Resolve: SCFA Deficiency Drives Microglial Hyperactivation via GPR43/NF-κB Dysregulation

Falsifiable prediction from high-scoring hypothesis (score=0.728, gene=GPR43 (FFAR2)). Hypothesis: Does restoring gut-microbiome-derived SCFA (butyrate/propionate) levels rescue microglial GPR43-mediated HDAC inhibition and reduce NF-κB-driven neuroinflammation in early AD? Success criteria: 1. FMT from SCFA-supplemented donors reduces IBA1+/CD68+ microglia in 5xFAD mice by >30% vs FMT from vehicle controls. 2. GPR43-KO microglia show >50% increase in TNF-α/IL-6 vs WT under butyrate-reduced conditions. 3. HDAC3 inhibitor (RGFP966) reduces NF-κB p65 acetylation and IL-1β secretion by >40% in butyrate-depleted primary microglia. 4. CSF IL-1β decreases by >25% in SCFA-supplemented 5xFAD mice after 8 weeks.