Background: Research on the brain-gut-microbiota axis has led to accumulating interest in gut microbiota dysbiosis and intestinal barrier dysfunction in Alzheimer’s disease (AD). Our previous studies have demonstrated neurotoxic effects of 27-hydroxycholesterol (27-OHC) in in vitro and in vivo models. Here, alterations in the gut microbiota and intestinal barrier functions were investigated as the possible causes of cognitive deficits induced by 27-OHC treatment. Methods: Male APP/PS1 transgenic and C57BL/6J mice were treated for 3 weeks with 27-OHC (5.5 mg/kg/day, subcutaneous injection) and either a 27-OHC synthetase inhibitor (anastrozole, ANS) or saline. The Morris water maze and passive avoidance test were used to assess cognitive impairment. Injuries of the intestine were evaluated by histopathological examination. Intestinal barrier function was assessed by plasma diamine oxidase (DAO) activity and d-lactate. Systemic and intestinal inflammation were evaluated by IL-1β, TNF-α, IL-10, and IL-17 concentrations as determined by ELISA. The fecal microbiome and short-chain fatty acids (SCFAs) were analyzed using 16S rDNA sequencing and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Tight junction proteins were evaluated in the ileum and colon by qRT-PCR and Western blots. Tight junction ultrastructure was examined by transmission electron microscopy. Results: Treatment with 27-OHC resulted in severe pathologies in the ileum and colon. There was impaired intestinal barrier integrity as indicated by dilated tight junctions and downregulation of tight junction proteins, including occludin, claudin 1, claudin 5, and ZO-1, and signs of inflammation (increased IL-1β, TNF-α, and IL-17). Fecal 16S rDNA sequencing and taxonomic analysis further revealed a decreased abundance of Roseburia and reduced fecal levels of several SCFAs in 27-OHC-treated mice. Meanwhile, co-treatment with ANS reduced intestinal inflammation and partially preserved intestinal barrier integrity in the presence of 27-OHC. Conclusions: The current study demonstrates for the first time that 27-OHC treatment aggravates AD-associated pathophysiological alterations, specifically gut microbiota dysbiosis and intestinal barrier dysfunction, which suggests that the gut microbiome and intestinal barrier function warrant further investigation as potential targets to mitigate the neurotoxic impact of 27-OHC on cognitive function and the development of AD.

Objective: The aim of this retrospective study was to explore the correlation between daily energy intake from macronutrients and cognitive functions in a Chinese population aged less than 65 years. Design: This is a cross-sectional study to explore the relationships between macronutrients' intake and cognitive function. The analysis of variance (ANOVA) and χ ² test were used to compare the demographic and physical characteristics, lifestyle and laboratory parameters with the intake of macronutrients among different quartiles of % fat/energy. Multivariate logistic regression analysis was applied to identify the potential risk factors of mild cognitive impairment (MCI). Participants: Young and middle-aged participants (age <65 years) were recruited from Beijing, China. The Montreal cognitive assessment (MoCA) and mini-mental state examination (MMSE) were used to evaluate the cognitive functions, and the dietary intake of the participants was estimated with a semi-quantitative food frequency questionnaire (FFQ). Results: Among the 661 participants, 80 (12.1%) had MCI, while 581 (87.9%) had normal cognitive functions. On evaluating the data based on the age group, educational background, and conditions of hyperlipidaemia and total energy intake, the results revealed that high % fat (upper quartile: adjusted OR (aOR) 3.90, 95% CI1.53 to 9.89, P=0.004), and high % protein intake (upper quartile: aOR 2.77, 95% CI 1.24 to 6.15) were greatly associated with increased frequency of MCI, while high % carbohydrate intake (upper quartile: aOR0.30, 95% CI 0.12 to 0.72) was correlated with decreased prevalence of MCI. Conclusion: The dietary pattern with high percentage of energy intake from fat and protein, and low-energy intake from carbohydrate might have been associated with cognitive decline in a Chinese population under 65 years of age.