Sex-specific alterations in gut microbiome composition in patients with Alzheimer's disease

Background The microbiota-gut-brain axis plays a significant role in the pathology of Alzheimer's disease (AD). However, alterations in the gut microbiome structure of AD patients and the sex-specific differences in signature microbial taxa remain inadequately characterized. Methods A total of 100 participants were enrolled, including 60 in the AD case group. Gut microbiota was analyzed by 16S ribosomal RNA (16S rRNA) sequencing. Models incorporating disease group, sex, and a disease-sex interaction term were constructed to test whether sex modifies the effect of AD on gut microbiota α diversity. Stratified analyses were performed to compare α and β diversity between the AD and healthy control (HC) groups in male and female populations, respectively. Differential signature taxa between the two groups were explored using linear discriminant analysis effect size (LEfSe) and random forest analysis. Results A total of 36,168 amplicon sequence variants (ASVs) were obtained, with 1,917 ASVs shared between the AD and HC groups. No interaction effect between AD and sex on gut microbiota diversity was observed (interaction p-FDR > 0.05). In the sex-stratified analysis, gut microbiota evenness indices (Simpson, Shannon, and Pielou's indices) were lower in AD patients than in controls among both male and female populations ( p-FDR < 0.05), whereas species richness (Chao1 and Observed_species) was significantly reduced only in female AD patients ( p-FDR < 0.05). Significant differences in gut microbiota beta diversity were observed between the AD and control groups in both the male population (Stress = 0.213) and the female population (Stress = 0.253) (ANOSIM; males: R = 0.365, p = 0.001; females: R = 0.133, p = 0.001). In the male population, 11 signature taxa, including Bacilli, Lactobacillales, and Macellibacteroides , were significantly enriched in the AD group; in the female population, 12 signature taxa, including [ Ruminococcus ], Alistipes , and Rikenellaceae, were significantly enriched in the AD group. In the overall prediction of the random forest model distinguishing the AD group from the control group, the accuracy was 85.71% and 90.77% in the male and female populations, respectively, and the taxa contributing most to group classification were Pseudoramibacter_Eubacterium and Lachnospira , respectively (Gini importance = 0.059 for both). Conclusion The gut microbiota of AD patients exhibits distinct, sex-specific signature taxa.