Abstract
Disruption of the gut-microbiome-brain axis contributes to the development of chronic inflammation, impaired intestinal barrier integrity, and progressive tissue damage, ultimately reducing quality of life and increasing risk of comorbidities, including neurodegenerative diseases. Current therapies are often limited by adverse effects and insufficient long-term efficacy, highlighting the need for more comprehensive therapeutic approaches. Berberine (BRB), a plant-derived isoquinoline alkaloid, has attracted growing attention due to its pleiotropic immunomodulatory, neuroprotective, and gut-homeostasis-modulating properties, which involve reshaping the gut microbiota and underscore its therapeutic relevance within the gut-microbiome-brain axis. The aim of this review is to synthesize current scientific evidence regarding the anti-inflammatory mechanisms of BRB in inflammatory bowel disease (IBD). We compare its activity with first-line therapies and discuss its impact on microbial composition, including the bidirectional regulation of specific bacterial taxa relevant to intestinal and systemic disorders that originate in the gut. Furthermore, we emphasize that gut bacteria convert BRB into bioactive metabolites, contributing to its enhanced intraluminal activity despite its low systemic bioavailability. By integrating molecular and microbiological evidence, this review fills a critical knowledge gap regarding the comprehensive therapeutic potential of BRB as a promising candidate for future IBD interventions. The novelty of this work lies in unifying fragmented findings into a framework that explains how BRB acts simultaneously at the levels of host immunity, microbial ecology, and neuroimmune communication-thus offering a new conceptual model for its role within the gut-microbiome-brain axis.