Hypoxia and HIF-1 as key regulators of gut microbiota and host interactions

Oxygen consumption by mammalian intestinal epithelial cells (IECs) results in intestinal hypoxia, which is stimulated by metabolites (short-chain fatty acids, SCFAs) derived from the microbiota. Hypoxia and activation of hypoxia-inducible factor (HIF)-responses are relevant for IEC metabolism, regulation of epithelial barrier function, and gut microbiota segregation in humans and mice. The activation of type-3 innate lymphoid cells (ILC3) and their key cytokine production are boosted in hypoxia through a HIF-1-dependent mechanism in mice, an effect that may be partly due to SCFAs. Strategies that contribute to the maintenance or re-establishment of epithelial hypoxia, luminal amounts of SCFAs, and HIF-1 responses in human and murine intestinal cells may be relevant for modulating inflammatory and infectious conditions. Oxygen (O2) availability is a key factor regulating microbiota composition and the homeostatic function of cells in the intestinal mucosa of vertebrates. Microbiota-derived metabolites increase O2 consumption by intestinal epithelial cells (IECs), reducing its availability in the gut and leading to hypoxia. This physiological hypoxia activates cellular hypoxic sensors that adapt the metabolism and function of IECs and mucosa-resident cells, such as type-3 innate lymphoid cells (ILC3s). In this review, we discuss recent evidence suggesting that the intricate and multidirectional interactions among the microbiota, hypoxia/hypoxic sensors, and mammalian host cells (IECs and ILC3s) determine how the intestinal barrier and host–microbiota–pathogens connections are molded. Understanding these interactions might provide new treatment possibilities for dysbiosis, as well as certain inflammatory and infectious diseases. Oxygen (O2) availability is a key factor regulating microbiota composition and the homeostatic function of cells in the intestinal mucosa of vertebrates. Microbiota-derived metabolites increase O2 consumption by intestinal epithelial cells (IECs), reducing its availability in the gut and leading to hypoxia. This physiological hypoxia activates cellular hypoxic sensors that adapt the metabolism and function of IECs and mucosa-resident cells, such as type-3 innate lymphoid cells (ILC3s). In this review, we discuss recent evidence suggesting that the intricate and multidirectional interactions among the microbiota, hypoxia/hypoxic sensors, and mammalian host cells (IECs and ILC3s) determine how the intestinal barrier and host–microbiota–pathogens connections are molded. Understanding these interactions might provide new treatment possibilities for dysbiosis, as well as certain inflammatory and infectious diseases. catabolic fatty acid process that generates acetyl-CoA for the mitochondrial citric acid cycle and reduces coenzymes (NADH and FADH2), which provide energy for the electron transport chain production of ATP. state in which there is no O2 availability to the organs and tissues (0% pO2). small peptides (including defensins and cathelicidins) secreted in the intestine lumen mainly by Paneth cells to prevent bacterial colonization close to the intestinal epithelium. transcription factor activated by a range of endogenous (e.g., kynurenine) and exogenous ligands (e.g., natural plant flavonoids and polyphenols and xenobiotics); regulates the expression of genes associated with several biological processes, including metabolism, immunity, cellular proliferation, and differentiation. conserved catabolic process in which cytoplasmic constituents and organelles are degraded in the lysosome. immunoprecipitation method that, combined with PCR or DNA sequencing, is useful for identifying genome-binding sites for transcription factors and other proteins. colon absorptive epithelial cells. administration of DSS, a highly sulfated polysaccharide, causes intestinal inflammation in rodents. DSS-induced colitis is a useful and widely used experimental model of intestinal inflammation that shares some similarities with human ulcerative colitis. pathological condition in which there are significant alterations in the profile of the normal microbiota (qualitatively and quantitatively). lack all microorganisms (microbiologically sterile) and are housed in a controlled sterile environment to avoid contamination. one of the main cellular mechanisms for generating energy (ATP) in cells. This pathway involves several enzymatic reactions that convert glucose into pyruvate in the presence of O2, or lactate in the absence of O2 (anaerobic glycolysis). under hypoxic conditions, the activity of HIF prolyl-hydroxylases and ubiquitin ligases is inhibited, allowing the accumulation of the α subunit of HIF in the cytoplasm (stabilization). This subunit then translocates to the nucleus and binds to the β subunit, forming the HIF-1 complex that regulates the expression of several genes. O2 availability is higher than the physiological condition (pO2 >21%). a condition characterized by low O2 tensions (pO2 <10%). The O2 availability is below the demands of organs and tissues, requiring their adaptation. This condition can be considered physiological or pathological depending on context. dimeric protein complex formed by an α and a β subunit that acts as a transcription factor for cellular adaptation in response to low O2 concentration. immune cells known as the innate counterparts of adaptive T cells; secrete cytokines to modulate several immune responses in distinct tissues. distinct cell types that form the intestinal epithelium, a dynamic monolayer that provides a physical/chemical barrier to the external environment within the intestinal lumen. It includes absorptive enterocytes/colonocytes, goblet cells, Paneth cells, enteroendocrine cells, microfold (M) cells, tuft cells, and intestinal stem cells. diverse group of commensal microorganisms (Archaea, bacteria, fungi, viruses, and parasites) colonizing host tissues (e.g., the gastrointestinal tract). multimeric intracellular protein complex, the activation of which leads to the maturation and secretion of proinflammatory cytokines IL-1β and IL-18. O2 level is similar to that found in the atmospheric air at sea level (20–21% pO2). A state of O2 availability that exceeds the metabolic demands of organs and tissues. the individual contribution of O2 to the total pressure of a gas mixture. member of the nuclear receptor family of transcription factors responsible for mediating ligand-dependent transcriptional activation and repression; activated by several endogenous and exogenous ligands, including polyunsaturated fatty acids, such as arachidonic acid and its metabolites, SCFAs, and thiazolidinediones. model of mucosal wounding in which a 2-mm piece of the mucosal tissue is removed with the guidance of an endoscope. transcription factor expressed by immature CD4+CD8+ thymocytes, T helper 17 lymphocytes (Th17), and ILC3s. metabolites produced and released by the microbiota during the process of bacterial fermentation of dietary fibers;have important roles in the physiology of the host. cell–cell transmembrane adhesion complexes that have a role in the organization of epithelial tissue preventing molecules from passing in between the cells. murine model of colonic inflammation with similar aspects to Crohn's disease and Th1-mediated bowel inflammation. The disease develops after administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS).