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

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=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=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=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=1.20E-06). Notably, both the family Defluviitaleaceae (β: -0.1215, 95% CI: -0.1604, -0.0827, P=8.40E-10) and genus DefluviitaleaceaeUCG011 (β: -0.1142, 95% CI: -0.1614, -0.0670, P=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.