Intestinal Homeostasis

Ileum IHC

The gastrointestinal (GI) tract is an organ system not only absorbing nutrients from food, but also secreting a large body of endocrine hormones, and possessing a rich defensive arsenal of immune cells. The organ is constantly challenged by the changing environment to balance its primary functions of nutrient uptake and host defense. Inability of the GI tract in adapting to environmental changes leads to diseases such as obesity, malabsorption, autoimmune, and inflammation.  We aim to characterize how the GI tract relays signals from food, microbiota and parasites to regulate body weight, glucose metabolism, and immune responses.

Intestinal inflammation

In genetically susceptible humans, inappropriate activation of immune cells and the resulting chronic inflammation in response to infiltrating commensal and/or pathogenic microbial species lead to inflammatory bowel disease (IBD). Intestinal epithelial cells (IECs) establish a barrier between the luminal and the internal environment, placing IECs at the center of interactions between the mucosal immune system and luminal antigens/metabolites. A healthy and robust layer of IECs is required for intestinal homeostasis. Defects in IECs cause intestinal inflammation in animal models and are associated with IBD in humans.

Microbe-host interactions

The commensal microbiota, as an "organ", has significant impact on host physiology by producing microbe-associated molecular patterns and bioactive metabolites such as short-chain fatty acids and secondary bile acids. We found that intestinal epithelial levels of O-GlcNAcylation are controlled by gut microbiota and type 2 immune signals. Optimal O-GlcNAc signaling in intestinal epithelial cells is required for the fitness of intestinal epithelium, the control of enteroendocrine lineage development and function, and tuft cell-mediated type 2 immune responses to helminth infections.

Related publications:

1. Zhao M, Ren K, Xiong X, Xin Y, Zou Y, Maynard JC, Kim A, Battist AP, Koneripalli N, Wang Y, Chen Q, Xin R, Yang C, Huang R, Yu J, Huang Z, Zhang Z, Wang H, Wang D, Xiao Y, Salgado OC, Jarjour NN, Hogquist KA, Revelo XS, Burlingame AL, Gao X, von Moltke J, Lin Z, Ruan HB. (2022). Epithelial STAT6 O-GlcNAcylation drives anti-helminth immunity via a concerted anti-helminth alarmin response dependent on tuft cell hyperplasia and Gasdermin C. Immunity. 55(4), 623–638. DOI: 10.1016/j.immuni.2022.03.009.
2. Zhao M, Ren K, Xiong X, Cheng M, Zhang Z, Huang Z, Han X, Yang X, Alejandro EU, Ruan HB. (2020). Protein O-GlcNAc modification links dietary and gut microbial cues to the differentiation of enteroendocrine L cells. Cell Reports. 32(6): 108013. doi: /10.1016/j.celrep.2020.108013.
3. Zhao M, Xiong XW, Ren K, Xu B, Cheng M, Sahu C, Wu K, Nie Y, Huang Z, Blumberg RS, Han X, Ruan HB. (2018). Deficiency in intestinal epithelial O-GlcNAcylation predisposes to gut inflammation. EMBO Molecular Medicine. doi: 10.15252/emmm.201708736.

Microbiota, IECs, and immune cells—a trio in IBD