Normoxia and hypoxia represent two distinct oxygen concentration states in cellular environments (23). Normoxia denotes the normal oxygen levels in organs, tissues, and cells in healthy states, with an oxygen partial pressure of 10%-20% (23, 24). In this state, oxygen supply is sufficient for bodily functions without restriction. However, hypoxia arises when oxygen supply falls short of demand, resulting in subnormal levels, often under 5% oxygen partial pressure (23, 25). Nonetheless, hypoxia does not always indicate pathology. It occurs under normal physiological conditions as well, thus hypoxia is classified into physiological and pathological types (26, 27).

Physiological hypoxia is influenced by factors such as diet (28), exercise (29), and living environment (such as at high altitude) (30). The body triggers regulatory and adaptive responses to mitigate oxygen deficiency, restore hypoxic conditions for oxygen homeostasis, or boost cellular tolerance to hypoxia. For instance, the body may enhance cardiac output or elevate erythropoiesis to augment tissue oxygenation, processes intimately associated with HIF (30–32). Additionally, pathways such as HIF signaling are employed for tissue cell acclimatization to hypoxia (33). It’s critical to recognize that hypoxia is not inherently detrimental. In certain areas, such as the gastrointestinal tract, moderate and stable physiological hypoxia is essential for maintaining key physiological processes like immune homeostasis, cellular metabolism, and angiogenesis (34, 35). In contrast, pathological hypoxia, a common feature in many diseases, is more prevalent and severe, playing a vital role in the pathology of cardiac (36), pulmonary (37), autoimmune diseases (38), and cancer (39). Importantly, pathological hypoxia is significantly linked to physiological hypoxia. Disruption of physiological hypoxia can initiate a series of cellular alterations, precipitating pathological hypoxia (27). Both hypoxia types are modulated by HIF, with IBD research centering on gut physiological hypoxia. Therefore, understanding the role and mechanism of HIF-related signaling pathways is crucial for treating hypoxia-associated diseases, including IBD.

Relative hypoxia is a normal physiological condition for certain organs and tissues. The gastrointestinal tract, influenced by its anatomical structure, complex vascular system, and the distribution and metabolism of the microbiota, naturally forms steep oxygen gradients both horizontally and vertically, with extensive research conducted in the colon (40–42). Studies have confirmed a gradient decrease in oxygen tension from the stomach to the intestines, with gastric luminal oxygen tension at about 7.7 kPa, small intestinal luminal tension at 4.2 - 4.6 kPa, and colonic tension dropping to 0.4 - 1.5 kPa (43–45). Interestingly, a near-vertical oxygen tension drop is noted from various intestinal wall layers to the lumen, where muscularis mucosae holds much higher tensions than the lumen. Colonic muscle oxygen levels range from 5.6 to 9.5 kPa, the submucosa around 5.6 kPa, and the luminal mucosa surface between 0.13 to 0.8 kPa (34, 46–50). Thus, hypoxia and oxygen gradients are crucial physiological features of the gut, with disruption potentially leading to disease.

Notably, the established oxygen gradients are closely associated with HIF-1α and the spatial distribution of intestinal microbiota. Studies have indicated that in the oxygen-rich stomach and duodenum, aerobic and facultative anaerobic bacteria are dominant; in the small intestine, facultative anaerobes are most common; and in the oxygen-depleted large intestine, obligate anaerobes prevail (34, 51–53). These findings suggest that microbiota distribution critically influences intestinal oxygen gradients, as evidenced by germ-free mouse studies. Kelly et al. reported that antibiotics or germ-free conditions significantly reduce SCFAs levels, diminish HIF-1α in intestinal epithelial cells (IEC), and nearly eliminate physiological hypoxia and oxygen gradients (54). Wang et al. also discovered that gut microbiota and SCFAs, especially butyrate, are intimately linked to intestinal hypoxia; butyrate enhances oxygen consumption and stabilizes HIF via prolyl hydroxylase enzymes (PHD) inhibition (55). Additionally, the formation of intestinal oxygen gradients is also related to other metabolic products such as trimethylamine oxide and indole derivatives, with antibiotic exposure altering these processes (49). Research by Nicolas et al. validated these points (56). In summary, HIF-1α and/or the gut microbiota and their metabolites, SCFAs, are key factors in the formation of intestinal hypoxia.

HIF functions as a heterodimer composed of α and β subunits, primarily including HIF-1 (HIF-1α and HIF-1β), HIF-2 (HIF-2α and HIF-2β), and HIF-3 (HIF-3α and HIF-3β) (57, 58). Among these types, HIF-1 is the most thoroughly researched and is vital for hypoxic pathophysiology. HIF-1 is ubiquitous in tissues and cells, with HIF-1α expression regulated by oxygen levels and HIF-1β expressed continuously (44). HIF-1 exerts its extensive and potent biological functions only when HIF-1α and HIF-1β combine to form a heterodimeric structure. Under normoxia, HIF-1α, hydroxylated by oxygen-dependent PHD, binds to von Hippel-Lindau (VHL) protein, which recruits ubiquitin ligases to HIF-1α, leading to its proteasomal degradation and functional inactivity. However, in hypoxia, the absence of oxygen impedes the ubiquitination of HIF-1α, enabling its nuclear translocation to form a heterodimeric complex with HIF-1β. This complex then binds to specific DNA regions (hypoxia-response elements, HRE) of target genes, activating the transcription of numerous downstream genes. This activation plays a crucial role in processes such as cellular metabolism, intestinal barrier function, immune regulation, angiogenesis, erythropoiesis, tumorigenesis, cell apoptosis, and autophagy (33, 59, 60). In summary, HIF-1α plays a pivotal role in maintaining cellular oxygen homeostasis under hypoxic conditions and offers significant protection during pathological and physiological hypoxia by mediating adaptive responses to oxygen insufficiency ( Figure 1 ).

Inflammatory states are considered a key pathological feature of IBD, while hypoxia is seen as a common characteristic of most inflammation. Research has confirmed significant hypoxia in IBD’s inflamed regions, which mutually affects each other, with HIF-1α being central to the connection between host hypoxia and inflammation (44). Current consensus in research posits physiological hypoxia as a crucial environmental characteristic of the gut, with IBD pathogenesis closely linked to disruptions in this hypoxic milieu. A stable hypoxic environment effectively controls and alleviates intestinal inflammation, closely linked to the activation of HIF-1α, which promotes adaptation to hypoxia, mitigates gut inflammation, and maintains intestinal barrier, serving a definitive protective role in IBD (48). For example, moderate hypoxia preserves the intestinal barrier in mouse dextran sulfate sodium (DSS)-induced colitis via HIF-1α modulation of Vitamin D Receptor (VDR) signaling (61). Additionally, hypoxia significantly reduces inflammatory gene expression in CD patients and colitis mice, linked to the inhibition of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3)/mammalian target of rapamycin (mTOR) pathway and autophagy induction by hypoxia-driven HIF-1α (62). Furthermore, in colitis mouse models, butyrate upregulation activates IEC peroxisome proliferator-activated receptor γ (PPAR-γ), reducing cellular oxygenation in inflammation, boosting mitochondrial function and β-oxidation of SCFAs to sustain hypoxia and curb pathogenic bacterial growth in IBD (63–65). Conversely, deficiency or impairment of HIF-1α in the gut exacerbates intestinal inflammation. Myeloid HIF deficiency in DSS-induced colitis leads to increased infiltration of neutrophils and Ly6C monocytes, with a more marked impact from HIF-1α loss compared to HIF-2α (66).

Interestingly, research has indicated hypoxia induces or exacerbates inflammation, with HIF-1α activation contributing to IBD’s inflammatory processes. For instance, frequent high-altitude activities have been associated with gastrointestinal inflammation, increasing the risk of IBD flares (67). Hypoxia markers HIF-1α, macrophage inflammatory protein 3α (MIP-3α), and vascular endothelial growth factor (VEGF) were significantly elevated in colonic epithelial tissues and serum of both pediatric and adult patients with active IBD, correlating positively with histological severity (68). In DSS-induced colitis mice, myeloid HIF-1α deletion lessened inflammation, HIF-2α deletion worsened it, and the absence of both showed no significant changes (69); however, increased myeloid expression of HIF-1α accelerated colitis progression (70). Moreover, hypoxia was found to not only exacerbates DSS-induced colitis but also augments neuroinflammation in mice (71). However, the specific mechanisms and pathways by which hypoxia/HIF-1α induces or exacerbates intestinal inflammation have not been elucidated in these studies, necessitating further research for clarification. It is worth noting that inflammation also aggravates hypoxia. In the pathology of IBD, prolonged intestinal inflammation sharply increases the severity of mucosal hypoxia, potentially transitioning to a chronic pathological state (44). This exacerbates intestinal damage and perpetuates a vicious cycle. In IBD, the exacerbation of local hypoxia by intestinal inflammation may be associated with the following factors. On the one hand, inflammatory recurrence in IBD leads to vascular damage, endothelial dysfunction, and reduced perfusion (72, 73), while chronic inflammation increases oxygen consumption due to immune cell infiltration, exacerbating hypoxia (7, 74, 75). On the other hand, changes in the gut microbiota and their metabolites also consume oxygen, with obligate anaerobes switching to facultative anaerobes and less butyrate production, disrupting physiological hypoxia (76). Additionally, anaerobic bacteria metabolites enhance the consumption of oxygen in IEC, maintaining gut hypoxia (77–79). Hence, intestinal hypoxia is considered a common microenvironmental feature of IBD pathology, with inflammatory damage spreading hypoxia to deeper layers like the submucosa, exacerbating gut hypoxia.

Certainly, in the face of hypoxia, inflammation is not passive. In UC, it prompts a transcriptional reprogramming of the HIF pathway, downregulating PHD1 to favor HIF-1α’s protective role over HIF-2’s harmful effects, aiding mucosal repair (80). This highlights the close relationship between HIF-1α and the protective mechanisms against inflammatory hypoxia in IBD. Notably, different subtypes of HIF play distinct roles in hypoxia and the pathogenesis of IBD. HIF-1 is primarily involved in acute hypoxic response, whereas HIF-2 and HIF-3 are implicated in chronic hypoxia adaptation (33, 58). There is also cross-talk among these subtypes. A decrease in HIF-1 levels leads to an increase in HIF-2 and HIF-3, a shift reminiscent of cell polarization, which is necessary for the long-term hypoxic adaptation of cells (58). Moreover, in IBD, different HIF subtypes exert critical but opposing effects. As mentioned earlier, HIF-1α suppresses intestinal inflammation and promote resolution in IBD. Conversely, HIF-2α activation upregulates inflammatory expression, intensifying the inflammatory response, aggravating IBD, and is associated with colorectal cancer (CRC) progression (81–84).

Although the impact of hypoxia in IBD is contested, a stable hypoxic environment is pivotal for gastrointestinal wellness, with HIF-1α’s protective role acknowledged. HIF-1α orchestrates cellular adaptation to hypoxic and inflammatory conditions via downstream genes regulation, essential for cells coping with such stresses. Therefore, therapeutic approaches for IBD have diversified to include tactics like PHD inhibition to manage HIF-1α, enhancing treatment options (85, 86). The debate surrounding hypoxia’s pro-inflammatory or anti-inflammatory effects in IBD may hinge on varying experimental hypoxia parameters (the level, duration, and degree of hypoxia), HIF-1α’s cell-specific roles, the target genes or pathways affected by HIF-1α, and interactions between HIF isoforms. Thus, in exploring HIF’s role or therapeutic use in IBD, these considerations are essential.

Growing research underscores the influence of gut microbiota and their metabolites, particularly SCFAs, on health and disease. SCFAs, as one of the gut microbiota’s main metabolite, are extensively confirmed to be a key contributor to the pathogenesis of IBD. IBD patients have fewer SCFAs-producing bacteria and lower fecal SCFAs levels than healthy individuals (132–134). Dietary fiber scarcity worsens colitis, while supplementation encourages SCFAs-producing bacteria and SCFAs levels in IBD, restoring gut homeostasis (135, 136). Notably, significant SCFAs concentration gradients exist along the gastrointestinal tract, with cecum and colon’s anaerobic conditions being prime for fermenting dietary fibers into SCFAs. Hence, the absence of the cecum decreases SCFAs-producing microbiota and SCFAs levels, intensifying inflammation (137). Understanding the role and related mechanisms of SCFAs in IBD is therefore crucial for the disease’s prevention and treatment.

The gut microbiota and hypoxia are closely linked, engaging in crosstalk within the host’s intestines. Microbial-derived SCFAs elevate IEC oxygen consumption to maintain intestinal hypoxia which activates and stabilizes HIF, triggering the adaptive cellular responses to hypoxia essential for intestinal function and pathology (54). HIF-1α in the gut induces pyruvate dehydrogenase kinases (PDK or PDHK) expression, such as PDK1 and PDK3, inactivating the pyruvate dehydrogenase complex (PDC) and blocking pyruvate’s conversion to acetyl-CoA for the TCA cycle. Thus, colonocytes depend on SCFAs β-oxidation, especially of butyrate, for acetyl-CoA production, a highly oxygen-consuming process (207). Moreover, butyrate directly inhibits HDAC, inducing PDK1-4 expression (208). In short, SCFAs, particularly butyrate, directly or indirectly promote PDK activation to switch acetyl-CoA generation from glycolysis to SCFAs oxidation, key in SCFAs’ regulation of HIF-1α to preserve IEC energy supply and gut hypoxia. Thus understanding the physiological regulation of HIF-1α by SCFAs in IBD could inform prevention and treatment strategies for the condition.

SCFAs trigger HIF-1α in IEC, essential for maintaining IEB function and gut homeostasis. They enhance IEC survival, metabolism, and tight junction through HIF-1α activation, protecting the IEB from inflammatory and infectious damage (54, 209). For example, butyrate enhances IEB function by activating HIF-1α in IEC to upregulate tight junction protein expression, reducing barrier permeability and bacterial translocation, thereby mitigating colonic damage caused by colitis or Clostridioides difficile infection (CDI) (93, 210). However, butyrate’s precise mechanism in HIF-1α modulation remains unclear, suspected to involve physiological hypoxia. Additionally, butyrate stabilizes HIF-1α via HDAC inhibition, enhancing antimicrobial lysozyme activity (211). Research has revealed that the butyrate-producing bacterium Faecalibacterium prausnitzii can modulate HIF-1α to enhance IEC IL-18 expression, potentially aiding in mucosal healing in IBD, offering new insights into HIF-1α-mediated SCFA regulation of intestinal mucosal repair and IEB function maintenance (212). Antibiotic-induced experiment has suggested butyrate stabilizes colonic HIF-1α in mice by inhibiting PHD and increasing 2-oxoglutarate levels, beneficial for gut homeostasis (55). Moreover, SCFAs and HIF-1α play roles in VDR-mediated mucosal barrier protection under hypoxia. Moderate hypoxia induces HIF-1α-VDR promoter binding, enhancing barrier function, with VDR deficiency altering gut microbiota and reducing SCFAs-producing bacteria (61). The role of SCFAs in HIF-1α-regulated VDR signaling under hypoxia needs further investigation. Additionally, SCFAs stimulate mucin expression, critical for barrier function, with HIFs, particularly HIF-1α, being key mucin regulators (213). In asthma studies, butyrate affects HDAC1 through PI3K/Akt/HIF-1α/VEGF pathways, moderating mucus secretion and inflammation (214). However, current IBD research lacks understanding of the synergistic impact of SCFAs and HIF-1α on mucin. While HIF-2α is pivotal in propionate-induced mucin expression, promoting MUC2 secretion from goblet cells, no HIF-1α involvement has been observed, as propionate’s HIF-2α activation for MUC2 production may suppress HIF-1α influence (215). This aligns with findings that increased HIF-1α suppresses HIF-2α and HIF-3α, and vice versa (58). In conclusion, HIF-1α maintains stable expression in IEC under physiological hypoxia, with SCFAs, especially butyrate, being essential for this stability. Therefore, butyrate holds substantial promise as endogenous PHD inhibitors to stabilize HIF-1α and maintain IEB function ( Figure 2 ).

In IBD, SCFAs stabilize HIF-1α, modulating immune cells function in the gut. José Luís’s team demonstrated that butyrate triggers the HIF-1α-IL-22 axis in ILC3s, reducing CDI-triggered gut inflammation and reinforcing IEB integrity (216). It also upregulates HIF-1α and Aryl hydrocarbon receptor (AhR) via GPR41 activation and HDAC inhibition, promoting IL-22 in CD4+ T cells and ILCs (217). This mechanism involves butyrate’s histone modifications, which increase HIF-1α binding to the IL-22 promoter, augmenting IL-22 expression (217). These studies provide new insights into SCFAs’ role in anti-inflammatory mediator production. Furthermore, butyrate enhances macrophage antibacterial activity by upregulating HIF-1α through HDAC inhibition without GPCR involvement, enhancing antimicrobial components’ expression like lysozyme and ROS, and raising oxygen consumption by about 50%. However, inhibition of HIF-1α could block the effects of butyrate (218). In research on Streptococcus pneumoniae, acetate boosts macrophage glycolysis, activating HIF-1α and NLRP3 inflammasome, triggering IL-1β release and enhancing nitric oxide (NO) synthesis, which in turn improves macrophage bactericidal function through NO reliance (219). Hence, the glycolysis-HIF-1α pathway is pivotal for SCFAs-mediated macrophages cytotoxicity regulation. However, focused research on HIF-1α in SCFAs-modulated colitis macrophages remains scarce, representing a promising research avenue, especially given its importance in conditions like pneumonia. Additionally, pentanoate facilitates iron uptake in intestinal cells, thereby augmenting HIF-2α expression and inducing c-Maf production, which is crucial for intestinal Treg differentiation and homeostasis (220). Notably, c-Maf typically acts as a positive regulator of IL-10 across various immune cells. However, whether pentanoate prompts Treg or other immune cells to secrete IL-10 was not clarified and warrants further study ( Figure 3 ).

SCFAs not only modulate immune cells directly but also influence downstream inflammatory pathways through HIF-1α. Butyrate suppresses HDAC and activates the p-glycogen synthase kinase-3β (GSK-3β)/β-catenin/HIF-1α/NF-κB pathway, reducing inflammation in sleep deprivation-induced colitis mice (221). In human peripheral blood mononuclear cells, butyrate mitigates inflammation by blocking TLR4 signaling without affecting HIF-1α expression and the HIF-1α/HIF-2α ratio. In contrast, caprate, a medium-chain fatty acid (MCFA), activates inflammation via TLR2, reduces IL-10 and HIF-1α, and increases HIF-2α transcription, altering the HIF-1α/HIF-2α ratio (222). The differential immunomodulatory effects of fatty acids may relate to their origins or structures, with SCFAs being endogenous and MCFAs exogenous from diet. Structurally, SCFAs and MCFAs differ by a few carbon atoms. The variance in HIF-1α and HIF-2α expressions might be a compensatory response to inflammation induced by caprate. Besides, high concentrations of acetate in organoid-derived epithelial monolayers from UC patients exhibits anti-inflammatory effects and reinforces barrier function, concurrently elevating HIF-1α levels, though mechanisms are uncertain (223). Notably, acetate lowers IL-10 levels, which contrasts with the view that SCFAs promote IL-10 expression, suggesting that SCFAs type, concentration, or cell-type differences might play a role. Overall, SCFAs-targeted HIF-1α modulation offers a strategy to combat intestinal inflammation. The promotion of HIF-1α in IEC by SCFAs is largely linked to physiological hypoxia, and the HIF pathway is one of the most important pathways to communicate between the host and the intestinal microecology in addition to GPCR and HDAC signaling.

SCFAs activate HIF-1α to induce autophagy in IEC, beneficial for suppressing intestinal inflammation in IBD. In mouse IEC, butyrate eases DSS-induced colitis by upregulating HIF-1α to modulate autophagy and gut microbiota; however, HIF-1α deficiency lowers intestinal butyrate concentration and autophagy levels to increase susceptibility to colitis ( Figure 2 ) (76). The reduced autophagy from HIF-1α deficiency may relate to the disruption of gut physiological hypoxia. Hypoxia or increased oxygen consumption also induces IEC autophagy (62), highlighting HIF-1α’s role in SCFAs-mediated autophagy regulation. Besides, SCFAs and HIF-1α are closely linked to PTEN induced putative kinase 1 (PINK1), an ubiquitin kinase essential for mitochondrial autophagy (224). In CAC models, PINK1 hampers tumor growth by activating p53 and HIF-1α/PDHK1/PDHE1α pathways, reducing acetyl-CoA production; contrastingly, acetate exposure increases acetyl-CoA in tumors, counteracting PINK1’s anti-tumorigenic effects (225). This indicates that the roles of SCFAs and HIF-1α in CAC and IBD are not constant and necessitate tailored analysis for future therapeutic applications.