Yang Lianjun, You Ke, Wang Kun, Liu Bin, Chen Tao, Cui Zhifei, Zhang Dawei, Su Zhihai, Liu Xiang, Lu Hai
Department of Spine Surgery, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, Guangdong, China.
Faculty of Health Sciences, University of Macau, Macao, Macao SAR, China.
J Transl Med. 2025 Jul 1;23(1):715. doi: 10.1186/s12967-025-06681-2.
BACKGROUND: Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by progressive spinal fusion and systemic inflammation. Recent studies suggest that gut microbiota plays a crucial role in the pathogenesis of AS. METHODS: This study investigated the therapeutic effects of Limosilactobacillus reuteri (L. reuteri) on AS progression and its underlying mechanisms using a proteoglycan (PG)-induced mouse model. Female BALB/c mice (n = 10/group) were randomized into control group, PG group and PG + L. reuteri group. Disease severity was assessed via arthritis scores, Micro-CT images, and histopathology. Serum cytokines (IL-1β, IL-18, IL-17A, IL-23) were measured by ELISA. Intestinal barrier integrity was evaluated using FITC-dextran permeability, immunofluorescence (ZO-1, occludin), and colon histology. Gut microbiota (16S rRNA sequencing) and fecal metabolites (untargeted metabolomics) were analyzed. AhR/NLRP3 pathway activity was assessed via qRT-PCR (AhR, CYP1A1, CYP1B1, and NLRP3). RESULTS: Our findings demonstrated that L. reuteri significantly alleviated AS progression, as evidenced by reduced joint swelling and erythema, alongside a decreased arthritis index and paw thickness. Furthermore, treatment with L. reuteri resulted in a marked reduction in serum levels of pro-inflammatory cytokines, including IL-1β, IL-18, IL-17A, and IL-23, indicating its potential to modulate systemic inflammation. Additionally, L. reuteri enhanced intestinal mucosal barrier function, as demonstrated by improved histopathological integrity, reduced intestinal permeability, and restored expression of tight junction proteins ZO-1 and occludin. Moreover, L. reuteri treatment restored gut microbiota composition and metabolite profiles, aligning them more closely with control groups. Notably, L. reuteri may exert its effects partially through the AhR/NLRP3 pathway, as evidenced by increased mRNA levels of AhR, CYP1A1, and CYP1B1, along with reduced NLRP3 expression. CONCLUSION: In conclusion, L. reuteri effectively prevents the progression of AS in mice by restoring gut microbiota-metabolism homeostasis and modulating inflammatory pathways, highlighting its potential as a therapeutic agent for AS.
背景：强直性脊柱炎（AS）是一种慢性炎症性疾病，其特征为进行性脊柱融合和全身炎症。最近的研究表明，肠道微生物群在AS的发病机制中起关键作用。 方法：本研究使用蛋白聚糖（PG）诱导的小鼠模型，研究罗伊氏乳杆菌（L. reuteri）对AS进展的治疗效果及其潜在机制。将雌性BALB/c小鼠（每组n = 10只）随机分为对照组、PG组和PG + L. reuteri组。通过关节炎评分、Micro-CT图像和组织病理学评估疾病严重程度。采用酶联免疫吸附测定法（ELISA）检测血清细胞因子（IL-1β、IL-18、IL-17A、IL-23）。使用异硫氰酸荧光素-葡聚糖通透性、免疫荧光（ZO-1、闭合蛋白）和结肠组织学评估肠道屏障完整性。分析肠道微生物群（16S rRNA测序）和粪便代谢产物（非靶向代谢组学）。通过定量逆转录聚合酶链反应（qRT-PCR）（AhR、CYP1A1、CYP1B1和NLRP3）评估芳香烃受体（AhR）/NLRP3炎性小体通路活性。 结果：我们的研究结果表明，L. reuteri显著减轻了AS的进展，表现为关节肿胀和红斑减轻，同时关节炎指数和爪厚度降低。此外，L. reuteri治疗导致促炎细胞因子血清水平显著降低，包括IL-1β、IL-18、IL-17A和IL-23，表明其具有调节全身炎症的潜力。此外，L. reuteri增强了肠道黏膜屏障功能，表现为组织病理学完整性改善、肠道通透性降低以及紧密连接蛋白ZO-1和闭合蛋白的表达恢复。此外，L. reuteri治疗恢复了肠道微生物群组成和代谢产物谱，使其更接近对照组。值得注意的是，L. reuteri可能部分通过AhR/NLRP3通路发挥作用，表现为AhR mRNA水平升高、CYP1A1和CYP1B1表达增加，同时NLRP3表达降低。 结论：总之，L. reuteri通过恢复肠道微生物群-代谢稳态和调节炎症通路，有效预防了小鼠AS的进展，突出了其作为AS治疗药物的潜力。
Microbiome. 2024-12-20
Front Cell Infect Microbiol. 2024
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