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.