High throughput screening of patient's iPSC-derived neurons identifies gut microbial metabolites as a potential treatment for Alzheimer's disease

Recent discoveries highlight the critical role of gut microbiota and their metabolites in regulating communication between the gut and the brain. In Alzheimer's disease (AD), shifts in gut microbial composition are known to influence disease progression, yet the specific microbial-derived molecules and their mechanisms of action remain poorly understood.In this study, we systematically screened a library of 352 gut microbial metabolites using neurons derived from induced pluripotent stem cells (iPSCs) of AD patients. Our goal was to identify metabolites that could reduce the pathological phosphorylation of tau protein - a hallmark of AD. From this screen, we identified three promising candidates: 4-methylcatechol, menaquinone-4, and agmatine. Among them, we selected agmatine for further investigation due to its potential as a naturally occurring therapeutic molecule.Agmatine, a polyamine synthesized from the amino acid L-arginine, demonstrated significant efficacy in reducing hyperphosphorylation at multiple tau sites (pTau181, pTau205, and pTau231) in both AD patient iPSC-derived neurons and cerebral organoids. Beyond in vitro models, we evaluated the therapeutic potential of agmatine in vivo using the 5xFAD mouse model of AD. Agmatine treatment led to notable improvements in cognitive performance, enhanced learning and memory, and reductions in amyloid plaque deposition and neuroinflammation.To assess the impact of agmatine on gut microbiota, we conducted 16S rRNA sequencing on fecal and cecum samples from treated 5xFAD mice. The analysis revealed an increased abundance of beneficial gut bacteria, including Turicibacter and Bifidobacterium, both associated with gut health and anti-inflammatory profiles. This finding supports the hypothesis that agmatine not only affects brain pathology directly but may also modulate the gut-brain axis through microbial community restructuring.Transcriptomic profiling of patient-derived cerebral organoids further demonstrated that agmatine treatment leads to downregulation of several components of the complement cascade (e.g., C1S, C2, C3AR1, and C5AR1), a system increasingly recognized for its role in AD neuroinflammation and synaptic loss. Intriguingly, prior computational analyses from our group - utilizing machine learning and multi-omics approaches - predicted a strong interaction between agmatine and the complement receptor C3aR. In line with this, agmatine administration resulted in decreased levels of C3aR and its downstream effector pSTAT3, aligning with reduced tau phosphorylation.Taken together, our findings highlight the importance of gut microbiota-derived metabolites in shaping brain health and disease. We demonstrate that agmatine, a metabolite with both microbial and endogenous origins, exerts neuroprotective effects in multiple AD models. This is achieved, at least in part, through modulation of the C3aR-STAT3 signaling pathway - a novel mechanism that opens up new avenues for therapeutic intervention.This study underscores the potential of harnessing microbiome-derived small molecules to influence complex neurological disorders like Alzheimer's disease. Agmatine stands out as a promising candidate for further clinical exploration, with the dual capacity to restore gut microbial balance and directly target disease-relevant signaling pathways in the brain.