Background/Objectives: Helicobacter pylori is a major contributor to gastric infections; it is prevalent in humans and associated with gastrointestinal diseases. In recent years, the increase in antimicrobial resistance has contributed to the need for alternative approaches, prompting interest in natural products with antimicrobial and antivirulence properties. This study investigated the effect of bioaccessible melanoidins from common and soft bread crust against H. pylori infection. Methods: Melanoidins were extracted using dead-end ultrafiltration, and bioaccessible fractions were obtained through in vitro digestion. The bactericidal effect of melanoidins was assessed at 2% and 4% concentrations over 24 and 48 h. The effect on H. pylori adhesion of 100 μg/mL and 200 μg/mL of gastric and intestinal bioaccessible fractions of melanoidins was evaluated in Caco-2 cells. Results: The bactericidal effect of melanoidins revealed significant efficacy, with a greater effect for soft bread melanoidins. The gastric fractions exhibited a higher inhibitory effect, which is crucial for gastric mucosa, the primary site of H. pylori infection. Both bioaccessible fractions showed anti-inflammatory and antioxidant effects against H. pylori-induced inflammation, particularly in the gastric fractions. This was evidenced by a reduction in interleukin-6 and interleukin-8 release and an enhancement in interleukin-10 release. The observed reduction in reactive oxygen species (ROS) and the maintenance of glutathione levels indicate an improved redox status. Conclusions: This study emphasizes the potential of melanoidins, especially from soft bread, as bioactive compounds against H. pylori, offering insights for future functional food development.
