The complex of gut microbial metabolites and sex hormones in Alzheimer's disease.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder with a complex pathophysiological mechanism and a marked sex difference in prevalence and disease severity, with women being more affected and showing a more aggressive disease course. Recent studies indicate that a complex interplay among gut microbiota (GM), their metabolites, and sex hormones is a crucial factor in AD pathogenesis. In this review, we attempted to synthesize current studies to critically discuss the tripartite interplay among GM, sex hormones, and the brain in AD. Firstly, we discuss the role of the microbiota-gut-brain axis in AD pathogenesis with a focus on how gut dysbiosis contributes to neuroinflammation, disruption of the blood-brain barrier (BBB), and accumulation of pathological proteins. Then, we discuss the mechanistic roles of various GM-derived metabolites in AD pathogenesis, with a focus on the two-edged role of SCFAs and their derivatives, the neuroactive role of tryptophan and its derivatives, and the modulatory roles of bile acids and trimethylamine N-oxide. Finally, we discuss a novel concept, the "microgenderome," referring to the bidirectional interplay between sex hormones and GM, and how GM regulates sex hormone levels through unique enzymatic functions termed the "estrobolome" and a newly proposed "testobolome."