Gut microbiota signatures associated with lithium treatment and clinical response in patients with bipolar disorder

Lithium, the gold-standard treatment for bipolar disorder, exhibits highly heterogeneous clinical responses and no validated biological predictors of responsiveness are currently available. Emerging evidence suggests that the gut microbiota influences mood disorders and psychotropic drug response, raising the hypothesis that specific microbial signatures may modulate lithium responsiveness. In this study, we characterized taxonomic and functional gut microbiota profiles in 77 patients with bipolar disorder, of whom 40 were receiving lithium (20 responders, 20 non-responders) and 37 were treated with valproate as the main mood stabilizer (valproate, n = 31; lamotrigine, n = 6), with the aim of identifying potential microbial markers of clinical response. Microbiota composition was assessed through 16S rRNA sequencing targeting the V3-V4 region. Differential abundance was evaluated using Analysis of Composition of Microbiomes with Bias Correction (ANCOM-BC2), and the functional potential was inferred using the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2 (PICRUSt2). Our finding showed that lithium treatment was associated with a selective gut microbiota reorganization, including reduced Actinobacteria (Actinomycetota) phylum, notably Coriobacteriia class, and enrichment in Firmicutes (Bacillota) taxa, including Selenomonadales, Megamonas and Clostridia taxa, alongside reductions in primary fermentative and biosynthetic pathways. This shift, characterized by a reduction of primary fermenters and enrichment of secondary fermenters and SCFA-producing taxa, suggests a more efficient fermentative ecosystem in lithium-treated patients. Responders showed enrichment in methanogenic taxa (Methanobrevibacter) and Clostridiales vadinBB60 group when compared with patients treated with other mood stabilizers; however, these differences were not observed in the direct comparison between lithium responders and non-responders. While causal relationships cannot be inferred, these findings indicate treatment-associated microbial patterns and support further investigation into microbiota-directed adjunctive therapies.