Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease with a poorly defined etiology. Traditional fermented foods may serve as a potential source of therapeutic agents for UC, which can be applied as probiotics. Lactiplantibacillus plantarum HBM1, a strain with high gastrointestinal fluid tolerance, was isolated from fermented foodsoriginating from Bama, a longevity village. This study investigated its potential to alleviate intestinal barrier dysfunction and inflammation in both in vitro and in vivo UC models. We identified a fat-soluble component less than 3 kDa (FCLPS_l3000) from the HBM1 culture supernatant, and validated that it maintained tight junction protein expression and suppressesd pro-inflammatory cytokine release in an LPS-induced Caco-2/Raw264.7 co-culture UC model. Through combined analysis of transcriptomic and metabolomic analyses, we found that FCLPS_l3000 relieved barrier function damage and inflammation in the LPS-induced Caco-2/Raw264.7 cell co-culture model by regulating the TLR4/NLRP3/Caspase-1 axis. In animal experiments, we further confirmed that the improvement effects of FCLPS_l3000 and live HBM1 probiotics on DSS-induced UC were related to the TLR4/NLRP3/Caspase-1 axis. Additionally, FCLPS_l3000 and live HBM1 alleviated UC-induced neuronal damage and neuroinflammation, thereby improving accompanying secondary neurological dysfunction. Interestingly, FCLPS_l3000 demonstrated superior efficacy with live HBM1 across multiple indicators. Collectively, this work reveals novel active components and the underlying regulatory mechanisms of probiotic intervention for UC and underscores the therapeutic potential of probiotic derivatives. Our findings provide a new direction for the development of multi-target therapies for UC and associated neurological complications.