Gut Microbiota Signatures Associated with Lithium Treatment and Clinical Response in Patients with Bipolar Disorder

Abstract: Background: Lithium (Li), the gold-standard treatment for Bipolar Disorder (BD), exhibits highly heterogeneous clinical responses, and no validated biological predictors of responsiveness are currently available. Growing evidence indicates that the gut microbiota (GM) modulates the gut-brain axis, influences mood disorders, and may shape the efficacy of psychotropic treatments, including lithium. This supports the hypothesis that specific GM signatures may contribute to interindividual variability in treatment response. This study aimed at characterizing the taxonomic and functional microbial signatures associated with lithium treatment in comparison with valproate, and at identifying potential microbial markers of clinical response. Methods: Fecal samples from 77 patients with BD were analyzed. At the time of recruitment, 40 patients were receiving lithium (20 responders and 20 non-responders), while 37 were being treated with valproate. 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-BC), and the functional potential of the microbiota was inferred using the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2 (PICRUSt2). Results: Alpha- and beta-diversity analyses showed no major global differences between groups, except for reduced Pielou's evenness in Li-treated patients, suggesting selective ecological reorganization rather than generalized depletion. Lithium treatment was associated with a significant decrease in the Actinobacteria phylum, particularly taxa within the Coriobacteriia class, including the Senegalimassilia genus, and with enrichment in Firmicutes taxa, including the Selenomonadales order and its genus Megamonas, as well as multiple taxa within the Clostridia class, such as Flavonifractor, Ruminiclostridium 9 (Oscillospiraceae), Tyzzerella and Unclassified Lachnospiraceae 958 (Lachnospiraceae). These compositional shifts were paralleled by predicted functional changes characterized by decreased primary fermentative and biosynthetic pathways, including mixed acid fermentation, heterolactic fermentation and the Bifidobacterium shunt, which contribute to intestinal lactate production. These functional shifts suggest a reorganization of microbial carbohydrate metabolism, consistent with hypothesized rebalancing of intestinal fermentative networks. Li-responders, compared with valproate-treated patients, showed enrichment in methanogenic taxa (Euryachaeota, Methanobrevibacter) and the Clostridiales vadinBB60 group, suggesting enhanced fermentative efficiency. No statistically significant differences were observed between Li-responders and Li non-responders. Functional stratification analyses revealed suggestive differences when comparing responders and non-responders separately with valproate-treated patients. Integration with peripheral metabolomic data revealed treatment-associated alterations in systemic energy metabolism, supporting the hypothesis of coordinated host-microbiota metabolic remodeling under lithium exposure. Conclusions: Lithium treatment in BD is associated with a selective reorganization of the gut microbiota, characterized by reduced primary fermenters and enrichment in taxa associated with fermentative cross-feeding networks, suggesting a reconfiguration of intestinal metabolic ecology, including pathways potentially contributing to microbial lactate production. This ecological shift may contribute to improved metabolic homeostasis and modulation of gut-brain signaling pathways relevant to lithium's therapeutic effects. Lithium responders display distinct microbial signatures compatible with greater ecological resilience and fermentative capacity. Although causal relationships cannot be established in this cross-sectional design, these findings suggest that gut microbial configuration may represent a potential biomarker of lithium response and a target for adjunctive microbiota-directed interventions.