Increasing evidence shows that the early lesions of Parkinson's disease (PD) originate from gut, and correction of microbiota dysbiosis is a promising therapy for PD. FLZ is a neuroprotective agent on PD, which has been validated capable of alleviating microbiota dysbiosis in PD mice. However, the detailed mechanisms still need elucidated. Through metabolomics and 16S rRNA analysis, we identified glycoursodeoxycholic acid (GUDCA) was the most affected differential microbial metabolite by FLZ treatment, which was specially and negatively regulated by Clostridium innocuum, a differential microbiota with the strongest correlation to GUDCA production, through inhibiting bile salt hydrolase (BSH) enzyme. The protection of GUDCA on colon and brain were also clarified in PD models, showing that it could activate Nrf2 pathway, further validating that FLZ protected dopaminergic neurons through promoting GUDCA production. Our study uncovered that FLZ improved PD through microbiota-gut-brain axis, and also gave insights into modulation of microbial metabolites may serve as an important strategy for treating PD.

Although enteric glial cell (EGC) abnormal activation is reported to be involved in the pathogenesis of Parkinson's disease (PD), and inhibition of EGC gliosis alleviated gut and dopaminergic neuronal dysfunction was verified in our previous study, the potential role of gut microbiota on EGC function in PD still need to be addressed. In the present study, fecal microbiota transplantation revealed that EGC function was regulated by gut microbiota. By employing 16S rRNA and metabolomic analysis, we identified that 3-indolepropionic acid (IPA) was the most affected differential microbial metabolite that regulated EGC gliosis. The protective effects of IPA on PD were validated in rotenone-stimulated EGCs and rotenone (30 mg/kg i.g. for 4 weeks)-induced PD mice, as indicated by decreased inflammation, improved intestinal and brain barrier as well as dopaminergic neuronal function. Mechanistic study showed that IPA targeted pregnane X receptor (PXR) in EGCs, and inhibition of IL-13Rα1 involved cytokine-cytokine receptor interaction pathway, leading to inactivation of downstream JAK1-STAT6 pathway. Our data not only provided evidence that EGC gliosis was critical in spreading intestinal damage to brain, but also highlighted the potential role of microbial metabolite IPA in alleviating PD pathological damages through gut-brain axis.

[This corrects the article DOI: 10.1016/j.apsb.2025.02.029.].

Objective To discuss the influence of μ-opioid receptor ( OPRM1) and CYP3A gene polymor-phism on analgesic effect of fentanyl for abdominal hysterectomy patients .Methods 198 cases of gynecologic anes-thesia patients who were treated by elective abdominal hysterectomy surgery ,were selected in the hospital .The rela-tionship between the fentanyl consumption of intravenous analgesia and OPRMI and CYP 3A gene polymorphisms was detected by using polymerase chain reaction-restriction fragment length polymorphism detection .Results In 198 pa-tients,OPRM1 genotyping was 186 cases,the other 10 patients failed to typing were excluded ,including 89 cases of type A/A,type A/G 76 cases,type G/G 21 cases,OPRM1 the frequency of A118G allele was 31.7%.No statistically significant differences were found in mean VAS score of CYP 3A4*1/*1,CYP3A4*1/*1G,CYP3A4*1G/*1G instantly after operation in the three groups and 24h postoperation.By using analysis of variance with body mass ,age and intraoperative volume as a covariate factors after first 24h fentanyl consumption ,the difference was statistically sig-nificant among the three groups (P<0.05),CYP3A4*1G/*1G group was significantly lower than that in CYP3A4*1/*1G group and CYP3A4*1/*1 group,there was no significant difference between CYP 3A4*1/*1G group and CYP3A4*1/*1 group (P>0.05).In addition,because the OPRM1 A118G interacts with CYP3A4*1G, reducedthe quantity of expression of opioid receptor carrying CYP 3A4*1 and OPRM1 A118G/G,and thus more fent-anyl was needed postoperation to achieve the same effect .Conclusion It provided a theoretical basis and reference for clinical application of personalized medicine by analyzing the gynecological patients μopioid receptor gene A118G and CYP3A4*1G polymorphism.