J Stroke.  2023 Sep;25(3):350-360. 10.5853/jos.2023.00381.

Dissecting Causal Relationships Between Gut Microbiota, Blood Metabolites, and Stroke: A Mendelian Randomization Study

• Wang Q
• Dai H
• Hou T
• Hou Y
• Wang T
• Lin H
• Zhao Z
• Li M
• Zheng R
• Wang S
• Lu J
• Xu Y
• Liu R
• Ning G
• Wang W
• Bi Y
• Zheng J
• Xu M

• KMID: 2546436
• DOI: http://doi.org/10.5853/jos.2023.00381

Abstract

Background and Purpose
We investigated the causal relationships between the gut microbiota (GM), stroke, and potential metabolite mediators using Mendelian randomization (MR).
Methods
We leveraged the summary statistics of GM (n=18,340 in the MiBioGen consortium), blood metabolites (n=115,078 in the UK Biobank), and stroke (cases n=60,176 and controls n=1,310,725 in the Global Biobank Meta-Analysis Initiative) from the largest genome-wide association studies to date. We performed bidirectional MR analyses to explore the causal relationships between the GM and stroke, and two mediation analyses, two-step MR and multivariable MR, to discover potential mediating metabolites.
Results
Ten taxa were causally associated with stroke, and stroke led to changes in 27 taxa. In the two-step MR, Bifidobacteriales order, Bifidobacteriaceae family, Desulfovibrio genus, apolipoprotein A1 (ApoA1), phospholipids in high-density lipoprotein (HDL_PL), and the ratio of apolipoprotein B to ApoA1 (ApoB/ApoA1) were causally associated with stroke (all P<0.044). The causal associations between Bifidobacteriales order, Bifidobacteriaceae family and stroke were validated using the weighted median method in an independent cohort. The three GM taxa were all positively associated with ApoA1 and HDL_PL, whereas Desulfovibrio genus was negatively associated with ApoB/ApoA1 (all P<0.010). Additionally, the causal associations between the three GM taxa and ApoA1 remained significant after correcting for the false discovery rate (all q-values <0.027). Multivariable MR showed that the associations between Bifidobacteriales order, Bifidobacteriaceae family and stroke were mediated by ApoA1 and HDL_PL, each accounting for 6.5% (P=0.028) and 4.6% (P=0.033); the association between Desulfovibrio genus and stroke was mediated by ApoA1, HDL_PL, and ApoB/ApoA1, with mediated proportions of 7.6% (P=0.019), 4.2% (P=0.035), and 9.1% (P=0.013), respectively.
Conclusion
The current MR study provides evidence supporting the causal relationships between several specific GM taxa and stroke and potential mediating metabolites.

Keyword

Gastrointestinal microbiome; Stroke; Metabolomics; Mendelian randomization analysis

Figure

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  Figure 1. Assumptions and design of the bidirectional and mediation Mendelian randomization (MR) analyses. Firstly, a two-sample bidirectional MR was performed to investigate the causal relationships between gut microbiota (exposure) and stroke (outcome). Secondly, 51 blood metabolites (mediator) were selected for subsequent mediation analyses. Finally, a two-step MR analysis was conducted to detect potential mediating metabolites (Step 1, the effect of gut microbiota on metabolites; Step 2, the effect of metabolites on stroke), followed by a validation analysis using multivariable MR. GBMI, Global Biobank Meta-analysis Initiative. The images for gut microbiota, blood metabolites, and stroke were adapted from emojipng.com under the terms of the Non-Commercial Use License.

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  Figure 2. Mendelian randomization analyses show causal effects between gut microbiota and stroke. (A) The causal effect of gut microbiota on stroke. (B) The causal effect of stroke on gut microbiota. The dots colored in red and green indicate positive and negative odds ratios respectively from the inverse-varianceweighted analysis (truncated at P-value <0.05). CI indicates confidence intervals and prefix “p_/c_/o_/f_/g_” represents phylum/class/order/family/genus, respectively. Taxonomy with the same background color belongs to the same phylum.

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  Figure 3. Mendelian randomization analyses show causal effects of blood metabolites on gut microbiota and stroke. The diagram displays the mediation mode of “gut microbiota-blood metabolites-stroke” in two-step Mendelian randomization. Beta values (β) indicate the causal effect estimates using the inverse- variance-weighted method (truncated at P<0.05). Characters colored in red and green signify positive and negative associations, respectively. HDL_PL, phospholipids in high-density lipoprotein; ApoA1, apolipoprotein A1; ApoB/ApoA1, the ratio of apolipoprotein B to apolipoprotein A1.

Reference

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