Causal Effects of Gut Microbiota on Sleep-Related Phenotypes: A Two-Sample Mendelian Randomization Study

Abstract

Increasing evidence suggests a correlation between changes in the composition of gut microbiota and sleep-related phenotypes. However, it remains uncertain whether these associations indicate a causal relationship. The genome-wide association study summary statistics data of gut microbiota (n = 18,340) was downloaded from the MiBioGen consortium and the data of sleep-related phenotypes were derived from the UK Biobank, the Medical Research Council-Integrative Epidemiology Unit, Jones SE, the FinnGen consortium. To test and estimate the causal effect of gut microbiota on sleep traits, a two-sample Mendelian randomization (MR) approach using multiple methods was conducted. A series of sensitive analyses, such as horizontal pleiotropy analysis, heterogeneity test, MR Steiger directionality test and “leave-one-out” analysis as well as reverse MR analysis, were conducted to assess the robustness of MR results. The genus Anaerofilum has a negative causal effect on getting up in the morning (odd ratio = 0.977, 95% confidence interval: 0.965–0.988, p = 7.28 × 10−5). A higher abundance of order Enterobacteriales and family Enterobacteriaceae contributed to becoming an “evening person”. Six and two taxa were causally associated with longer and shorter sleep duration, respectively. Specifically, two SCFA-produced genera including Lachnospiraceae UCG004 (odd ratio = 1.029, 95% confidence interval = 1.012–1.046, p = 6.11 × 10−4) and Odoribacter contribute to extending sleep duration. Two obesity-related genera such as Ruminococcus torques (odd ratio = 1.024, 95% confidence interval: 1.011–1.036, p = 1.74 × 10−4) and Senegalimassilia were found to be increased and decreased risk of snoring, respectively. In addition, we found two risk taxa of insomnia such as the order Selenomonadales and one of its classes called Negativicutes. All of the sensitive analysis and reverse MR analysis results indicated that our MR results were robust. Our study revealed the causal effect of gut microbiota on sleep and identified causal risk and protective taxa for chronotype, sleep duration, snoring and insomnia, which has the potential to provide new perspectives for future mechanistic and clinical investigations of microbiota-mediated sleep abnormal patterns and provide clues for developing potential microbiota-based intervention strategies for sleep-related conditions.

Causality Investigation between Gut Microbiome and Sleep-Related Traits: A Bidirectional Two-Sample Mendelian Randomization Study

“…While previous research has explored the causal relationship between the gut microbiome and sleep phenotypes [ 25 , 36 , 37 ], many studies have predominantly focused on the genus level, limiting the exploration of specific species of gut microbes and their potential influence on sleep patterns. Our study advances this exploration by utilizing summary statistics of microbial taxa and pathways from the DMP cohort, which can allow identification to the species level and identify pathways.…”

The causal relationship between gut microbiota and leukemia: a two-sample Mendelian randomization study

“…We applied a series of SNP selection criteria to the acquired GWAS summary data to ensure they met the three aforementioned assumptions: Assumption 1: We selected SNPs associated with risk factors at p-value <1 × 10 −5 . Considering the limited number of SNPs, we slightly adjusted the threshold based on the genome-wide significance level (5 × 10 −8 ) to meet the requirements for further analysis (Gou et al, 2023;Yue et al, 2023). We calculated the proportion of variance in exposure explained by SNP using the formula r2 = 2 * eaf * (1 − eaf) * beta^2 (Codd et al, 2013).…”

The Causal Relationship between the Morning Chronotype and the Gut Microbiota: A Bidirectional Two-Sample Mendelian Randomization Study

“…Disruptions to the circadian system can lead to alterations in the composition of microbiome communities, consequently impacting the host’s metabolism, energy regulation, and inflammatory pathways, and thus play a role in the development of metabolic syndrome. Previous research has shown that two SCFA-produced genera, Lachnospiraceae UCG004 and Odoribacter, promote extended sleep duration, while the order Selenomonadales and the class Negativicutes are associated with insomnia risk [ 21 ].…”

“…MR has been extensively utilized to investigate the causal links between the gut microbiota and various diseases, encompassing both metabolic and autoimmune conditions [ 23 , 24 ]. An association between the gut microbiota and the sleep phenotype was found in a recent Mendelian randomization study, but no inverse relationship was demonstrated [ 21 ]. Thus, understanding the relationship between the morning chronotype and the gut microbiota represents a burgeoning field of research that holds the significant potential to advance our knowledge of human biology and health.…”