Potential causal association between the oral microbiome and bipolar disorder

Background: The oral microbiome can influence the growth, development, and regulation of the nervous system through various pathways; however, its relationship with bipolar disorder (BD) remains ambiguous. This study aims to investigate the causal relationship between the oral microbiome and BD through Mendelian randomization (MR) analysis. Methods: Data regarding single nucleotide polymorphisms (SNPs) in GWAS summary statistics for oral microbiota and BD were obtained from two studies: one reported the association between the oral microbiome and the human genome, encompassing both the dorsum of the tongue and saliva microbiomes. The other study investigated the association between BD and the human genome, categorizing BD into BD I and BD II for separate analyses. Thus, three data components were utilized: BD, BD I, and BD II. In this study, GWAS data for saliva and dorsum of the tongue microbiomes were analyzed separately for BD, BD I, and BD II. The inverse variance weighted (IVW) method was used to assess the causal relationship between the oral microbiome and BD. Analyses were conducted only when the number of instrumental variable SNPs was no less than two. The MR-Egger regression and IVW methods were employed to evaluate heterogeneity, whereas the MR-Egger intercept test was utilized to assess pleiotropy. For MR results exhibiting heterogeneity or pleiotropy, sensitivity analyses were performed using the weighted median, simple mode, weighted mode, MR-Egger test, and leave-one-out methods. Furthermore, funnel plots were employed to evaluate publication bias. Reverse MR analysis was also performed to investigate the potential bidirectional interactions between BD and the oral microbiota. Results: A causal relationship exists between the oral microbiome and BD. The effects of the microbiome from different regions of the oral cavity on BD are variable, with a more pronounced impact noted on BD I. This study identified two overlapping causal relationships shared between BD I and BD II, both exhibiting the same directional influence: (R) Salivary s Prevotella aurantiaca SGB 2854 (Taxonomy ID: 596085, species); (2) Tongue s Prevotella sp000467895 SGB 1817 (Taxonomy ID: 838, genus). Additionally, there are two overlapping bacteria with opposing directional effects: (R) Salivary g Eggerthia (Taxonomy ID: 1279384, genus); (2) Salivary s unclassified SGB 2636. Three differential bacteria that exclusively regulate one subtype were identified: (R) Salivary s Lachnoanaerobaculum sp000296385 SGB 3537 (Taxonomy ID: 1164882, genus); (2) Tongue s unclassified SGB 689; (3) Tongue s unclassified SGB 572. Among these, the genus g Eggerthia in saliva inhibits BD I while promoting BD II; conversely, salivary s unclassified SGB 2636 inhibits BD II while promoting BD I. The analysis of tongue s unclassified SGB 489 and s unclassified SGB 1215 demonstrated pleiotropy without causal significance. The reverse MR analysis identified that BD I may influence four microbial species, including f Leptotrichiaceae (Taxonomy ID: 1129771, family), f Streptococcaceae (Taxonomy ID: 1300, family), s unclassified SGB 1210, and s unclassified SGB 1950. There may be a bidirectional causal relationship between s unclassified SGB 1950 and BD I. Additionally, Reverse Mendel suggested that there was no significant causal relationship between BD and salivary and dorsal tongue microbes.