Emerging antimicrobial peptides in gastrointestinal disorders: Dual role in immunity and therapy

Abstract

Antimicrobial peptides (AMPs) are small, cationic effectors of innate immunity that are central to gastrointestinal homeostasis and increasingly attractive as therapeutics for infection, inflammation, and malignancy. Produced by intestinal epithelial and immune cells, AMPs such as defensins and cathelicidins act as frontline regulators, responding to microbial cues through pattern-recognition receptors, shaping microbiota composition, reinforcing the mucosal barrier, and tuning the balance between pro-inflammatory and anti-inflammatory signalling. This review frames AMP biology around a central duality: The same peptides that defend the gut can, when dysregulated in concentration, location, or context, contribute to pathology, from the α-defensin deficiency that initiates ileal Crohn’s disease to the concentration-dependent switch by which LL-37 turns from a wound-healing mediator into a tumour-promoting one. This duality dictates therapeutic strategy, favouring restoration where disease arises from deficiency and restraint where it arises from aberrant signalling. We examine the mechanistic basis of AMP action (membrane disruption, intracellular targeting, and receptor-mediated immunomodulation) and evaluate preclinical and clinical evidence across inflammatory bowel disease, enteric infection, and gastrointestinal cancers, drawing the recurring lesson that microbiological success rarely guarantees clinical benefit. Persistent barriers of proteolytic instability, narrow therapeutic windows, and manufacturing cost are increasingly addressed through convergent advances in artificial intelligence–guided peptide design, sequence stabilisation, gut-targeted and stimulus-responsive delivery, and engineered live biotherapeutics that produce peptides in situ. Together, these developments are transforming AMPs from endogenous immune mediators into next-generation precision therapeutics for gut disease—agents designed to be not merely potent, but deliverable, selective, and stable where needed most.

Keywords: Antimicrobial peptide; Gut microbiota; Antimicrobial resistance; Immunomodulation; Intestinal barrier integrity; Inflammatory bowel disease; Nanotechnology-based delivery; Artificial intelligence in peptide design; Microbiome-targeted therapeutics

Core Tip: Antimicrobial peptides represent promising next-generation therapeutics that counter antimicrobial resistance through membrane disruption, immune modulation, and microbiome regulation. Their dual role in host defence and tissue homeostasis, particularly within gastrointestinal environments, underscores their broader physiological significance. Advances in artificial intelligence–driven peptide design and nanotechnology-based delivery systems are progressively addressing pharmacokinetic limitations and enhancing clinical viability. However, challenges remain, including cytotoxicity, proteolytic instability, and high production costs. Integrating bioengineering, precision medicine, and microbiome-guided strategies holds considerable potential to establish antimicrobial peptides as personalised, clinically translatable anti-infective and immunomodulatory therapeutics.