Shanghai Jiao Tong University School of Medicine Affiliated Sixth People's Hospital, Shanghai, China.
Digestive Endoscopic Center, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Microbiol Spectr. 2022 Oct 26;10(5):e0051822. doi: 10.1128/spectrum.00518-22. Epub 2022 Aug 29.
Cholesterol gallstone (CGS) disease is characterized by an imbalance in bile acid (BA) metabolism and is closely associated with gut microbiota disorders. However, the role and mechanism by which probiotics targeting the gut microbiota attenuate cholesterol gallstones are still unknown. In this study, Limosilactobacillus reuteri strain CGMCC 17942 and Lactiplantibacillus plantarum strain CGMCC 14407 were individually administered to lithogenic-diet (LD)-fed mice for 8 weeks. Both strains significantly reduced LD-induced gallstones, hepatic steatosis, and hyperlipidemia. These strains modulated BA profiles in the serum and liver, which may be responsible for the activation of farnesoid X receptor (FXR). At the molecular level, L. reuteri and L. plantarum increased ileal fibroblast growth factor 15 (FGF15) and hepatic fibroblast growth factor receptor 4 (FGFR4) and small heterodimer partner (SHP). Subsequently, hepatic cholesterol 7α-hydroxylase (CYP7A1) and oxysterol 7α-hydroxylase (CYP7B1) were inhibited. Moreover, the two strains enhanced BA transport by increasing the levels of hepatic multidrug resistance-associated protein homologs 3 and 4 (Mrp3/4), hepatic multidrug resistance protein 2 (Mdr2), and the bile salt export pump (BSEP). In addition, both L. reuteri and L. plantarum reduced LD-associated gut microbiota dysbiosis. L. reuteri increased the relative abundance of , while L. plantarum increased that of Akkermansia. The changed gut microbiota was significantly negatively correlated with the incidence of cholesterol gallstones and the FXR-antagonistic BAs in the liver and serum and with the FXR signaling pathways. Furthermore, the protective effects of the two strains were abolished by both global and intestine-specific FXR antagonists. These findings suggest that might relieve CGS through the FXR signaling pathways. Cholesterol gallstone (CGS) disease is prevalent worldwide. None of the medical options for prevention and treatment of CGS disease are recommended, and surgical management has a high rate of recurrence. It has been reported that the factors involved in metabolic syndrome are highly connected with CGS formation. While remodeling of dysbiosis of the gut microbiome during improvement of metabolic syndrome has been well studied, less is known about prevention of CGS formation after regulating the gut microbiome. We used the lithogenic diet (LD) to induce an experimental CGS model in C57BL/6J mice to investigate protection against CGS formation by Limosilactobacillus reuteri strain CGMCC 17942 and Lactiplantibacillus plantarum strain CGMCC 14407. We found that these L. reuteri and L. plantarum strains altered the bile acid composition in mice and improved the dysbiosis of the gut microbiome. These two strains prevented CGS formation by fully activating the hepatic and ileal FXR signaling pathways. They could be a promising therapeutic strategy for treating CGS or preventing its recurrence.
胆固醇结石（CGS）病的特征是胆汁酸（BA）代谢失衡，与肠道微生物群紊乱密切相关。然而，靶向肠道微生物群的益生菌减轻胆固醇结石的作用和机制仍不清楚。在这项研究中，鼠李糖乳杆菌 CGMCC 17942 和植物乳杆菌 CGMCC 14407 分别被给予致石饮食（LD）喂养的小鼠 8 周。两种菌株均显著减少 LD 诱导的胆结石、肝脂肪变性和高脂血症。这些菌株调节了血清和肝脏中的 BA 谱，这可能是法尼醇 X 受体（FXR）激活的原因。在分子水平上，鼠李糖乳杆菌和植物乳杆菌增加了回肠成纤维细胞生长因子 15（FGF15）和肝成纤维细胞生长因子受体 4（FGFR4）和小异二聚体伴侣（SHP）。随后，抑制了肝胆固醇 7α-羟化酶（CYP7A1）和氧化固醇 7α-羟化酶（CYP7B1）。此外，两种菌株通过增加肝多药耐药相关蛋白同源物 3 和 4（Mrp3/4）、肝多药耐药蛋白 2（Mdr2）和胆汁盐输出泵（BSEP）的水平来增强 BA 转运。此外，两种菌株都减少了 LD 相关的肠道微生物群失调。鼠李糖乳杆菌增加了 的相对丰度，而植物乳杆菌增加了阿克曼氏菌的相对丰度。改变的肠道微生物群与胆固醇结石的发生率以及肝脏和血清中的 FXR 拮抗型 BA 和 FXR 信号通路呈显著负相关。此外，两种菌株的保护作用均被全身和肠道特异性 FXR 拮抗剂所消除。这些发现表明，可能通过 FXR 信号通路缓解 CGS。胆固醇结石（CGS）病在全球范围内普遍存在。目前尚无预防和治疗 CGS 病的医学方法推荐，手术治疗的复发率很高。据报道，代谢综合征涉及的因素与 CGS 形成高度相关。虽然代谢综合征改善过程中肠道微生物群失调的重塑已得到充分研究，但关于调节肠道微生物群后预防 CGS 形成的研究较少。我们使用致石饮食（LD）在 C57BL/6J 小鼠中诱导实验性 CGS 模型，以研究鼠李糖乳杆菌 CGMCC 17942 和植物乳杆菌 CGMCC 14407 对 CGS 形成的保护作用。我们发现，这些鼠李糖乳杆菌和植物乳杆菌菌株改变了小鼠的胆汁酸组成，并改善了肠道微生物群的失调。这两种菌株通过完全激活肝和回肠 FXR 信号通路来预防 CGS 形成。它们可能是治疗 CGS 或预防其复发的一种有前途的治疗策略。
