Natural and Synthetic Peptides as Alternatives to Antibiotics in Intestinal Infections—A Review

Background/Objectives: Antimicrobial peptides (AMPs), evolutionarily conserved components of innate immunity characterized by their broad-spectrum efficacy and minimal resistance development, are increasingly recognized as promising therapeutic candidates. This review aims to integrate current knowledge concerning natural and synthetic antimicrobial peptides and their therapeutic effectiveness in addressing gastrointestinal infections. Methods: A literature review was performed, evaluating recent peer-reviewed studies on AMPs. The research concentrated on their molecular mechanisms of action, antimicrobial spectrum, as well as on their interactions with standard antibiotics. More in detail, the peptide classes examined herein included defensins, cathelicidins, histatins, and various natural peptides such as lactoferricin, protamines, RegIII, and hepcidin, along with synthetic analogs like WR12, D-IK8, MSI-78, IMX942. Results: Natural AMPs demonstrated significant antimicrobial and immunomodulatory effects against Escherichia coli, Klebsiella pneumoniae, Salmonella spp., and Shigella spp. Beyond direct antimicrobial activity, intestinal antimicrobial peptides act as integrated anti-infective agents by modulating host–microbiota interactions, preserving epithelial barrier integrity, and limiting inflammation, thereby offering a multifaceted strategy to control gastrointestinal infections. On the other hand, synthetic peptides showed better stability, less toxicity, and synergistic interactions with antibiotics, which suggests that they could be used either alone or in combination with other treatments. Conclusions: AMPs constitute a promising category endowed with anti-infective activity especially for therapy of intestinal diseases, which is attributed to their distinctive anti-infective mechanisms, immune-modulating characteristics, and a relatively low propensity for resistance development compared to conventional antibiotics. However, more clinical trials and improvements to their formulation are needed to translate promising in vitro results into reliable patient outcomes.