Association between sleep-related phenotypes and gut microbiota: a two-sample bidirectional Mendelian randomization study

Abstract

Background: An increasing body of evidence suggests a profound interrelation between the microbiome and sleep-related concerns. Nevertheless, current observational studies can merely establish their correlation, leaving causality unexplored.

Study objectives: To ascertain whether specific gut microbiota are causally linked to seven sleep-related characteristics and propose potential strategies for insomnia prevention.

Methods: The study employed an extensive dataset of gut microbiota genetic variations from the MiBioGen alliance, encompassing 18,340 individuals. Taxonomic classification was conducted, identifying 131 genera and 196 bacterial taxa for analysis. Sleep-related phenotype (SRP) data were sourced from the IEU OpenGWAS project, covering traits such as insomnia, chronotype, and snoring. Instrumental variables (IVs) were selected based on specific criteria, including locus-wide significance, linkage disequilibrium calculations, and allele frequency thresholds. Statistical methods were employed to explore causal relationships, including inverse variance weighted (IVW), MR-Egger, weighted median, and weighted Mode. Sensitivity analyses, pleiotropy assessments, and Bonferroni corrections ensured result validity. Reverse causality analysis and adherence to STROBE-MR guidelines were conducted to bolster the study's rigor.

Results: Bidirectional Mendelian randomization (MR) analysis reveals a causative interplay between selected gut microbiota and sleep-related phenotypes. Notably, outcomes from the rigorously Bonferroni-corrected examination illuminate profound correlations amid precise compositions of the intestinal microbiome and slumber-associated parameters. Elevated abundance within the taxonomic ranks of class Negativicutes and order Selenomonadales was markedly associated with heightened susceptibility to severe insomnia (OR = 1.03, 95% CI: 1.02-1.05, p = 0.0001). Conversely, the augmented representation of the phylum Lentisphaerae stands in concord with protracted sleep duration (OR = 1.02, 95% CI: 1.01-1.04, p = 0.0005). Furthermore, heightened exposure to the genus Senegalimassilia exhibits the potential to ameliorate the manifestation of snoring symptoms (OR = 0.98, 95% CI: 0.96-0.99, p = 0.0001).

Conclusion: This study has unveiled the causal relationship between gut microbiota and SRPs, bestowing significant latent value upon future endeavors in both foundational research and clinical therapy.

Keywords: Mendelian randomization; causal effect; gut microbiota; insomnia; sleep-related phenotypes.

Figure 1

IVW estimates from gut microbiota on SRPs. The color of each block represents the IVW-derived p-values of every MR analysis. p-values of <0.05 were shown in red and p-values of >0.05 were shown in yellow or green. p-value <0.05 is set as nominal significant, whereas ^▲ represents significant [genera: 0.05/131 (3.81 × 10⁻⁴), families: 0.05/35 (1.4 × 10⁻³), orders: 0.05/20 (2.5 × 10⁻³), classes: 0.05/16 (3.1 × 10⁻³), and phyla: 0.05/9 (5.5 × 10⁻³)]. ↑ and ↓ represent, respectively, an increased and decreased risk of developing sleep-related traits in the gut microbiota.

Figure 2

IVW estimates from SRPs on gut microbiota. The color of each block represents the IVW-derived odds ratio of every MR analysis. Odds ratio of <1.00 were shown in green and odds ratio of >1.00 were shown in yellow or orange.

Figure 3

(A) Intestinal flora play an important role between different SRPs. (B) Intestinal flora play an important role in self-regulation between the same SRPs. (C) Intestinal flora play an important role in a vicious cycle between the same SRPs.