Oxygen battle in the gut: Hypoxia and hypoxia-inducible factors in metabolic and inflammatory responses in the intestine

Abstract

The gastrointestinal tract is a highly proliferative and regenerative tissue. The intestine also harbors a large and diverse microbial population collectively called the gut microbiome (microbiota). The microbiome-intestine cross-talk includes a dynamic exchange of gaseous signaling mediators generated by bacterial and intestinal metabolisms. Moreover, the microbiome initiates and maintains the hypoxic environment of the intestine that is critical for nutrient absorption, intestinal barrier function, and innate and adaptive immune responses in the mucosal cells of the intestine. The response to hypoxia is mediated by hypoxia-inducible factors (HIFs). In hypoxic conditions, the HIF activation regulates the expression of a cohort of genes that promote adaptation to hypoxia. Physiologically, HIF-dependent genes contribute to the aforementioned maintenance of epithelial barrier function, nutrient absorption, and immune regulation. However, chronic HIF activation exacerbates disease conditions, leading to intestinal injury, inflammation, and colorectal cancer. In this review, we aim to outline the major roles of physiological and pathological hypoxic conditions in the maintenance of intestinal homeostasis and in the onset and progression of disease with a major focus on understanding the complex pathophysiology of the intestine.

Keywords: HIF-2α; colitis; colon cancer; hypoxia; hypoxia-inducible factor (HIF); hypoxia-inducible factor 1α (HIF-1α); inflammation; inflammatory bowel disease (IBD); intestinal epithelium; intestinal metabolism; iron; iron metabolism; mucosal barrier.

Figure 1.

Intestinal O₂ and metabolic regulation. A, countercurrent blood flow reduces local pO₂ along the crypt-villus axis and the microbiome alters pO₂ from small intestine to the colon. B, transit-amplifying cells of the proximal small intestine rely on fatty acid oxidation (FAO) transcriptionally regulated by PRMD16 to support the differentiation of intestinal epithelial cells. Colonocytes rely on SCFAs for fuel. Increased utilization of SCFAs increases oxygen consumption and activates HIF activity, contributing to the basal hypoxic tone of the intestine. During high ATP demand in the intestine, HIF-1α can replenish the ATP pool via the PCr/CK system. C, Lgr5+ stem cells are dependent on lactate exchange from neighboring Paneth cells. Paneth cells fuel oxidative phosphorylation to maintain stemness and diets high in fat fuel fatty acid oxidation to increase the stemness of Lgr5 stem cell cells.

Figure 2.

Intestinal gas exchange and hypoxic signaling. In the presence of O₂, α-ketoglutarate (α-KG), and Fe²⁺, PHD enzymes hydroxylate the two proline residues on HIF, enabling the binding of VHL, a tumor suppressor protein, to the HIF-α subunit. VHL binding is coupled with E3 ubiquitin ligase activity, which degrades HIF-α subunits under normoxic conditions. As oxygen, iron, or α-ketoglutarate levels decrease in a cell, PHDs are no longer active. In addition, if succinate, fumarate, or ROS levels are elevated, PHD activity is decreased. HIF-α is stabilized and binds to ARNT to activate transcription of target genes. The intestinal cells, diet, and microbiome generate numerous gaseous signaling mediators that cross-talk with HIF signaling. NO, H₂S, and CO₂ inhibit HIF activity, whereas carbon monoxide and NH₃ activate HIF (red lines indicate inhibitory mechanism, and blue lines denote activation).

Figure 3.

The role of HIF-1α and HIF-2α in intestinal homeostasis. Activation of HIF-1α in the intestine induces a barrier-protective pathway by increasing mucus, defensin, and tight junctional proteins and replenishing the ATP pool during injury via the PCr/CK system. HIF-2α activation increases the expression of iron-absorptive genes and pro-inflammatory cytokines and chemokines.