Zonulin as a Potential Therapeutic Target in Microbiota-Gut-Brain Axis Disorders: Encouraging Results and Emerging Questions.

This review examines the role of zonulin — a protein regulator of tight junctions in intestinal epithelial cells — in the context of the microbiota-gut-brain axis. The authors synthesize evidence from the past decade linking gut dysbiosis to increased intestinal permeability, whereby bacterial fragments and toxins enter systemic circulation, trigger local and systemic inflammation, and ultimately affect the brain. The review discusses how zonulin may also influence blood-brain barrier integrity, suggesting a dual role in both gut and neurological health. The authors survey potential pharmaceutical strategies targeting zonulin-associated pathways, including larazotide acetate and various zonulin receptor agonists and antagonists. Notably, the review also raises important methodological concerns, including inconsistent and potentially misleading nomenclature surrounding "zonulin" in the literature, as well as unresolved questions about the protein's exact molecular sequence. As a narrative review, it does not present new experimental data and is subject to selection bias. Its strength lies in synthesizing emerging findings and clearly identifying open scientific questions, making it a useful conceptual reference but not a source of direct clinical evidence.

Why this grade: This is a narrative review synthesizing existing literature rather than presenting original experimental or clinical trial data, so it cannot independently establish a specific evidence grade for human efficacy claims.