Background: Obesity is a highly prevalent chronic disease characterized by excessive weight gain and fat accumulation. There is growing evidence that Lactiplantibacillus plantarum strains with bile salt hydrolase (BSH) activity are effective in preventing and alleviating obesity. Methods: Initially, we screened bacterial strains with high hydrolytic activity against glycochenodeoxycholic acid (GDCA), and constructed an isogenic bsh1 knockout mutant. Subsequently, male C57BL/6J mice fed a high-fat diet (HFD) were randomly assigned to receive daily gavage of either the wild-type Lp20 (Lp20-WT) or the bsh1-deficient mutant (Lp20-Δbsh1) for 8 weeks. Serum cholesterol levels and histopathological changes in liver sections were monitored. Hepatic gene expression was quantified by RT-qPCR, and fecal bacterial communities were analyzed via 16S rRNA gene sequencing. These comprehensive assessments aimed to evaluate metabolic improvements and uncover the potential mechanisms behind the observed effects. Results:L. plantarum Lp20 hydrolyzed 91.62% of GDCA, exhibiting the highest bile-salt hydrolase (BSH) activity among tested isolates. Whole-genome sequencing and in-silico analyses mapped this activity to bsh1; gene deletion of bsh1 confirmed the role of bsh1 in GDCA hydrolysis. Daily gavage of the wild-type strain (Lp20-WT) to diet-induced obese mice markedly attenuated weight gain, reduced inguinal white adipose tissue and mesenteric fat mass, and lowered serum TC and LDL-C by 20.8% and 33.3%, respectively, while decreasing ALT and AST levels and reversing hepatic steatosis. In contrast, the bsh1-null mutant (Lp20-Δbsh1) failed to elicit any measurable metabolic benefit. Mechanistically, Lp20-WT upregulated rate-limiting bile-acid synthetic enzymes CYP7A1 and CYP27A1, thereby accelerating the catabolism of cholesterol into bile acids. Concurrently, it activated hepatic TGR5 and FXR signaling axes to modulate hepatic metabolism. Moreover, Lp20-WT restructured the gut microbiota by notably enhancing the abundance of beneficial bacteria such as norank_f__Muribaculaceae, Akkermansia, and Alistipes, while reducing the abundance of potentially harmful taxa, including norank_f__Desulfovibrionaceae, Dubosiella, and Mucispirillum. Conclusions: This study provides direct evidence of BSH’s anti-obesity effects through gene deletion. Specifically, BSH lowers cholesterol by modulating hepatic bile-acid metabolism-related gene expression and altering the gut microbiota composition. However, the study is limited by a small sample size (n = 6), the use of male mice only, and its preclinical stage, indicating a need for further validation across diverse strains and human populations.

Pain is an unpleasant but essential sensory experience that serves as a protective mechanism, yet it can also manifest maladaptively in a wide range of pathological conditions. Current analgesic strategies rely heavily on opioid medications and non-steroidal anti-inflammatory drugs (NSAIDs); however, concerns regarding addiction, tolerance, and dose-limiting adverse effects highlight the urgent need for safer and more effective therapeutics. Voltage-gated sodium (Na_v) channels, which govern the initiation and propagation of action potentials, have emerged as promising targets for mechanism-based analgesic development. In particular, the Na_v1.7–Na_v1.9 subtypes have attracted substantial interest owing to their enrichment in the peripheral nervous system—despite broader expression elsewhere—and their central roles in nociception, offering the potential for non-addictive, subtype-selective pain modulation. This review summarizes the physiological roles of these channels in nociception, examines how disease-associated mutations shape pain phenotypes, and highlights recent advances in drug discovery targeting Na_v1.7 and Na_v1.8. The recent FDA approval of VX-548 (suzetrigine), a first-in-class and highly selective Na_v1.8 inhibitor, marks a major milestone that validates peripheral Na_v channels as clinically actionable targets for analgesia. We also discuss the remaining challenges and emerging opportunities in the pursuit of next-generation, mechanism-informed analgesics.