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

• Published in: The Journal of biological chemistry Vol. 295; no. 30; pp. 10493 - 10505
• Main Authors: Singhal, Rashi, Shah, Yatrik M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.07.2020; American Society for Biochemistry and Molecular Biology
• Subjects: Adaptive Immunity; Animals; Basic Helix-Loop-Helix Transcription Factors - immunology; colitis; colon cancer; Colorectal Neoplasms - blood supply; Colorectal Neoplasms - immunology; Colorectal Neoplasms - microbiology; Colorectal Neoplasms - pathology; Gastrointestinal Microbiome - immunology; HIF-2α; Humans; hypoxia; Hypoxia - immunology; Hypoxia - microbiology; Hypoxia - pathology; hypoxia-inducible factor (HIF); hypoxia-inducible factor 1α (HIF-1α); Immunity, Innate; inflammation; Inflammation - immunology; Inflammation - microbiology; Inflammation - pathology; inflammatory bowel disease (IBD); intestinal epithelium; intestinal metabolism; Intestinal Mucosa - blood supply; Intestinal Mucosa - immunology; Intestinal Mucosa - microbiology; Intestinal Mucosa - pathology; iron; iron metabolism; JBC Reviews; mucosal barrier; Oxygen - immunology; hypoxia; colitis; HIF-2α; colon cancer; inflammatory bowel disease (IBD); hypoxia-inducible factor 1α (HIF-1α); iron metabolism; hypoxia-inducible factor (HIF); mucosal barrier; inflammation; iron; intestinal epithelium; intestinal metabolism
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.REV120.011188

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