Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany.
University of Cologne, Faculty of Medicine, and University Hospital Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany; Department of Medicine, University of California San Diego, La Jolla, CA, USA.
J Hepatol. 2022 Apr;76(4):788-799. doi: 10.1016/j.jhep.2021.11.029. Epub 2021 Dec 10.
BACKGROUND & AIMS: Studies investigating the gut-liver axis have largely focused on bacteria, whereas little is known about commensal fungi. We characterized fecal fungi in patients with non-alcoholic fatty liver disease (NAFLD) and investigated their role in a fecal microbiome-humanized mouse model of Western diet-induced steatohepatitis.
We performed fungal internal transcribed spacer 2 sequencing using fecal samples from 78 patients with NAFLD, 16 controls and 73 patients with alcohol use disorder. Anti-Candida albicans (C. albicans) IgG was measured in blood samples from 17 controls and 79 patients with NAFLD. Songbird, a novel multinominal regression tool, was used to investigate mycobiome changes. Germ-free mice were colonized with feces from patients with non-alcoholic steatohepatitis (NASH), fed a Western diet for 20 weeks and treated with the antifungal amphotericin B.
The presence of non-obese NASH or F2-F4 fibrosis was associated with a distinct fecal mycobiome signature. Changes were characterized by an increased log-ratio for Mucor sp./Saccharomyces cerevisiae (S. cerevisiae) in patients with NASH and F2-F4 fibrosis. The C. albicans/S. cerevisiae log-ratio was significantly higher in non-obese patients with NASH when compared with non-obese patients with NAFL or controls. We observed a different fecal mycobiome composition in patients with NAFLD and advanced fibrosis compared to those with alcohol use disorder and advanced fibrosis. Plasma anti-C. albicans IgG was increased in patients with NAFLD and advanced fibrosis. Gnotobiotic mice, colonized with human NASH feces and treated with amphotericin B were protected from Western diet-induced steatohepatitis.
Non-obese patients with NAFLD and more advanced disease have a different fecal mycobiome composition to those with mild disease. Antifungal treatment ameliorates diet-induced steatohepatitis in mice. Intestinal fungi could be an attractive target to attenuate NASH.
Non-alcoholic fatty liver disease is one of the most common chronic liver diseases and is associated with changes in the fecal bacterial microbiome. We show that patients with non-alcoholic fatty liver disease and more severe disease stages have a specific composition of fecal fungi and an increased systemic immune response to Candida albicans. In a fecal microbiome-humanized mouse model of Western diet-induced steatohepatitis, we show that treatment with antifungals reduces liver damage.
研究肠道-肝脏轴的研究主要集中在细菌上，而关于共生真菌知之甚少。我们对非酒精性脂肪性肝病（NAFLD）患者的粪便真菌进行了特征分析，并在西方饮食诱导的脂肪性肝炎的粪便微生物群人源化小鼠模型中研究了其作用。
我们使用 78 例 NAFLD 患者、16 例对照者和 73 例酒精使用障碍患者的粪便样本进行真菌内部转录间隔 2 测序。使用 17 例对照者和 79 例 NAFLD 患者的血液样本测量抗白色念珠菌（C. albicans）IgG。使用新的多分类回归工具 Songbird 研究真菌组变化。无菌小鼠用非酒精性脂肪性肝炎（NASH）患者的粪便定植，用西方饮食喂养 20 周，并接受抗真菌药物两性霉素 B 治疗。
非肥胖性 NASH 或 F2-F4 纤维化的存在与明显的粪便真菌群特征相关。变化的特征是 Mucor sp./Saccharomyces cerevisiae（S. cerevisiae）的对数比在 NASH 患者和 F2-F4 纤维化患者中增加。与非肥胖性 NAFL 或对照者相比，非肥胖性 NASH 患者的 C. albicans/S. cerevisiae 对数比显著升高。与酒精使用障碍和晚期纤维化患者相比，NAFLD 患者和晚期纤维化患者的粪便真菌群组成不同。NAFLD 患者和晚期纤维化患者的血浆抗 C. albicans IgG 增加。用人类 NASH 粪便定植的无菌小鼠并用两性霉素 B 治疗可预防西方饮食诱导的脂肪性肝炎。
非肥胖性 NAFLD 患者和更严重疾病患者的粪便真菌群组成与轻度疾病患者不同。抗真菌治疗可改善小鼠饮食诱导的脂肪性肝炎。肠道真菌可能是减轻 NASH 的一个有吸引力的靶点。
非酒精性脂肪性肝病是最常见的慢性肝病之一，与粪便细菌微生物群的变化有关。我们表明，非酒精性脂肪性肝病患者和更严重的疾病阶段具有特定的粪便真菌组成和对白色念珠菌的系统性免疫反应增加。在西方饮食诱导的脂肪性肝炎的粪便微生物群人源化小鼠模型中，我们表明用抗真菌药物治疗可减少肝损伤。
