AbstractIntroductionThe barrier function of the gut is important for many organs and systems, including the brain. If gut permeability increases, bacterial fragments may enter the circulation, giving rise to increased systemic inflammation. Increases in bacterial translocation are reflected in higher values of blood markers, including lipopolysaccharide binding protein (LBP) and soluble cluster of differentiation 14 (sCD14). Some pioneer studies showed a negative association between bacterial translocation markers and brain volumes, but this association remains scarcely investigated. We investigate the effect of bacterial translocation on brain volumes and cognition in both healthy controls and patients with a schizophrenia spectrum disorder (SSD).Materials and methodsHealthy controls (n= 39) and SSD patients (n= 72) underwent an MRI‐scan, venipuncture and cognition assessments. We investigated associations between LBP and sCD14 and brain volumes (intracranial volume, total brain volume, and hippocampal volume) using linear regression. We then associated LBP and sCD14 to cognitive function using a mediation analysis, with intracranial volume as mediator.ResultsHealthy controls showed a negative association between hippocampal volume and LBP (b= –0.11,p= .04), and intracranial volume and sCD14 (b= –0.25,p= .07). Both markers were indirectly associated with lower cognitive functioning in healthy controls (LBP:b= –0.071,p= .028; sCD14:b= –0.213,p= .052), mediated by low intracranial volume. In the SSD patients, these associations were markedly less present.ConclusionThese findings extend earlier studies suggesting that increased bacterial translocation may negatively affect brain volume, which indirectly impacts cognition, even in this young healthy group. If replicated, this finding stresses the importance of a healthy gut for the development and optimal functioning of the brain. Absence of these associations in the SSD group may indicate that other factors such as allostatic load, chronic medication use and interrupted educational carrier had larger impact and attenuated the relative contribution of bacterial translocation.