The gut microbiota-iron-brain axis in a mouse model of Alzheimer’s disease

Alzheimer’s disease (AD) is increasingly recognized as a multifactorial disorder in which peripheral systems contribute to disease onset and progression. Among these, the gut microbiome and iron homeostasis have emerged as potential modulators of neuroinflammatory and neurodegenerative processes, yet their functional interplay remains insufficiently defined in physiologically relevant AD models. In this pilot study, we investigated age and genotype dependent alterations in gut microbiota composition and intestinal iron handling using the APP ^{NL−F/NL−F} knock-in (APP-KI) mouse model of Alzheimer’s disease. Fecal samples collected from young (1 month) and aged (18 months) APP-KI mice and age-matched wild-type (WT) controls were analyzed using an integrated approach combining classical culture-based microbiology, 16S rRNA gene sequencing, and quantitative iron determination by ICP-MS. NGS-based profiling revealed pronounced age-associated microbiome remodeling in APP-KI mice, characterized by a reduction in saccharolytic and short-chain fatty (SCF) acid-producing families, including Muribaculaceae and Lachnospiraceae, alongside an expansion of inflammation-associated taxa, most notably Erysipelotrichaceae. Culture-based analyses demonstrated a marked simplification of the viable microbiota in aged APP-KI mice, with dominance of Lactobacillaceae and the selective emergence of opportunistic Enterococcaceae. Importantly, fecal iron concentrations exhibited a bidirectional, age-dependent shift, with significantly elevated levels detected in aged APP-KI mice compared with wild-type controls. Collectively, these findings identify coordinated alterations in gut microbiota structure, metabolic potential, and intestinal iron handling during AD-like pathology. The results support a conceptual framework in which microbiome-driven changes may influence intestinal barrier function, immune activation, and redox balance, thereby linking microbial metabolism, iron dyshomeostasis, and neurodegenerative processes. This integrated microbiome-iron axis may represent a previously underappreciated modifier of Alzheimer’s disease progression and a potential target for future mechanistic and therapeutic studies.