Gut-brain axis crosstalk in patients with Alzheimer's disease and high body mass index: Gut dysbiosis, blood-brain barrier disruption, and neuroinflammation

BackgroundAccumulating evidence indicates that body mass index (BMI) is related to Alzheimer's disease (AD).ObjectiveThis study aimed to investigate the impact of high BMI on cognitive function in AD patients and potential mechanisms involving gut dysbiosis, blood-brain barrier (BBB) disruption, and neuroinflammation in brain.MethodsA total of 50 AD patients were recruited and divided into AD with normal BMI (AD-nBMI) and AD with high BMI (AD-hBMI) groups. Cognitive function was assessed, the levels of BBB variables, neuroinflammatory factors, and AD biomarkers in cerebrospinal fluid (CSF) were measured, gut microbiota and metabolites were analyzed using 16S ribosomal ribonucleic acid gene sequencing and gas chromatography-mass spectrometry analysis, and the correlations among gut microbiota and metabolites, BBB variables, and neuroinflammatory factors in CSF were analyzed.ResultsAD-hBMI group exhibited impaired overall cognition, elevated CSF levels of zonula occludens-1 (ZO-1) and occludin (OCLN) (BBB disruption), and increased CSF levels of nitric oxide (NO) and hydroxyl radical (·OH) (neuroinflammation) compared with AD-nBMI group. Correlation analyses revealed that BMI was positively associated with impaired cognition, CSF levels of OCLN and NO in AD patients. AD-hBMI group displayed a unique gut dysbiosis pattern characterized by the alterations in specific metabolite levels. In AD-hBMI group, elevated thioridazine, 4-hydroxybenzaldehyde, and N-acetylleucine were positively correlated with ZO-1 level in CSF, reduced acesulfame and undecanoic acid were negatively correlated with OCLN level in CSF, and elevated (S)-S-methylcysteine sulfoxide was positiveiy correlated with both ZO-1 and OCLN levels in CSF. Elevated thioridazine and medroxyprogesterone were positively correlated with NO level in CSF, and decreased butyric acid was negatively correlated with ·OH level in CSF.ConclusionsHigh BMI may accelerate gut dysbiosis, leading to disrupted BBB, enhanced neuroinflammation, and ultimately accelerated cognitive impairment in AD patients.