Probiotic-based sequential delivery system for gut-brain co-therapy against inflammatory bowel disease-associated anxiety/depression

With the emergence of the gut-brain axis, inflammatory bowel disease (IBD) is no longer simply regarded as a localized intestinal disease but as a systemic disorder intimately associated with psychiatric comorbidities, including anxiety and depression. However, conventional therapeutic strategies predominantly target localized colonic inflammation, which often yields suboptimal outcomes. This highlights a critical need for gut-brain co-therapy to achieve comprehensive IBD management. Based on our observation that indole-3-acetic acid (IAA) possesses the potential to attenuate hippocampal neuroinflammation and subsequently modulate intestinal inflammation via the acetylcholine pathway, we engineered a gut-brain co-therapy delivery platform (CB-ASA/IAA/L). This system comprises Clostridium butyricum (CB) loaded with 5-aminosalicylic acid (5-ASA), encapsulated by a pH-responsive Eudragit L100-55 layer incorporating IAA. This microecological preparation is based on effective protection and delivery of CB, achieving the delivery of IAA to the brain and 5-ASA to the colon simultaneously. This sequential-release delivery system achieved intestinal barrier repair, promoted macrophage polarization toward the M2 phenotype, and restored Th17/Treg balance to recover intestinal homeostasis, while simultaneously alleviating anxiety- and depression-like behaviors in colitis mice. Importantly, the system demonstrated a robust ability to prevent inflammatory recurrence, a major clinical challenge in IBD treatment. This research offers a new avenue for the effective treatment of IBD-associated anxiety/depression by coordinating neuroimmune modulation with local intestinal repair. Schematic illustration of the synthesis, site-specific gastrointestinal delivery, and gut–brain axis-mediated therapeutic mechanisms of CB-ASA/IAA/L against inflammatory bowel disease and associated anxiety/depression.