肠道共生菌调控2型糖尿病胰岛β细胞功能分化重塑的机制研究

宏基因组研究提示肠道共生菌群与2型糖尿病存在相关性，但缺乏因果关系验证。尚无研究报道肠道共生菌可不依赖于周围组织直接作用于胰岛β细胞。胰岛细胞功能的不可逆受损是2型糖尿病的核心病理生理机制。β细胞退分化或向α/δ细胞的转分化是胰岛功能障碍的主要机制之一，如能逆转该过程，或诱导其他细胞分化为成熟β细胞，将有望实现2型糖尿病临床治愈。改变组蛋白乙酰化酶及去乙酰化酶可重塑β细胞分化状态。次级胆汁酸和短链脂肪酸作为肠道共生菌主要代谢产物介导其对肠道上皮及免疫细胞组蛋白修饰的调控，继而影响细胞分化及功能。本课题前期研究证明共生菌胆汁酸组分促进降糖药物疗效，与β细胞功能相关。因此，我们假设肠道共生菌可通过次级代谢物胆汁酸、短链脂肪酸，调控组蛋白修饰，从表观基因组层面重塑β细胞分化状态。课题将从菌-代谢物-宿主胰岛细胞三个层面设计研究，阐明菌-代谢物-胰岛轴的分子调控通路，找到2型糖尿病治疗新靶点。

Irreversible declining β cell function is the key pathogenesis of Type 2 diabetes （T2D）. It has been well accepted that the dedifferentiation and transdifferentiation of pancreatic endocrine cells are major mechanisms contributing to functional β cell loss in T2D. On the other hand, exploring potential approach to reverse β cell dedifferentiation or to coax differentiation from other cell lineages to β cell have allured plenty of academic and economic interests. Thus, understanding the underlying mechanism of changing β cell fate or its plasticity is key to achieve above goals. The rapid development of high throughput next generation sequencing, have flourished the advances in genetics, epigenetics and metagenomics. The recent studies on single cell RNAseq, CHIPseq and ATACseq enable us to map the epigenome, cistrome and landscape of chromatin accessibility with the epigenetics codes of DNA methylation and histone posttranslational modifications (PTM) of key pancreas transcription factors which determine the fate of pancreatic islet cells. The progress of metagenomics studies on the correlation between gut microbiome and T2D urge studies to confirm the causality. The study to investigate the impact of gut microbiota on type 2 diabetes is also lacking. It has been recently proved that gut microbiome plays a indispensable role to maintain the histone PTM of host cells via its co-metabolites with host, such as short fatty acids and bile acids. Thus, we propose that the gut microbiota could impact the plasticity of β cell via altering histone or other proteins PTM of key pancreatic transcription factors by its secondary metabolites, bile acids in particular. We will perform the study on the chain of bacterial-metabolite-host interaction to elucidate the causality correlations between gut microbiota and T2D as well as the underlying mechanisms.