploring the underlying mechanisms comprehensively are crucial steps towards achieving primary prediction, targeted prevention, and personalized treatment of insomnia. Working hypothesis and methodology We hypothesized that alterations in the composition of specific GM could induce insomnia through inflammatory response, which postulates the existence of a GM-Inflammation-Insomnia pathway. Mendelian randomization (MR) analyses were employed to examine this pathway and explore the mediative effects of inflammation. We utilized genetic proxies representing GM, insomnia, and inflammatory indicators [including 41 circulating cytokines and C-reactive protein (CRP)], specifically identified from European ancestry. The primary method used to identify insomnia-related GM and examine the medicative effect of inflammation was the inverse variance weighted method, supplemented by MR-Egger and weighted median methods. Our findings have the potential to identify individuals at risk of insomnia through screening for GM imbalances, leading to the development of targeted prevention and personalized treatment strategies for the condition. Results Nine genera and three circulating cytokines were identified to have causal effects on insomnia, only the associations of Clostridium (innocuum group) and β-NGF on insomnia remained significant after FDR test, OR = 1.08 (95% CI = 1.04–1.12, P = 1.45×10− 4, q = 0.02) and OR = 1.06 (95% CI = 1.02–1.10, P = 1.06×10− 3, q = 0.04), respectively. CRP were associated with increased risk of insomnia, OR = 1.05 (95% CI = 1.01–1.10, P = 6.42×10− 3). After adjusting for CRP, causal effects of Clostridium (innocuum group), Bilophila, Candidatus Soleaferrea, Coprococcus 1, Holdemania, Prevotella 7, and Rikenellaceae (RC9gut group) on insomnia were changed significantly (P > 0.05). In addition, the causal pathway from Candidatus Soleaferrea and Holdemania to insomnia were mediated by most circulating cytokines. No heterogeneity and pleiotropy were detected. Conclusions Our study highlights the role of specific GM alterations in the development of insomnia and provides insights into the mediating effects of inflammation. Targeting these specific GM alterations presents a promising avenue for advancing the transition from reactive medicine to PPPM in managing insomnia, potentially leading to significant clinical benefits.