Abstract body - Sulforaphane (SFN), a foodborne compound, exhibits notable antibiotic properties against Helicobacter pylori (H. pylori). However, its utility is limited by poor stability and susceptibility to environmental degradation. Here, we developed a gastric-responsive-release microgel for delivering antibiotic SFN. The layer-modified microgels were formed by chitosan coating on cross-linked α-lactalbumin nanotubes microgels (CTS-MGs). The CTS-MG exhibited high stability in the stomach condition and protected SFN from early degradation. The microgels also showed strong adhesion to the gastric mucosa, prolonging gastric retention for up to 24 h and responsively releasing SFN. Furthermore, CTS-MG/SFN dissociated and released nanotubes/SFN, which could penetrate into the gastric mucus layer and arrived at the gastric epithelial cells surface colonized by H. pylori . Our results revealed that CTS-MG/SFN displayed an obvious inhibitory effect against H. pylori. The gavage administration of CTS-MG/SFN in H. pylori-infected mice effectively mitigated H. pylori-induced gastritis and modulated gastric microbiota homeostasis. This work demonstrated high potential of CTS-MG microgels for gastric-targeted and oral delivery of antibiotic natural compounds against H. pylori infection.