Nagano Ayaka, Tsuruno Yudai, Sugita Koshiro, Onishi Shun, Tabata Yumiko, Kedoin Chihiro, Murakami Masakazu, Yano Keisuke, Harumatsu Toshio, Kawano Takafumi, Hasuzawa Nao, Nomura Masatoshi, Kaji Tatsuru, Ieiri Satoshi
Department of Pediatric Surgery, Medical and Dental Area, Research and Education Assembly, Research Field in Medical and Health Sciences, Kagoshima University, Kagoshima, Japan.
Division of Pediatric Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
Pediatr Surg Int. 2025 Aug 18;41(1):254. doi: 10.1007/s00383-025-06155-y.
Previous research suggests that clodronate, a vesicular nucleotide transporter inhibitor, may suppress intestinal failure-associated liver disease (IFALD) in short bowel syndrome (SBS). The present study investigated the effects of clodronate on the gut microbiota and colonic barrier in SBS rat model.
Sprague-Dawley rats underwent 90% small bowel resection and then were randomized into three groups (n = 8 each): SBS/TPN (Control), SBS/TPN with low-dose clodronate (Low, 20 mg/kg/day), and SBS/TPN with high-dose clodronate (High, 60 mg/kg/day). After 7 days, fecal and colon samples were collected to analyze the gut microbiota, histological findings, gene expression of tight junction, and inflammatory markers.
While alpha diversity showed no significant differences between the groups, high-dose clodronate-induced heterogeneity in the bacterial community structure. At the phylum level, the Firmicutes/Bacteroidota ratio significantly decreased in the High group. The crypt depth at distal colon was significantly deepest in the High group (p = 0.01). The Claudin-1 expression decreased significantly in the Low group in proximal colon (p = 0.019). The NLRP3 and IL-6 expressions in proximal colon showed significant differences among the groups (NLRP3: p < 0.001, IL-6: p = 0.021).
Clodronate-induced alterations in the gut microbiota may contribute to IFALD suppression, albeit with potentially adverse effects on the colonic barrier.
先前的研究表明，氯膦酸盐作为一种囊泡核苷酸转运体抑制剂，可能会抑制短肠综合征（SBS）患者的肠衰竭相关肝病（IFALD）。本研究调查了氯膦酸盐对SBS大鼠模型肠道微生物群和结肠屏障的影响。
将Sprague-Dawley大鼠进行90%小肠切除术，然后随机分为三组（每组n = 8）：SBS/TPN（对照组）、低剂量氯膦酸盐的SBS/TPN组（低剂量组，20 mg/kg/天）和高剂量氯膦酸盐的SBS/TPN组（高剂量组，60 mg/kg/天）。7天后，收集粪便和结肠样本，分析肠道微生物群、组织学结果、紧密连接的基因表达和炎症标志物。
虽然α多样性在各组之间没有显著差异，但高剂量氯膦酸盐导致细菌群落结构出现异质性。在门水平上，高剂量组的厚壁菌门/拟杆菌门比率显著降低。高剂量组远端结肠的隐窝深度显著最深（p = 0.01）。低剂量组近端结肠中Claudin-1的表达显著降低（p = 0.019）。各组近端结肠中NLRP3和IL-6的表达存在显著差异（NLRP3：p < 0.001，IL-6：p = 0.021）。
氯膦酸盐引起的肠道微生物群改变可能有助于抑制IFALD，尽管可能对结肠屏障有潜在的不利影响。
