Magnoflorine alleviates colitis-induced anxiety-like behaviors through regulating gut microbiota and microglia mediated neuroinflammation

Background Inflammatory bowel disease (IBD) and anxiety are often comorbid, and are interconnected through the microbiota-gut-brain axis. The therapeutic medications for anxiety are often constrained by adverse effects that limit their long-term use. The pursuit of natural, safe drug for anxiety is important, with the precise mechanisms elucidating the interplay between drugs and the gut-brain axis in modulating mood remaining elusive. Results We revealed a significant association between active ulcerative colitis(UC) patients and anxiety. Mendelian randomisation analysis suggested that UC has a causal relationship on anxiety, but not on depression. Next we identified Ziziphus jujuba , a natural plant, as a dual therapeutic agent for both UC and anxiety through Batman database. Magnoflorine, as the predominant compound found in Ziziphus jujuba , exhibits promising therapeutic properties for the treatment of UC and anxiety disorders. Our experiments found that magnoflorine not only alleviated colitis, but also reduced colitis-induced anxiety behaviors through gut microbiota. Mechanistically, magnoflorine could increase the abundance of Odoribacteraceae and Ruminococcus , regulate bile acid metabolism, especially hyodeoxycholic acid (HDCA) in colitis mice. HDCA supplement could alleviate both colitis and colitis-induced anxiety. Meanwhile HDCA could inhibit the binding site of lipopolysaccharide to the TLR4/MD2 complex, thereby inhibiting microglia activation and alleviating neuroinflammation. Conclusion Our study unveils that magnoflorine alleviates colitis-induced anxiety-like behaviors through regulating gut microbiota and microglia mediated neuroinflammation, which has the potential therapeutic for IBD comorbid with anxiety disorders.