Cognitive impairment in bipolar disorder associated with abnormal serum short-chain fatty acids and cytokines

Objective: We investigated changes in serum short-chain fatty acids (SCFAs) levels in patients with bipolar disorder (BD) and explored the relationship between these levels and peripheral cytokines and their impact on cognitive function. Methods: This study enrolled 64 patients with BD and 54 healthy controls (HCs) in a case-control design. Levels of 16 SCFAs and 9 cytokines in serum were measured via targeted metabolomics and Luminex multiplex assay, respectively. A subgroup (33 BD and 38 HCs) completed the MATRICS Consensus Cognitive Battery (MCCB) for neurocognitive assessment. Multiple linear regression and mediation analysis were used to examine the cross-sectional relationships among SCFAs (independent variable), cytokines (mediator), and cognitive function (dependent variable). Results: Serum propionic acid (PA) and butyric acid (BA) were elevated, whereas isovaleric acid (IVA), caproic acid (CA), and octanoic acid (OA) were reduced in patients with BD compared to HCs. Multiple linear regression models indicated that CA, IVA, Interleukin (IL)-6, and IL-8 collectively explained 16.6%–41.4% of the variance in Trail Making Test (TMT), Neuropsychological Assessment Battery (NAB) and Wechsler Memory Scale (WMS) cognitive tests. Mediation analysis revealed that CA and IVA contributed to impairments in working memory and reasoning (as measured by WMS and NAB) by partially mediating the upregulation of IL-6 and IL-8, with the proportion mediated ranging from 5.1% to 21.2%. A random forest model based on distinct SCFAs and cytokines accurately distinguished BD patients from HCs (AUC = 0.98). Conclusion: By integrating multi-omics with mediation analysis, our study is the first to delineate a novel gut-brain pathway in BD, wherein maladjusted SCFAs appear to drive cognitive deficits via pro-inflammation. This mechanistic insight suggests that augmenting beneficial SCFA-producing bacteria or targeting IL-6/IL-8 could be potential strategies worthy of future validation for alleviating cognitive impairment in BD.