The causal effects of gut microbiota on quantitative susceptibility mapping (QSM) and T2* imaging-derived phenotypes: insights from a Mendelian randomization study

Abstract

Background: Gut microbiota are associated with brain imaging-derived phenotypes (IDPs); however, the specific causal relationship between the gut microbiota and brain iron-related IDPs remains unclear. Thus, we sought to analyze the potential causal effects of gut microbiota on brain iron-related IDPs using Mendelian randomization (MR).

Methods: We obtained the data of 196 gut microbiota from a genome-wide association study (GWAS) from the MiBioGen database, as well as the data of 18 quantitative susceptibility mapping (QSM) IDPs and 10 T2* IDPs from the United Kingdom Biobank (UKB). We then conducted one-way two-sample MR analyses to examine their causal interactions. To guarantee the robustness of the results, we performed two independent analysis processes by selecting statistically significant instrumental variables (IVs) with a distinct level of statistical strictness, and derived the intersection of these two analyses.

Results: Our results showed that the genus Howardella was positively correlated with the median susceptibility in the right caudate [β: 0.0935, 95% confidence interval (CI): 0.0601, 0.1269, P_{inverse variance weighting (IVW)}=4.00E-08]; the genus Dialister was positively correlated with the median susceptibility in the right accumbens (β: 0.0949, 95% CI: 0.0575, 0.1324, P_IVW=6.90E-07); the genus Butyricicoccus was positively associated with the median T2* in the left hippocampus with the additional deconfounding of the background field gradient (β: 0.1543, 95% CI: 0.0959, 0.2127, P_IVW=2.20E-07); the genus Desulfovibrio was positively related to the T2* white matter hyperintensity (WMH) IDP with WMH volume regressed out (β: 0.1168, 95% CI: 0.0697, 0.1639, P_IVW=1.20E-06). Notably, both the family Defluviitaleaceae (β: -0.1215, 95% CI: -0.1604, -0.0827, P_IVW=8.40E-10) and genus DefluviitaleaceaeUCG011 (β: -0.1142, 95% CI: -0.1614, -0.0670, P_IVW=2.10E-06) were negatively correlated with the median T2* in the right accumbens with the additional deconfounding of the background field gradient.

Conclusions: This study found genetic evidence that gut microbiota dysbiosis has causal effects on brain iron-related IDPs. Our findings provide novel insights into the diagnosis and therapeutic management of central nervous system (CNS) diseases.

Keywords: Gut microbiota; Mendelian randomization (MR); T2* mapping; imaging-derived phenotypes (IDPs); quantitative susceptibility mapping (QSM).

Figure 1

The relationship between the gut microbiota and brain QSM and T2* IDPs. Gut microbiota act on the brain through signaling molecules, including food-related metabolites (e.g., SCFAs), metabolites of endogenous molecules (e.g., secondary bile acids and tryptophan metabolites), and microbial cell wall components (e.g., lipopolysaccharides). Abnormalities in biological mechanisms of microbiota microenvironment could cause CNS diseases, which can be visualized by neuroimaging. Brain iron-related IDPs, including QSM IDPs and T2* IDPs, can be obtained by transforming brain iron imaging data into visualized image phenotypes. The figure is created by Servier Medical Art under a Creative Common Attribution 3.0 Generic License (https://creativecommons.org/licenses/by/3.0/). SCFAs, short-chain fatty acids; CNS, central nervous system; IDPs, imaging-derived phenotypes; QSM, quantitative susceptibility mapping.

Figure 2

Flow path of the Mendelian randomization study of the causal relationships between the gut microbiota and QSM and T2* IDPs. The figure is created by Servier Medical Art under a Creative Common Attribution 3.0 Generic License (https://creativecommons.org/licenses/by/3.0/). QSM, quantitative susceptibility mapping; IDPs, imaging-derived phenotypes; WMH, white matter hyperintensity; MR-PRESSO, MR-pleiotropy residual sum and outlier; IVs, instrumental variables; SNPs, single nucleotide polymorphisms; IVW, inverse variance weighting; MR, Mendelian randomization.