Lacticaseibacillus rhamnosus alleviates hyperuricemia through a substrate-restriction mechanism whereby intracellular nucleoside hydrolases convert guanosine and inosine into poorly absorbed purine bases, thereby limiting intestinal nucleoside uptake and reducing hepatic substrate supply for urate synthesis.
Key Findings
Methods
L. rhamnosus was isolated from traditional fermented dairy products and demonstrated nucleoside-degrading probiotic properties.
The strain was isolated from traditional fermented dairy products.
The strain was identified as Lacticaseibacillus rhamnosus.
The strain exhibited nucleoside-degrading activity, specifically acting on guanosine and inosine.
Results
L. rhamnosus significantly reduced serum urate levels in a hyperuricemia rat model.
The urate-lowering effect was demonstrated in a hyperuricemia rat model.
Serum urate levels were significantly reduced following L. rhamnosus administration.
The reduction in serum urate was a statistically significant finding in the animal model.
Results
L. rhamnosus reduced serum urate levels without altering renal urate transporter expression, indicating a mechanism independent of renal excretion.
Renal urate transporter expression was measured and found to be unaltered by L. rhamnosus treatment.
This finding suggested the urate-lowering mechanism operates upstream of renal excretion.
The mechanism was described as 'independent of renal excretion,' distinguishing it from previously characterized microbiota-based strategies.
Results
L. rhamnosus expresses intracellular nucleoside hydrolases that convert guanosine and inosine into poorly absorbed purine bases, limiting intestinal nucleoside uptake.
Multi-omics and Caco-2 cell assays were used to reveal the mechanism.
The hydrolases act intracellularly to convert guanosine and inosine into purine bases.
The resulting purine bases are poorly absorbed in the intestine, thereby reducing substrate availability for hepatic urate synthesis.
This mechanism was characterized as 'substrate-restriction,' described as 'previously uncharacterized' for probiotics in the context of hyperuricemia.
Results
Two key nucleoside hydrolases were functionally validated by gene cloning and enzymatic assays.
Two specific hydrolase genes from L. rhamnosus were cloned.
Enzymatic assays confirmed the functional activity of the two hydrolases.
The validated hydrolases were identified as the key enzymes responsible for nucleoside degradation activity of the strain.
Results
L. rhamnosus reshaped gut microbial composition, modulated host metabolic pathways, and alleviated systemic inflammation in the hyperuricemia model.
Gut microbial composition was altered following L. rhamnosus administration.
Host metabolic pathways were modulated as detected through multi-omics analysis.
Systemic inflammation was alleviated in the treated animals.
These effects were observed in addition to the primary substrate-restriction mechanism.