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

Lithium remains the gold‑standard pharmacological treatment for bipolar disorder; however, its clinical effectiveness is highly heterogeneous, and a substantial proportion of patients fail to achieve an adequate therapeutic response. At present, no validated biological markers exist to predict lithium responsiveness, representing a critical unmet need in personalized psychiatry. Increasing evidence indicates that the gut microbiota plays an important role in the regulation of mood, neuroinflammation, and metabolic pathways relevant to psychiatric disorders, and may also influence individual responses to psychotropic medications. These observations raise the hypothesis that specific gut microbial signatures could be associated with lithium treatment and potentially modulate clinical response.

In this study, we investigated both taxonomic composition and inferred functional potential of the gut microbiota in a cohort of 77 patients with bipolar disorder receiving long‑term mood stabilizer treatment. Forty patients were treated with lithium, including 20 clinically defined responders and 20 non‑responders, while 37 patients were receiving other mood stabilizers, primarily valproate (n = 31) or lamotrigine (n = 6). Long term lithium response was evaluated with the “Retrospective Assessment of the Lithium Response Phenotype Scale” (Alda scale). Gut microbiota composition was characterized using 16S rRNA gene sequencing targeting the V3–V4 hypervariable region. Differential taxonomic abundance was assessed using Analysis of Composition of Microbiomes with Bias Correction (ANCOM‑BC2), and microbial functional potential was inferred using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2 (PICRUSt2).

Lithium treatment was associated with a distinct and selective reorganization of gut microbiota composition and function. Specifically, lithium‑treated patients showed a reduction in the Actinobacteria (Actinomycetota) phylum, particularly within the Coriobacteriia class, alongside an enrichment of Firmicutes (Bacillota) taxa, including members of Selenomonadales, Megamonas, and several Clostridia lineages. These taxonomic shifts were accompanied by a reduction in predicted primary fermentative and biosynthetic pathways, suggesting a restructuring of microbial metabolic activity.

Overall, this microbial configuration was characterized by a reduction in primary fermenters and an enrichment of secondary fermenters and short‑chain fatty acid–producing taxa, consistent with a more efficient and metabolically integrated fermentative ecosystem in lithium‑treated patients. When compared with patients treated with other mood stabilizers, lithium responders exhibited increased abundance of methanogenic taxa (Methanobrevibacter) and the Clostridiales vadinBB60 group, potentially reflecting enhanced hydrogen utilization and fermentative efficiency. Notably, these differences were not observed when directly comparing lithium responders and non‑responders, suggesting that treatment exposure rather than clinical response per se may drive the observed microbial patterns.

Although causal relationships cannot be inferred from this cross‑sectional analysis, our findings indicate that lithium treatment is associated with specific gut microbiota configurations. These treatment‑related microbial signatures may represent promising candidate biomarkers of lithium treatment and provide a rationale for future longitudinal studies and microbiota‑directed adjunctive therapeutic strategies in bipolar disorder with important implications for future precision medicine strategies.

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