The Human Antimicrobial Peptide LL-37 May Bridge Gut Health and Brain Inflammation

Narrative review synthesizing animal and human research on cathelicidin biology in the gastrointestinal and central nervous systems, with focus on the gut-brain axis communication pathways.

The gut-brain axis is increasingly recognized as central to neuroinflammatory and neurodegenerative diseases. Finding that a single peptide — LL-37 — can act as both a local effector in the gut and a systemic messenger reaching the brain fundamentally changes how we think about antimicrobial peptides. It suggests that gut health interventions (probiotics, vitamin D, dietary changes that boost cathelicidin) could influence brain inflammation, and that cathelicidin itself could be a therapeutic target or diagnostic biomarker for gut-brain axis disorders.

This review reconceptualizes LL-37 from a simple antimicrobial peptide to an active molecular bridge between peripheral and central immunity. The implications extend across multiple fields: gastroenterology (gut barrier), neurology (neuroinflammation), immunology (innate immunity), and even nutrition (vitamin D regulation). The finding that the same peptide has opposite effects depending on its source adds important nuance to peptide therapeutic development — boosting LL-37 in the gut might help, but increasing it in the brain via immune cells could worsen inflammation.

As a review, this synthesizes existing literature rather than presenting new data. Much of the mechanistic evidence comes from animal models (primarily rodent CRAMP studies), and the human relevance of all findings is not confirmed. The context-dependent effects of cathelicidin are complex and not fully characterized. The review proposes cathelicidin as a gut-brain mediator, but direct causal evidence for this communication pathway in human neuroinflammatory disease is limited.