Immunomodulatory effects of cathelicidin in the gut–brain axis: A novel link between mucosal immunity and neuroinflammation

Cathelicidins are evolutionarily conserved host defence peptides known for their dual antimicrobial and immunomodulatory functions. Among them, LL-37 in humans and CRAMP in rodents have emerged as crucial regulators of both mucosal immunity and CNS inflammation. This review explores the emerging evidence that positions cathelicidins as key modulators of the gut-brain axis, a bidirectional communication network increasingly implicated in neuroinflammatory and neurodegenerative disorders. Drawing on a diverse body of animal and human research, we examine the multifaceted roles of cathelicidin in maintaining intestinal barrier integrity, shaping microbiota composition and regulating innate immune signalling. Particular attention is paid to how gut-derived metabolites, such as short-chain fatty acids and vitamin D, influence cathelicidin expression, with downstream consequences for both gastrointestinal and neural health. In the CNS, cathelicidin exhibits context-dependent effects, acting as a neuroprotective modulator when derived from neurons, but exacerbating glial-mediated inflammation when sourced from peripheral immune cells. This functional dichotomy underscores the importance of cellular origin, concentration and microenvironmental cues. Furthermore, we delineate how cathelicidin facilitates crosstalk between peripheral and central compartments, serving as both a local effector and a systemic messenger. Collectively, these insights support a reconceptualization of cathelicidin not merely as a passive antimicrobial peptide, but as an active molecular bridge between mucosal immunity and neuroinflammation, with promising implications for diagnostics and therapeutics targeting dysfunction of the gut-brain axis.