Sex-related gut microbiota signatures in bipolar disorder with metabolic syndrome: a cross-sectional 16S rRNA gene sequencing study

Bipolar disorder is frequently accompanied by metabolic syndrome, contributing to increased morbidity and poorer clinical outcomes. Growing evidence implicates gut microbiota alterations in both metabolic and psychiatric conditions; however, whether such alterations vary by sex in bipolar disorder with metabolic comorbidity remains insufficiently explored. In this cross-sectional study, we enrolled 60 inpatients with bipolar disorder and stratified them by sex and the presence of metabolic syndrome. Fecal samples were analyzed using 16S rRNA gene sequencing. Alpha and beta diversity metrics were assessed, and differential taxa were identified using linear discriminant analysis effect size (LEfSe). The four groups differed significantly in BMI, waist circumference, FPG, HDL-C, TG, and systolic blood pressure (all P < 0.001), consistent with the predefined MetS stratification. Gut microbiota α-diversity differed across the four groups, with an overall tendency toward higher diversity in female groups than in male groups. Principal coordinates analysis based on Bray–Curtis dissimilarity showed a separation trend in overall microbial community structure across subgroups defined by sex and MetS status. Genus-level relative abundance and exploratory LEfSe analyses indicated that patients with BD and comorbid MetS showed lower relative abundances of some short-chain fatty acid-producing and probiotic-associated genera, together with higher relative abundances of some genera previously linked to metabolic or inflammatory dysregulation, with possible sex-related patterns. Within this cohort of patients with BD, MetS status and sex were associated with differences in gut microbiota diversity and composition. However, given the cross-sectional design, absence of healthy controls, modest subgroup size, and lack of detailed adjustment for medication exposure and lifestyle factors, these findings should be interpreted as exploratory within-cohort associations rather than causal, BD-specific, or medication-independent microbial signatures. Further validation is needed in larger, longitudinal studies including appropriate control groups.