RESUMEN
Hyperuricemia is a prevalent metabolic disorder that arises from abnormal purine metabolism and reduced excretion of uric acid (UA). The gut microbiota plays a significant role in the biosynthesis and excretion of UA. Probiotics capable of purine degradation possess the potential to prevent hyperuricemia. Our study aimed to screen probiotics in areas with abundant dairy products and longevity populations in China, which could attenuate the level of UA and explore the underlying mechanism. In this study, twenty-three lactic acid bacteria isolated from healthy Chinese infant feces and traditional fermented foods such as hurood and lump milk were evaluated for the ability to tolerance acid, bile, artificial gastric juice, and artificial intestinal juice to determine the potential of the candidate strains as probiotics. Eight strains were identified as possessing superior tolerance to simulated intestinal conditions and were further analyzed by high-performance liquid chromatography (HPLC), revealing that Limosilactobacillus reuteri HCS02-001 (Lact-1) and Lacticaseibacillus paracasei HCS17-040 (Lact-2) possess the most potent ability to degrade purine nucleosides. The effect of Lact-1 and Lact-2 on hyperuricemia was evaluated by intervening with them in the potassium oxonate and adenine-induced hyperuricemia Balb/c mice model in vivo. Our results showed that the level of serum UA in hyperuricemic mice can be efficiently reduced via the oral administration of Lact-1 (p < 0.05). It significantly inhibited the levels of liver inflammatory cytokines and hepatic xanthine oxidase through a TLR4/MyD88/NF-κB pathway across the gut-liver axis. Furthermore, UA transporters ABCG2 and SLC2A9 were substantially upregulated by the intervention of this probiotic. Fecal ATP levels were significantly induced, while fecal xanthine dehydrogenase and allantoinase levels were increased following probiotics. RNA sequencing of HT-29 cells line treated with Lact-1 and its metabolites demonstrated significant regulation of pathways related to hyperuricemia. In summary, these findings demonstrate that Limosilactobacillus reuteri HCS02-001 possesses a capacity to ameliorate hyperuricemia by inhibiting UA biosynthesis via enhancing gastrointestinal barrier functions and promoting UA removal through the upregulation of urate transporters, thereby providing a basis for the probiotic formulation by targeting the gut microbiota.
RESUMEN
Ferroptosis is an iron-dependent type of regulated cell death resulting from extensive lipid peroxidation and plays a critical role in various physiological and pathological processes. However, the regulatory mechanisms for ferroptosis sensitivity remain incompletely understood. Here, we report that homozygous deletion of Usp8 (ubiquitin-specific protease 8) in intestinal epithelial cells (IECs) leads to architectural changes in the colonic epithelium and shortens mouse lifespan accompanied by increased IEC death and signs of lipid peroxidation. However, mice with heterozygous deletion of Usp8 in IECs display normal phenotype and become resistant to azoxymethane/dextran sodium sulfate-induced colorectal tumorigenesis. Mechanistically, USP8 interacts with and deubiquitinates glutathione peroxidase 4 (GPX4), leading to GPX4 stabilization. Thus, USP8 inhibition destabilizes GPX4 and sensitizes cancer cells to ferroptosis in vitro. Notably, USP8 inhibition in combination with ferroptosis inducers retards tumor growth and enhances CD8+ T cell infiltration, which potentiates tumor response to anti-PD-1 immunotherapy in vivo. These findings uncover that USP8 counteracts ferroptosis by stabilizing GPX4 and highlight targeting USP8 as a potential therapeutic strategy to boost ferroptosis for enhancing cancer immunotherapy.