The Integrative Role of Berberine in Gut Microbiota Modulation and Cardiometabolic Outcomes: A Systematic Review of Randomised Clinical Trials

Background/Aim: Berberine, an isoquinoline alkaloid widely used in traditional medicine, has attracted considerable interest for its capacity to modulate the gut microbiota and improve cardiometabolic outcomes. Although preclinical evidence is promising, no systematic review has previously synthesised evidence from randomised controlled trials (RCTs) in humans. This review aimed to evaluate the effects of berberine supplementation on gut microbiota and to explore associated cardiometabolic, inflammatory, and immunological changes. Methods: Prospectively registered in PROSPERO (CRD42024524143) and conducted in accordance with PRISMA guidelines, this review searched PubMed, Web of Science, Scopus, and Embase from inception to 10 January 2026. Eligible studies were RCTs in adults reporting gut microbiota outcomes following berberine supplementation. Methodological quality was assessed using the Cochrane Risk of Bias tool. Microbiota assessment methods, including sequencing platforms and bioinformatic pipelines, were systematically characterised across the included studies. Results: Seven RCTs enrolling 34 to 446 participants per intervention arm were included across diverse clinical populations—type two diabetes mellitus (T2DM), hyperlipidaemia, colorectal adenoma, psychiatric disorders, and Parkinson’s disease. Six of seven studies reported significant compositional shifts; the most extensively characterised changes—observed predominantly in T2DM populations—included enrichment of γ-Proteobacteria and depletion of butyrate-producing taxa, with specific taxa and the breadth of compositional changes varying considerably across clinical populations and sequencing methodologies. These shifts co-occurred with improvements in fasting glucose, lipid profiles, and inflammatory markers; however, causal inference cannot be established. Conclusions: Berberine consistently modulated gut microbial composition across heterogeneous clinical populations, with concurrent cardiometabolic and anti-inflammatory improvements. Compositional shifts were not uniformly favourable, and findings should be interpreted as hypothesis-generating. Geographically diverse, mechanistically focused RCTs are required to establish causality.