Spontaneous episodic inflammation in the intestines of mice lacking HNF4A is driven by microbiota and associated with early life microbiota alterations.
Spontaneous episodic inflammation in the intestines of mice lacking HNF4A is driven by microbiota and associated with early life microbiota alterations.
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DOI：
10.1128/mbio.01504-23
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发表时间：
2023-08-31
期刊：
影响因子：
6.4
通讯作者：
Rawls, John F.
中科院分区：
文献类型：
--
作者：
Kelly, Cecelia;Jawahar, Jayanth;Davey, Lauren;Everitt, Jeffrey I.;Galanko, Joseph A.;Anderson, Chelsea;Avendano, Jonathan E.;McCann, Jessica R.;Sartor, R. Balfour;Valdivia, Raphael H.;Rawls, John F.
关键词：
炎症性肠病（IBD）发生在遗传易感个体中，这些个体对其微生物群产生不适当的免疫反应，导致慢性肠道炎症。虽然IBD的临床表现已得到很好的描述，但微生物群和宿主基因型之间的相互作用如何影响疾病的早期亚临床阶段仍不清楚。转录因子肝细胞核因子4 α（HNF 4A）与人类IBD相关，小鼠肠上皮细胞（IEC）中Hnf 4a的缺失（Hnf 4a ΔIEC）导致6-12月龄的自发性结肠炎症。在这里，我们测试了Hnf 4a ΔIEC小鼠的病理学是否在生命早期开始，以及微生物群是否有助于这一过程。纵向分析显示，在无特定病原体（SPF）条件下饲养的Hnf 4a ΔIEC小鼠从4-5周龄开始出现偶发性粪便脂质运载蛋白2（Lcn 2）升高和稀便。终生累积Lcn 2水平与12个月时结肠炎的组织病理学特征相关。抗生素和细菌学试验表明，Hnf 4a ΔIEC小鼠的这些表型依赖于微生物群。SPF Hnf 4a ΔIEC和对照小鼠的粪便16 S rRNA基因测序显示，基因型显著导致了12个月内微生物群组成的差异，对具有最高寿命累积Lcn 2的Hnf 4a ΔIEC小鼠的纵向分析显示，当首次检测到粪便Lcn 2升高时，微生物群落差异在生命早期出现。这些微生物群差异包括Hnf 4a ΔIEC小鼠中嗜粘蛋白阿克曼氏菌的一个新亚群的富集。我们得出结论，HNF 4A在IEC中发挥作用，以塑造肠道微生物群的组成，并在整个生命周期中保护免受微生物群诱导的偶发性炎症。炎症性肠病（IBD）以肠道慢性炎症为特征，影响着全世界数百万人。虽然IBD的临床管理已经取得了重大进展，但IBD的早期亚临床阶段尚未明确定义，并且难以在人体中进行研究。这项工作探讨了肠道上皮中缺乏IBD相关转录因子HNF 4A的小鼠疾病的亚临床阶段。虽然这些小鼠直到成年后期才出现明显的疾病，但我们发现它们在生命的早期阶段就开始出现偶发性肠道炎症，稀便和微生物群变化。使用无菌和抗生素治疗实验，我们揭示了这些小鼠的肠道炎症依赖于微生物群的存在。这些结果表明，宿主基因型和微生物群之间的相互作用可以驱动IBD明显发作之前的早期亚临床病理，并描述了探索这些重要过程的小鼠模型。
The inflammatory bowel diseases (IBD) occur in genetically susceptible individuals who mount inappropriate immune responses to their microbiota leading to chronic intestinal inflammation. Whereas IBD clinical presentation is well described, how interactions between microbiota and host genotype impact early subclinical stages of the disease remains unclear. The transcription factor hepatocyte nuclear factor 4 alpha (HNF4A) has been associated with human IBD, and deletion of Hnf4a in intestinal epithelial cells (IECs) in mice (Hnf4aΔIEC) leads to spontaneous colonic inflammation by 6–12 mo of age. Here, we tested if pathology in Hnf4aΔIEC mice begins earlier in life and if microbiota contribute to that process. Longitudinal analysis revealed that Hnf4aΔIEC mice reared in specific pathogen-free (SPF) conditions develop episodic elevated fecal lipocalin 2 (Lcn2) and loose stools beginning by 4–5 wk of age. Lifetime cumulative Lcn2 levels correlated with histopathological features of colitis at 12 mo. Antibiotic and gnotobiotic tests showed that these phenotypes in Hnf4aΔIEC mice were dependent on microbiota. Fecal 16S rRNA gene sequencing in SPF Hnf4aΔIEC and control mice disclosed that genotype significantly contributed to differences in microbiota composition by 12 mo, and longitudinal analysis of the Hnf4aΔIEC mice with the highest lifetime cumulative Lcn2 revealed that microbial community differences emerged early in life when elevated fecal Lcn2 was first detected. These microbiota differences included enrichment of a novel phylogroup of Akkermansia muciniphila in Hnf4aΔIEC mice. We conclude that HNF4A functions in IEC to shape composition of the gut microbiota and protect against episodic inflammation induced by microbiota throughout the lifespan. The inflammatory bowel diseases (IBD), characterized by chronic inflammation of the intestine, affect millions of people around the world. Although significant advances have been made in the clinical management of IBD, the early subclinical stages of IBD are not well defined and are difficult to study in humans. This work explores the subclinical stages of disease in mice lacking the IBD-associated transcription factor HNF4A in the intestinal epithelium. Whereas these mice do not develop overt disease until late in adulthood, we find that they display episodic intestinal inflammation, loose stools, and microbiota changes beginning in very early life stages. Using germ-free and antibiotic-treatment experiments, we reveal that intestinal inflammation in these mice was dependent on the presence of microbiota. These results suggest that interactions between host genotype and microbiota can drive early subclinical pathologies that precede the overt onset of IBD and describe a mouse model to explore those important processes.
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Strachan, David P.
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影响因子：
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作者：
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通讯作者：
Inoue, Yusuke