Histone Deacetylase 3 orchestrates commensal bacteria-dependent intestinal homeostasis

The development and severity of inflammatory bowel diseases (IBD) and other chronic inflammatory conditions can be influenced by host genetic and environmental factors, including signals derived from commensal bacteria1-6. However, the mechanisms that integrate these diverse cues remain undefined. Here we demonstrate that intestinal epithelial cells (IECs) isolated from IBD patients exhibit decreased expression of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3). Further, genome-wide analyses of murine IECs that lack HDAC3 (HDAC3?IEC) revealed that HDAC3 deficiency resulted in dysregulated gene expression coupled with alterations in histone acetylation. Critically, conventionally-housed HDAC3?IEC mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3?IEC mice exhibited significantly increased susceptibility to intestinal damage and inflammation, indicating that epithelial expression of HDAC3 plays a central role in maintaining intestinal homeostasis. Strikingly, rederivation of HDAC3?IEC mice into germ-free conditions revealed that dysregulated IEC gene expression, Paneth cell homeostasis, and intestinal barrier function were largely restored in the absence of commensal bacteria. Collectively, these data indicate that the HDAC3 is a critical factor that integrates commensal bacteria-derived signals to calibrate epithelial cell responses required to establish normal host-commensal relationships and maintain intestinal homeostasis.

炎症性肠病（IBD）及其他慢性炎症性疾病的发生发展与严重程度，可受宿主遗传与环境因素调控，其中包括源自共生细菌的信号1-6。然而，整合这些多样信号的具体机制仍未阐明。本研究证实，从IBD患者体内分离的肠上皮细胞（intestinal epithelial cells, IECs）中，表观基因组修饰酶组蛋白去乙酰化酶3（HDAC3）的表达水平显著降低。进一步针对组蛋白去乙酰化酶3（HDAC3）缺失的小鼠肠上皮细胞（HDAC3^ΔIEC）开展的全基因组分析显示，HDAC3缺失会导致基因表达失调，并伴随组蛋白乙酰化水平改变。尤为关键的是，常规饲养的HDAC3^ΔIEC小鼠出现了潘氏细胞丢失、肠上皮细胞功能受损，以及肠道共生菌群组成改变的表型。此外，该类小鼠对肠道损伤与炎症的易感性显著升高，表明肠上皮细胞表达的HDAC3在维持肠道稳态中发挥核心作用。值得注意的是，将HDAC3^ΔIEC小鼠饲养于无菌环境后，其失调的肠上皮细胞基因表达、潘氏细胞稳态及肠道屏障功能在共生细菌缺失的情况下得到了显著恢复。综上，本研究数据表明，HDAC3是整合共生细菌来源信号的关键因子，可精准调控上皮细胞应答，从而建立正常的宿主-共生菌群互作关系并维持肠道稳态。