Intestinal Epithelial Cells Respond to Chronic Inflammation and Dysbiosis by Synthesizing H2O2

Abstract

The microbes in the gastrointestinal tract are separated from the host by a single layer of intestinal epithelial cells (IECs) that plays pivotal roles in maintaining homeostasis by absorbing nutrients and providing a physical and immunological barrier to potential pathogens. Preservation of homeostasis requires the crosstalk between the epithelium and the microbial environment. One epithelial-driven innate immune mechanism that participates in host-microbe communication involves the release of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), toward the lumen. Phagocytes produce high amounts of ROS which is critical for microbicidal functions; the functional contribution of epithelial ROS, however, has been hindered by the lack of methodologies to reliably quantify extracellular release of ROS. Here, we used a modified Amplex Red assay to investigate the inflammatory and microbial regulation of IEC-generated H2O2 and the potential role of Duox2, a NADPH oxidase that is an important source of H2O2. We found that colonoids respond to interferon-γ and flagellin by enhancing production of H2O2 in a Duox2-mediated fashion. To extend these findings, we analyzed ex vivo production of H2O2 by IECs after acute and chronic inflammation, as well as after exposure to dysbiotic microbiota. While acute inflammation did not induce a significant increase in epithelial-driven H2O2, chronic inflammation caused IECs to release higher levels of H2O2. Furthermore, colonization of germ-free mice with dysbiotic microbiota from mice or patients with IBD resulted in increased H2O2 production compared with healthy controls. Collectively, these data suggest that IECs are capable of H2O2 production during chronic inflammation and dysbiotic states. Our results provide insight into luminal production of H2O2 by IECs as a read-out of innate defense by the mucosa.

The Future of Gastrointestinal Physiology: 2020 and Beyond

“…Frontiers in Gastrointestinal Sciences has played a significant role in publishing important papers in the emerging field. These include papers on the role of the gut microbiome in both alcoholic (Su et al, 2016;Yue et al, 2020;Zheng et al, 2020) and non-alcoholic (Bian et al, 2017;Porras et al, 2018;Zheng et al, 2018) liver disease; the role of sulfur metabolism by the microbiome on gut sensory signaling, colonic inflammation and cancer; (Carbonero et al, 2012;Bala et al, 2014;Guo et al, 2016;Burgueño et al, 2019;Fei et al, 2019;Song et al, 2019;Ren et al, 2020) glucose homeostasis and type 2 diabetes; (Lê et al, 2012;Su et al, 2016) tuberculosis (Luo et al, 2017) mood and behavior and Gulf war illness; (Grenham et al, 2011;Kimono et al, 2019) pulmonary tuberculosis; (Luo et al, 2017) and autoimmune pancreatitis (Haruta et al, 2012). Other papers provided information on the effects of xenobiotics, probiotics, vitamins, and medication affect the gut microbiome and physiology (Yang et al, 2015;Su et al, 2016;Atashgahi et al, 2018;Li et al, 2018;Zheng et al, 2018;Chang et al, 2019;Fei et al, 2019;Guan et al, 2019;Song et al, 2019;Xu et al, 2019;Zhu et al, 2020) while some addressed the interplay between endogenous processes and the gut microbiome including bile acids and cholesterol metabolism, adrenergic input and gut epithelial responses (Yang et al, 2017;Burgueño et al, 2019;Molinero et al, 2019).…”

Functional screen of Inflammatory bowel disease genes reveals key epithelial functions

“…Moreover, these pathophysiologic mechanisms extend beyond the classical physical barrier that epithelium provides and beyond the cells specialized in host defense, such as Paneth cells, that have previously been implicated by previous genetic studies of IBD (1,12,17,41,64,65,86). Moreover, this adds to the growing evidence in support of epithelial cells playing key roles in the local inflammatory processes (87)(88)(89). epithelial cells, had the strongest effect (1123 HITS).…”

How do immune and mesenchymal cells influence the intestinal epithelial cell compartment in inflammatory bowel disease? Let’s crosstalk about it!

“…IECs are the first line of defense in the GI tract providing a physical barrier to keep digested food, commensals, and pathogenic microorganisms from entering the body. They also provide an important chemical barrier, through secretion of electrolytes, mucins, anti‐microbial peptides, and reactive oxygen species (ROS) 4 . However, when chronic inflammation develops, IEC barrier function is disrupted, and this can further drive inflammation by promoting anti‐commensal T cell responses 5 .…”