<i>Lacticaseibacillus paracasei</i> FL5 Inhibits <i>Helicobacter pylori</i> by Regulating Gastric Microbiota and NF-κB Signaling Pathway

<i>Helicobacter pylori</i> (<i>H. pylori</i>) infection causes severe gastropathies, and antibiotic resistance calls for alternative therapies. In this study, <i>Lacticaseibacillus paracasei</i> FL5 was the most potent <i>H. pylori</i> antagonist, showing excellent coaggregation (97.93%), high cell surface hydrophobicity (>50%), significant urease inhibition (77.58%), and a 22.00 mm inhibition zone. In vitro, its secreted metabolites induce bacterial lysis and inhibit urease. In vivo, FL5 and IFL5 (inactivated FL5) treated <i>H. pylori</i>-induced gastritis, reducing <i>H. pylori</i> colonization, regulating oxidative stress, and repairing the mucosal barrier. They also modulated gastric microbial homeostasis and attenuated inflammation via the TLR2/MyD88/NF-κB pathway (decreased TNF-α/IL-1β/IL-6/CXCL1, increased IL-10/IL-4 and IgG). Interestingly, IFL5 demonstrated superior efficacy to live FL5 in inhibiting TLR2/NF-κB signaling, highlighting the retained immunomodulatory activity of the heat-inactivated derivative. These findings establish <i>L. paracasei</i> FL5 as a promising multitarget therapeutic approach.