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. 2023 Oct 26;15(21):4544.
doi: 10.3390/nu15214544.

Causality Investigation between Gut Microbiota, Derived Metabolites, and Obstructive Sleep Apnea: A Bidirectional Mendelian Randomization Study

Weiheng Yan  1 , Miaomiao Jiang  2 , Wen Hu  3 , Xiaojun Zhan  3 , Yifan Liu  3 , Jiayi Zhou  1 , Jie Ji  4 , Shan Wang  5 , Jun Tai  3
Affiliations

Causality Investigation between Gut Microbiota, Derived Metabolites, and Obstructive Sleep Apnea: A Bidirectional Mendelian Randomization Study

Weiheng Yan et al. Nutrients. .

Abstract

Various studies have highlighted the important associations between obstructive sleep apnea (OSA) and gut microbiota and related metabolites. Nevertheless, the establishment of causal relationships between these associations remains to be determined. Multiple mendelian randomization (MR) analyses were performed to genetically predict the causative impact of 196 gut microbiota and 83 metabolites on OSA. Two-sample MR was used to assess the potential association, and causality was evaluated using inverse variance weighted (IVW), MR-Egger, and weighted median (WM) methods. Multivariable MR (MVMR) was employed to ascertain the causal independence between gut microbiota and the metabolites linked to OSA. Additionally, Cochran's Q test, the MR Egger intercept test and the MR Steiger test were used for the sensitivity analyses. The analysis of the 196 gut microbiota revealed that genus_Ruminococcaceae (UCG009) (PIVW = 0.010) and genus_Subdoligranulum (PIVW = 0.041) were associated with an increased risk of OSA onset. Conversely, Family_Ruminococcaceae (PIVW = 0.030), genus_Coprococcus2 (PWM = 0.025), genus_Eggerthella (PIVW = 0.011), and genus_Eubacterium (xylanophilum_group) (PIVW = 0.001) were negatively related to the risk of OSA. Among the 83 metabolites evaluated, 3-dehydrocarnitine, epiandrosterone sulfate, and leucine were determined to be potential independent risk factors associated with OSA. Moreover, the reverse MR analysis demonstrated a suggestive association between OSA exposure and six microbiota taxa. This study offers compelling evidence regarding the potential beneficial or detrimental causative impact of the gut microbiota and its associated metabolites on OSA risk, thereby providing new insights into the mechanisms of gut microbiome-mediated OSA development.

Keywords: causal inference; gut microbiota; inflammation; intestinal immunity; mendelian randomization; obstructive sleep apnea.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The outline of the methodology. (A) The assumptions for MR analysis. (B) The flow of two-sample MR analysis [26]. (C) The flow of MVMR analysis. IVs must have a significant correlation with exposure factor (assumption 1). There was no direct correlation between IVs and outcome (assumption 2). There should be no correlation between IVs and potential confounding factors (assumption 3). Jiayi Zhou IVW, inverse-variance weighted; WM, weighted median; MR, Mendelian randomization; MR-PRESSO, MR pleiotropy residual sum and outlier; OSA, obstructive sleep apnea; IVs, instrumental variables; MVMR, multivariate Mendelian randomization.
Figure 2
Figure 2
A forest plot of the potential causal relationship between gut microbiota and OSA. CI, confidence interval; OR, odds ratio; OSA, obstructive sleep apnea; SNP, single-nucleotide polymorphism; SE, standard error.
Figure 3
Figure 3
A forest plot of the potential causal relationship between OSA and gut microbiota. CI, confidence interval; OR, odds ratio; OSA, obstructive sleep apnea; SNP, single nucleotide polymorphism; SE, standard error.
Figure 4
Figure 4
Heatmap plot of the potential causal relationship between OSA and metabolite. For upper part, exposure: outcome (metabolite: OSA); for lower part, exposure: outcome (OSA: metabolite). Enrichment map of HMBD analysis for the metabolites. * p < 0.05. OSA, obstructive sleep apnea; IVW, inverse-variance weighted.
Figure 5
Figure 5
MVMR associations of OSA with gut microbiota and metabolites. For each MVMR analysis, we added each genetic confounding separately. (A) The direct causality between gut microbiota and OSA. (B) The direct causality between metabolites and OSA. Lasso, least absolute selection and shrinkage operator; IVW, inverse-variance weighted; MVMR, multivariate Mendelian randomization; Median, weighted-median; OR, odds ratio; OSA, obstructive sleep apnea. * p < 0.05.
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