Çirkin Gül, Aydemir Selma, Açıkgöz Burcu, Çelik Aslı, Güler Yunus, Kiray Müge, Baykara Başak, Dinleyici Ener Çağrı, Öztürk Yeşim
Department of Pediatric Gastroenterology Hepatology and Nutrition, Faculty of Medicine, Dokuz Eylul University, Izmir 35340, Türkiye.
Department of Histology and Embryology, Faculty of Medicine, Dokuz Eylul University, Izmir 35340, Türkiye.
Int J Mol Sci. 2025 Sep 4;26(17):8616. doi: 10.3390/ijms26178616.
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) encompasses a spectrum of liver conditions and involves gut-liver axis crosstalk. We aimed to evaluate whether oral vancomycin modifies liver injury and the cecal microbiota in a methionine-choline-deficient (MCD) diet model of NASH. Male C57BL/6J mice (n = 28) were block-randomized to four groups (n = 7 each) for 10 weeks: standard diet (STD); MCD diet; STD + vancomycin (VANC); and MCD + VANC (2 mg/mouse ≈ 50 mg/kg, every 72 h). After 10 weeks, liver tissues were analyzed for histological changes, cytokine levels [interleukin-6 (IL-6), interleukin-8 (IL-8), transforming growth factor beta 1 (TGF-β1)], and immunohistochemical markers [ubiquitin and cytokeratin 18 (CK18)]. Cecal microbiota composition was evaluated with 16S ribosomal RNA (rRNA) sequencing. The MCD reproduced key NASH features (macrovesicular steatosis, lobular inflammation). Vancomycin shifted steatosis toward a microvesicular pattern and reduced hepatocyte injury: CK18 and ubiquitin immunoreactivity were decreased in MCD + VANC vs. MCD, and hepatic IL-8 and TGF-β1 levels were lower in MCD + VANC vs. STD. Taxonomically, STD mice had -rich microbiota. The MCD diet alone reduced alpha diversity (α-diversity), modestly lowered Firmicutes and increased /. Vancomycin alone caused a much larger collapse in richness, depleting Gram-positive commensals and promoting blooms of , , , and . In the MCD + VANC group, vancomycin profoundly remodeled the microbiota, eliminating key commensals (e.g., ) and enriching , , and . Oral vancomycin in the MCD model of NASH improved liver injury markers and altered steatosis morphology, but concurrently reprogrammed the gut into a low-diversity, pathobiont-enriched ecosystem with near-loss of . These findings highlight a therapeutic trade-off-hepatic benefit accompanied by microbiome cost-that should guide microbiota-targeted strategies for NAFLD/NASH.
非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）涵盖了一系列肝脏疾病，涉及肠-肝轴的相互作用。我们旨在评估口服万古霉素是否能改善蛋氨酸-胆碱缺乏（MCD）饮食诱导的NASH模型中的肝损伤和盲肠微生物群。将雄性C57BL/6J小鼠（n = 28）随机分为四组（每组n = 7），持续10周：标准饮食（STD）组；MCD饮食组；STD + 万古霉素（VANC）组；以及MCD + VANC组（2 mg/小鼠≈50 mg/kg，每72小时一次）。10周后，对肝脏组织进行组织学变化、细胞因子水平[白细胞介素-6（IL-6）、白细胞介素-8（IL-8）、转化生长因子β1（TGF-β1）]和免疫组化标志物[泛素和细胞角蛋白18（CK18）]分析。用16S核糖体RNA（rRNA）测序评估盲肠微生物群组成。MCD饮食重现了关键的NASH特征（大泡性脂肪变性、小叶炎症）。万古霉素使脂肪变性转变为微泡模式并减轻肝细胞损伤：与MCD组相比，MCD + VANC组中CK18和泛素免疫反应性降低，且与STD组相比，MCD + VANC组中肝脏IL-8和TGF-β1水平更低。从分类学角度来看，STD组小鼠具有丰富的微生物群。单独的MCD饮食降低了α多样性，适度降低了厚壁菌门并增加了……。单独使用万古霉素导致丰富度大幅下降，消耗了革兰氏阳性共生菌并促进了……、……、……和……的大量繁殖。在MCD + VANC组中，万古霉素深刻重塑了微生物群，消除了关键共生菌（如……）并富集了……、……和……。在NASH的MCD模型中，口服万古霉素改善了肝损伤标志物并改变了脂肪变性形态，但同时将肠道重新编程为低多样性、富含致病共生菌的生态系统，且……几乎消失。这些发现凸显了一种治疗权衡——肝脏获益伴随着微生物群代价——这应该指导针对NAFLD/NASH的微生物群靶向策略。
