Oxygen metabolism and barrier regulation in the intestinal mucosa

Abstract

Mucosal surfaces are lined by epithelial cells and provide an important barrier to the flux of antigens from the outside. This barrier is provided at a number of levels, including epithelial junctional complexes, mucus production, and mucosa-derived antimicrobials. Tissue metabolism is central to the maintenance of homeostasis in the mucosa. In the intestine, for example, baseline pO2 levels are uniquely low due to counter-current blood flow and the presence of large numbers of bacteria. As such, hypoxia and HIF signaling predominates normal intestinal metabolism and barrier regulation during both homeostasis and active inflammation. Contributing factors that elicit important adaptive responses within the mucosa include the transcriptional regulation of tight junction proteins, metabolic regulation of barrier components, and changes in autophagic flux. Here, we review recent literature around the topic of hypoxia and barrier function in health and during disease.

Figure 1. Physiologic hypoxia and barrier regulation in the healthy intestinal mucosa.

(A) Localization of low pO₂ along the crypt-villus axis and the presence of “physiologic hypoxia.” Colonic mucosa of healthy mice retain small amounts of nitroimidazole adduct (Hypoxyprobe) that is detected along the luminal aspect of the colon (red). Blue depicts nuclei counterstaining with Dapi. (B) A mechanism in which microbially derived SCFAs, such as butyrate, elicit increased O₂ consumption to the extent that HIF is stabilized and transcriptionally active. Also shown here are barrier-related pathways that are directly regulated by HIF. (Cr, creatine; PCr, phosphocreatine; HIF, hypoxia-inducible factor; CK, creatine kinase; CLDN1, claudin-1; ITF, intestinal trefoil factor).

Figure 2. Epithelial autophagy and barrier function.

IBD results from dysregulated microbial, epithelial, and immune cell interactions. Autophagy is a key host defense mechanism for epithelial barrier protection against invasive bacteria and metabolic stressors during mucosal inflammation. IBD-associated mutations in autophagy genes have been linked to dysregulated IEC mitophagy, xenophagy, goblet cell mucus secretion, and paneth cell ER stress responses. Although the role of HIF in IEC-intrinsic autophagy in vivo has not yet been characterized, HIF has been identified as a transcriptional regulator of mitochondrial autophagy and xenophagy of IBD-associated AIEC under hypoxic conditions in vitro.