Theasinensin C Mitigates HFrD-Induced Neuroinflammation by Enriching <i>Akkermansia muciniphila</i> and Orchestrating a Gln/Ser-Centered Multiorgan Metabolic Relay to Drive Creatine Biosynthesis

This study synthesized and structurally validated theasinensin C (TSC, > 98%) and evaluated its neuroprotective effects in a high-fructose diet (HFrD)-induced mouse model of neuroinflammation. TSC (150 mg/kg/day, 8 weeks) improved cognition, reduced pro-inflammatory cytokines, mitigated neuropathology, and restored intestinal barrier integrity. Concomitantly, TSC remodeled the gut microbiota, selectively enriching <i>Akkermansia muciniphila</i>. We isolated <i>A. muciniphila</i> XJ 240720 and demonstrated that its synergy with TSC elevated creatine in serum and the brain, identifying creatine as a key mediator. Multiomics analyses showed that TSC enhanced <i>A. muciniphila</i> hydrolysis of mucin proline-threonine-serine (PTS) domains, releasing proline (Pro) and serine (Ser), and promoted the conversion of Pro via glutamate (Glu) to glutamine (Gln), driving luminal Gln and Ser accumulation. Enterocytes subsequently converted Gln to citrulline (Cit) and aspartate (Asp). In the kidney, the Cit/Asp→arginine (Arg) route coupled with the Ser→glycine (Gly) pathway generated guanidinoacetate (GAA), which the liver methylated via <i>S</i>-adenosylmethionine (SAM) to creatine. Circulating creatine reached the brain and suppressed neuroinflammation. Gln and Ser Supplementation in germ-free mice reproduced behavioral and antineuroinflammatory effects. Thus, TSC enriches <i>A. muciniphila</i> and drives a Gln/Ser-centered multiorgan creatine pathway that alleviates diet-induced neuroinflammation and informs gut-brain axis interventions.