With the widespread use of ionizing radiation (IR) in medical and industrial settings, irradiation has become increasingly common, posing significant risks to human health. Among the various organs affected, the gut is particularly sensitive to radiation-induced damage, leading to conditions such as radiation-induced intestinal damage (RIID). Recent studies have emphasized the critical role of gut microbiota and its metabolites in mitigating radiation-induced injury. This review discusses the effects of IR on the mammalian and human gut microbiota. We examine the dynamics of gut microbiota composition during and after irradiation, and emphasize the protective role of the gut flora and the metabolites in the pathophysiological mechanisms exhibited during radiation injury. In addition, this article investigates how specific metabolites, such as short-chain fatty acids and indole derivatives, may contribute to the mitigation of inflammation and promotion of gut barrier integrity. In addition, various therapeutic strategies based on modulating the gut microbiota, such as probiotics, antibiotics, and fecal microbiota transplantation, are discussed to understand their potential to prevent or mitigate RIID. Understanding the interactions between IR, gut microbiota and their metabolites provides new avenues for developing innovative therapeutic approaches to improve patient outcomes during and after radiotherapy. Future research directions could focus on optimizing microbiota-based therapies and exploring the role of diet and lifestyle in enhancing intestinal health during irradiation.

Helicobacter pylori (H. pylori) is the primary etiological agent for chronic gastritis, peptic ulcers, and gastric adenocarcinoma. The alarming rise in multidrug-resistant (MDR) strains, particularly against clarithromycin (CLR), metronidazole (MNZ), and levofloxacin (LVX), has severely compromised standard therapies. Thus, there is an urgent clinical need for novel antimicrobial agents that operate through distinct mechanisms to bypass resistance pathways and mitigate gastric cancer risk. We designed and synthesized a series of antimicrobial peptides, focusing on the proteolytically stable all-D-amino acid enantiomer, DT7-3, derived from a probiotic-sourced template. Minimum inhibitory concentrations (MICs) were determined against standard strains and 11 clinical MDR isolates via the broth microdilution method. Antimicrobial mechanisms were elucidated using scanning electron microscopy (SEM) for morphology, fluorescence-based assays for anti-adhesion activity, and real-time qPCR to quantify virulence gene expression (babA, ureA, and vacA). Biocompatibility was assessed using defibrinated sheep erythrocytes, gastric epithelial cells (GES-1), and representative beneficial gut microbiota. Analysis of the clinical isolates revealed resistance rates of 63.6% for CLR/LVX and 81.8% for MNZ, with 54.5% identified as MDR. DT7-3 exhibited superior potency (MIC 1–32 µg/mL) against all strains, significantly outperforming its L-enantiomer counterparts. Mechanistic studies unveiled a “triple-hit” mechanism: (1) rapid membrane disruption; (2) potent inhibition of bacterial adhesion to host cells (~60% reduction at 0.5 × MIC); (3) significant downregulation of critical virulence factors (babA, ureA, and vacA). Furthermore, DT7-3 showed an excellent safety profile, with negligible hemolysis ( 32 relative to mammalian cells. Crucially, DT7-3 showed high selectivity for the pathogen over beneficial gut microbiota (MIC > 128 µg/mL, SI > 16). Crucially, DT7-3 maintained potent bactericidal activity (MIC ≤ 16 µg/mL) even under cholesterol-enriched conditions. The engineered D-peptide DT7-3 is a potent candidate for combating MDR H. pylori. Its multifaceted mechanism, targeting bacterial viability while suppressing core virulence factors, positions it as a robust lead compound for next-generation eradication therapies aimed at reducing the burden of H. pylori-associated diseases.