Synbiotics of Lactobacillus suilingensis and inulin alleviates cognitive impairment via regulating gut microbiota indole‐3‐lactic acid metabolism in female AD mice

Abstract INTRODUCTION Recent studies have found that gut microbial tryptophan metabolism is altered in Alzheimer's disease (AD) patients. However, the functional consequences of these changes and their therapeutic potential remain unclear. METHODS The metagenomic data of 49 preclinical AD patients and 115 healthy controls were analyzed. A synbiotic with targeted metabolic functions was formulated based on in vitro testing, and its effect on AD was evaluated using female 5×FAD mice. RESULTS Indole lactic acid (ILA) synthesis was downregulated in AD patients. Synbiotic treatment combining Lactobacillus suilingensis and inulin outperformed probiotic treatment alone in enhancing tryptophan metabolism, and increasing ILA biosynthesis. Increased ILA could reduce Aβ accumulation and significantly alleviate cognitive impairment in female AD mice by inhibiting neuroinflammation through activation of the aryl hydrocarbon receptor (AhR) signaling pathway. DISCUSSION This study highlights the therapeutic potential of targeting gut microbial tryptophan metabolism in AD and provides a rationale for future precision strategies aimed at modulating microbiota‐derived metabolic pathways. Highlights Gut metagenomic analysis reveals reduced indole lactic acid (ILA) biosynthesis genes in preclinical AD patients. Screening and formulating ILA‐producing synbiotic by using whole‐genome analysis. Synbiotic treatment alleviates cognitive impairment and promotes ILA synthesis in female 5×FAD mice. ILA alleviates neuroinflammation in female 5×FAD mice by activating aryl hydrocarbon receptor (AhR) in the brain. Synbiotic targeting tryptophan metabolism provides a novel approach for Alzheimer's intervention.