The emerging role of hypoxia and environmental factors in inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a chronic and debilitating disorder characterized by inflammation of the gastrointestinal tract. Despite extensive research, the exact cause of IBD remains unknown, hampering the development of effective therapies. However, emerging evidence suggests that hypoxia, a condition resulting from inadequate oxygen supply, plays a crucial role in intestinal inflammation and tissue damage in IBD. Hypoxia-inducible factors (HIFs), transcription factors that regulate the cellular response to low oxygen levels, have gained attention for their involvement in modulating inflammatory processes and maintaining tissue homeostasis. The two most studied HIFs, HIF-1α and HIF-2α, have been implicated in the development and progression of IBD. Toxicological factors encompass a wide range of environmental and endogenous agents, including dietary components, microbial metabolites, and pollutants. These factors can profoundly influence the hypoxic microenvironment within the gut, thereby exacerbating the course of IBD and fostering the progression of colitis-associated colorectal cancer. This review explores the regulation of hypoxia signaling at the molecular, microenvironmental, and environmental levels, investigating the intricate interplay between toxicological factors and hypoxic signaling in the context of IBD, focusing on its most concerning outcomes: intestinal fibrosis and colorectal cancer.

Graphical abstract

Graphical Abstract.

Inflammatory bowel disease

Inflammatory bowel disease (IBD) is a long-lasting inflammatory condition affecting the intestines, commonly identified as Crohn’s disease (CD) or ulcerative colitis (UC). Although these conditions share certain pathological characteristics, they also possess distinct differences that set them apart (Zhang and Li, 2014). CD affects a larger area within the gastrointestinal (GI) tract, whereas UC is primarily limited to the colon and rectum (Seyedian et al., 2019). The etiology and pathogenesis of IBD remain multifaceted and not fully understood. Investigative efforts have revealed various factors contributing to the development of IBD, such as genetic mutations, hypoxic signaling, immune dysfunction, and environmental factors (Kim and Cheon, 2017). The objective of this review is to analyze existing literature to highlight the regulation of hypoxic signaling at the molecular, microenvironment, and environmental levels in IBD and the two severe outcomes of IBD: intestinal fibrosis and colitis-associated colorectal cancer (CAC).

Hypoxia signaling and IBD

Within the context of IBD, the intricate involvement of hypoxia and hypoxic signaling emerges as a multifaceted aspect of the disease pathophysiology. In the colon, it is common to find regions of hypoxia even in healthy individuals (Zheng et al., 2015). This is referred to as physiological hypoxia and arises from the normal colon anatomy, colonic blood supply from mesenteric arteries, microbial metabolism, and physiologic processes such as digestion. In regions of heightened inflammation within the gut mucosa, the intricate interplay of increased metabolic demands, immune cell infiltration, and altered blood flow often culminates in a demand for oxygen that exceeds supply (localized hypoxia) (Cramer et al., 2003; Taylor, 2008). This phenomenon sets the stage for the activation of hypoxia-inducible factors (HIFs), particularly HIF-1α and HIF-2α, which serve as principal molecular mediators orchestrating adaptive responses to the low oxygen levels prevalent in the inflamed mucosa.

HIFs, recognized for their pivotal role in cellular responses to hypoxia, extend their influence to modulating immune and inflammatory responses within the IBD microenvironment (Van Welden et al., 2017). This regulatory role encompasses the modulation of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6, thereby impacting the inflammatory milieu characteristic of IBD (Atreya and Neurath, 2005). Beyond immune modulation, hypoxic signaling prompts angiogenesis, a compensatory mechanism aimed at restoring oxygen supply to affected tissues. However, within the complex landscape of IBD, this process can take an aberrant turn, giving rise to dysfunctional vessels that contribute to tissue remodeling and fibrosis—a common severe outcome observed in the advanced stages of IBD (Rieder et al., 2018; Shah, 2016; Wilkens et al., 2018).

Moreover, hypoxia’s influence extends to the integrity of the epithelial barrier in the gut, a pivotal component for preventing the infiltration of harmful substances and pathogens. The compromised epithelial barrier function, hallmarking IBD, undergoes modulation under hypoxic conditions, further contributing to disease pathology (Azimi et al., 2018).

Prolonged or excessive hypoxic signaling in IBD is implicated in the intricate network of tissue remodeling and fibrosis (Wang et al., 2022). This involves the activation of fibroblasts and the excessive deposition of extracellular matrix components, underscoring the dysregulation of wound healing responses influenced by hypoxia.

Understanding the role of hypoxia and HIF signaling in IBD not only provides insights into the complex interplay of inflammatory processes, immune responses, and tissue remodeling but also opens avenues for potential therapeutic interventions. Strategies targeting HIF activity, angiogenesis, or epithelial barrier dysfunction emerge as promising avenues for managing IBD and addressing its intricate severe outcomes. Recent studies have shed light on the differential roles of HIF-1α and HIF-2α in IBD, with HIF-1α promoting intestinal barrier homeostasis and HIF-2α favoring inflammation and disease pathology (Figure 1). However, the precise mechanisms and contributions of these HIFs in the context of immune cells, barrier integrity, and disease progression in IBD are a topic of further investigation (Morales and Xue, 2023).

Figure 1.

Differential roles of HIF-1α and HIF-2α in IBD. In normal colon tissue, an appropriate and tightly regulated immune response promotes colon health and minimizes inflammatory insult and barrier disruption. On the other hand, in IBD inflammation runs rampant, causing massive tissue damage and localized hypoxia. HIF-1α expression has been shown to play a more favorable role in IBD that contributes to symptom resolution, whereas HIF-2α worsens the condition, allowing for progression into the disease state.

Hypoxia signaling regulation at the molecular level

HIFs are intricately regulated by a network of factors, including prolyl hydroxylase domain (PHD) proteins, noncoding RNAs (ncRNAs), cofactors, and coactivators (Table 1). We will explore the diverse mechanisms by which HIFs are regulated, shedding light on the intricate interplay between cellular processes and the microenvironment in maintaining oxygen homeostasis. Understanding these additional mechanisms of HIF provides new insights into the role of HIFs in various physiological and pathological processes.

Table 1.

Regulatory mechanism for HIF proteins at the molecular level

Type of regulatory molecule of HIF proteins	Know regulatory molecules
Protein modifiers	PHD 1, 2, and 3
miRNA	miR-199a-5p, miR-210, miR-155, miR-21, and miR-17-92 cluster
lncRNA	HIF1A-AS2, lncRNA-p21, lincRNA-p21, HOTAIR, H19, and MIR210HG
circRNA	CircDENND4C, Circ_0067934, CircRNA-000284, and Hsa_circ_0010729
Cofactors/coactivators	p300, CBP, mediator complex, and FIH

 

HIF regulation by PHD proteins

PHD proteins (PHD1, PHD2, and PHD3), act as oxygen sensors and play a central role in the regulation of HIFs under normoxic conditions. PHD2 (EGLN1) is the most abundant oxygen sensor among the PHD isoforms and plays a central role in the regulation of HIFs (Ivan et al., 2001; Jaakkola et al., 2001). Under normoxic conditions, PHD2 hydroxylates specific proline residues on the HIF-α subunits (HIF-1α, HIF-2α, and HIF-3α). This hydroxylation marks HIF-α subunits for recognition by the von Hippel-Lindau (VHL) protein, leading to their polyubiquitination and subsequent proteasomal degradation. As a result, HIF protein levels decrease rapidly in normoxic conditions, preventing the activation of HIF-mediated transcription. PHD1 (EGLN2) and PHD3 (EGLN3) also participate in HIF regulation.

It is worth noting that PHD1 knockout in mice has shown protective effects against IBD, reducing colonic epithelial cell apoptosis (Tambuwala et al., 2010). As we delve into the distinct roles of PHD1, PHD2, and PHD3 in HIF regulation, it becomes evident that PHD1 and PHD3 exhibit more robust effects on the inhibition of HIF-2α, whereas PHD2 has greater effects on HIF-1α (Appelhoff et al., 2004). Despite relatively stable expression levels among tissues, PHD2 is typically more abundant, except in specific cases such as the testes where PHD1 is more prevalent and the heart where PHD3 is the predominant form (Willam et al., 2006).

Under hypoxic conditions, the activity of PHD proteins is inhibited due to low oxygen availability, leading to reduced hydroxylation of HIF-α subunits and stabilization (Jaakkola et al., 2001; Semenza, 2012a). Additionally, nitric oxide (NO) can directly inhibit the enzymatic activity of PHDs (Metzen et al., 2003). NO binds to the active site of PHDs, competing with oxygen and preventing the hydroxylation of HIF-α subunits. This inhibition occurs through the formation of a complex between NO and the iron in the catalytic site of PHDs. NO can also induce post-translational modifications of PHDs, such as S-nitrosylation. S-nitrosylation involves the addition of an NO group to a cysteine residue in the protein. This modification can affect the conformation and activity of PHDs, influencing their ability to hydroxylate HIF.

PHDs are iron-dependent enzymes (Pan et al., 2007). The availability of iron can directly influence PHD activity. Changes in cellular iron levels or alterations in the regulation of iron metabolism can impact the function of PHDs. For example, iron deficiency may lead to decreased PHD activity due to iron’s essential role in catalytic center of PHDs. Additionally, ROS can directly influence PHD activity by interacting with the iron in their catalytic sites. ROS, particularly hydrogen peroxide, can oxidize and modify the iron, leading to inhibition of the enzymatic activity of PHDs. This interference prevents the normal hydroxylation of HIF-α subunits even under normoxic conditions (Chandel et al., 2000).

Stabilized HIF-α subunits form heterodimers with HIF-β subunits and translocate to the nucleus, where they bind to hypoxia-response elements in the promoter regions of target genes (Jaakkola et al., 2001; Semenza, 2012a). This binding initiates the transcription of various genes involved in cellular responses to hypoxia, including angiogenesis, glucose metabolism, and erythropoiesis (Semenza, 2012a). The HIF pathway is a central regulator of oxygen homeostasis, allowing cells to adapt to the hypoxic microenvironment.

In conclusion, the regulation of HIFs by PHD proteins serves as a fundamental oxygen-sensing mechanism in cells. The different PHD isoforms, collectively enable cells to fine-tune HIF responses according to the level of oxygen availability as well as other factors such as iron, NO, and ROS levels in the intracellular and extracellular environments. The dynamic interplay between PHD proteins, HIFs, oxygen, iron, ROS, and NO levels is critical for maintaining cellular oxygen homeostasis and orchestrating adaptive responses to changes in oxygen availability and demand.

Noncoding RNAs influence HIF expressions, stability, and signaling

Beyond protein-coding genes, ncRNAs have emerged as key players in the regulation and mediation of HIFs and their signaling in cellular responses to hypoxic stress (Peng et al., 2020). ncRNAs constitute a diverse class of RNA molecules that do not code for proteins but instead exert regulatory functions at various levels of gene expression. HIF stability and activity can be modulated by various ncRNAs, creating a nexus between ncRNA regulation, hypoxia, and the pathogenesis of diseases such as IBD and CRC (Shih and Kung, 2017; Slemc and Kunej, 2016). ncRNAs discussed in this review will include microRNAs (miRNA), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs).

MicroRNAs

miRNAs are short, single-stranded ncRNAs that post-transcriptionally regulate gene expression by binding to the 3′ untranslated region of target mRNAs, leading to mRNA degradation or translational inhibition. Several miRNAs have been identified as regulators of HIFs, such as miR-18a and miR-186, influencing their stability and activity. Under normoxic conditions, miR-18a and miR-186 target HIF-α transcripts, contributing to their degradation and suppressing HIF-dependent gene expression (Cho et al., 2019; Kulshreshtha et al., 2007). However, under hypoxic conditions, the expression of these miRNAs is downregulated, leading to increased HIF-α stability and enhanced HIF-mediated transcription (Kulshreshtha et al., 2007).

Aside from having a regulatory role on HIFs themselves, miRNA can also serve as mediators of the hypoxic response. One of the most well-conserved hypoxamirs (miRNA upregulated by HIFs) induced by HIF-1α and HIF-2α is miR-210 (Chan et al., 2012). Consequences of miR-210 induction include cell cycle arrest, stem cell survival, angiogenesis, decreases in mitochondrial metabolism, and decreased DNA repair (Kulshreshtha et al., 2007; Muniappan and Thilly, 2002). Another miRNA known to be induced by hypoxic stimuli is miR-155. miR-155 is known as a master regulator of inflammation (Bruning et al., 2011; Mahesh and Biswas, 2019). When induced by hypoxia, miR-155 induces robust increases in inflammatory signals as well as promoting activation of B cells, T cells, and macrophages that further increase inflammation (Alivernini et al., 2017). These resultant changes in the cellular transcriptome from miR-210 and miR-155 support HIF function and aid the cell in achieving an appropriate response to hypoxic stimuli.

Long noncoding RNAs

lncRNAs are a class of ncRNAs that are longer than miRNAs and have diverse regulatory functions. Some lncRNAs have been implicated in modulating HIF signaling and HIF-dependent gene expression. For instance, certain lncRNAs can act as coactivators or corepressors of HIFs, interacting with HIF-α subunits or other regulatory proteins to fine-tune HIF transcriptional activity (Boulberdaa et al., 2016). Additionally, lncRNAs can function as competitive endogenous RNAs (ceRNAs), sequestering miRNAs that target HIF-α subunits, thus indirectly influencing HIF stability and activity (Boulberdaa et al., 2016).

One example of lncRNAs induced by hypoxia is H19. H19 plays roles in cell growth and differentiation (Ghafouri-Fard et al., 2020). It is known to be upregulated in response to hypoxia, and has been implicated in stabilizing HIF-1α and promoting angiogenesis under hypoxic conditions (Gabory et al., 2006). In IBD, H19 has been associated with decreased tight junction protein expression and increased epithelial barrier destruction (Yarani et al., 2018). H19 also has strong implications in cancer and has been shown to promote epithelial-to-mesenchymal transition (EMT) and metastasis (Gao et al., 2018). HOX transcript antisense RNA (HOTAIR) is a lncRNA that regulates genes involved in mammalian embryonic development that is increased under HIF induction (Raju et al., 2023). HOTAIR is a well-studied lncRNA that plays a role in the development of several human cancers. HOTAIR expression is elevated in many cancers including CRC and is associated with metastasis and poor prognosis (Qu et al., 2019).

In summary, the involvement of lncRNAs, H19 and HOTAIR in the hypoxic response creates a fascinating intersection between lncRNA regulation, hypoxia adaptation, and the complex pathophysiology of CRC and IBD. Further investigations into the specific molecular mechanisms and downstream effects of these lncRNAs in the context of hypoxia will undoubtedly provide valuable insights for developing targeted therapeutic strategies and advancing our understanding of these debilitating diseases.

Circular RNAs

circRNAs are a subclass of ncRNAs that form covalently closed loops, resulting in resistance to degradation by exonucleases. Emerging evidence suggests that circRNAs may also participate in HIF regulation and hypoxia responses. Although the specific roles of circRNAs in HIF regulation are still being explored, some circRNAs have been found to interact with miRNAs and modulate their activity, potentially impacting HIF expression and HIF-dependent gene expression indirectly (Holdt et al., 2018; Legnini et al., 2017). circRNAs have a diverse mechanism of action and can influence the cell in many ways, such as acting as miRNA sponges, binding, and sequestration of RNA binding proteins, and can modulate alternative splicing events (Ghafouri-Fard et al., 2021).

Some circRNAs known to play roles in the hypoxic response are circRNA 100146 and circRNA 33186. circRNA100146 is involved in the regulation of cell proliferation and apoptosis. It is upregulated under hypoxic conditions and can help promote cell survival in the hypoxic environment by acting as a miRNA sponge and preventing miR-361-3p and miR-615-5p from exerting their effects (He et al., 2021). It has also been implicated in the promotion of CRC growth and metastasis by inhibiting miRNA-149 and high mobility group AT-Hook 2 (HMGA2) (Liu et al., 2021). Another circRNA involved in the hypoxic response is circRNA 33186 and is well-known for its role in promoting an inflammatory environment (Wang et al., 2021). circRNA 33186 is known to increase matrix metalloprotease and inflammatory cytokine expression. Although research into the role of circRNA 33186 in IBD and CRC is still ongoing its induction following hypoxia signaling and its known effects in inflammatory diseases such as osteoarthritis may identify it as an attractive therapeutic target in these diseases (He et al., 2021).

The involvement of ncRNAs in HIF regulation adds another layer of complexity to the hypoxia signaling network. These regulatory RNAs enable fine-tuning of HIF responses to hypoxic stress, ensuring a precise and context-specific cellular response to changes in oxygen levels. In conclusion, ncRNAs, including miRNAs, lncRNAs, and circRNAs, play crucial roles in the regulation of HIFs and the cellular response to hypoxia. By influencing HIF stability and transcriptional activity, these ncRNAs contribute to the adaptive response to varying oxygen levels, adding further sophistication to the intricate regulatory mechanisms that govern cellular responses to hypoxic stress.

HIF regulation by cofactors and coactivators

The activity and specificity of HIFs are modulated by various cofactors and coactivators that interact with HIF proteins to fine-tune their transcriptional responses.

p300/CBP

The transcriptional coactivators p300 and CREB-binding protein (CBP) play a central role in HIF-mediated gene expression. p300 and CBP interact with the HIF complex and act as bridging factors between HIFs and the basal transcriptional machinery (Arany et al., 1996; Kasper et al., 1999). These coactivators facilitate the recruitment of RNA polymerase II and other transcriptional coactivators to initiate gene transcription. Moreover, p300/CBP possesses intrinsic histone acetyltransferase activity, which results in the acetylation of histone proteins in the chromatin, leading to chromatin remodeling and enhanced accessibility of HIF target genes (Ebert and Bunn, 2007). This process promotes the assembly of a transcriptionally permissive chromatin structure, facilitating HIF-mediated gene transcription.

Mediator complex

The mediator complex is a large multisubunit protein complex that serves as a bridge between transcription factors and the RNA polymerase II machinery. It plays a crucial role in mediating the communication between enhancer-bound transcription factors and the basal transcriptional machinery at the core promoter of target genes. Recent studies have shown that the mediator complex interacts with HIF-1α and HIF-2α and is essential for the recruitment of RNA polymerase II to HIF target genes (Schödel et al., 2012). The mediator complex enables the activation of HIF target genes and facilitates their efficient transcription in response to hypoxia.

Factor inhibiting HIF

Apart from its role as an oxygen-dependent HIF hydroxylase, factor inhibiting HIF (FIH) can also function as a transcriptional coactivator. Under hypoxic conditions, when FIH activity is reduced, FIH interacts with HIF-α subunits and enhances HIF-mediated gene transcription (Chen et al., 2013). This coactivator function of FIH is independent of its hydroxylase activity and further contributes to the regulation of HIF target genes.

In conclusion, the regulation of HIFs involves a complex interplay of cofactors and coactivators that modulate HIF transcriptional activity and target gene specificity. Cofactors such as p300/CBP and the mediator complex facilitate the assembly of the transcriptional machinery and promote HIF-mediated gene transcription. Additionally, FIH, beyond its role as an oxygen sensor, can also act as a transcriptional coactivator and influence HIF transcriptional responses. The concerted actions of these cofactors and coactivators ensure a tightly regulated and context-specific cellular response to hypoxia.

Hypoxia signaling regulation at the microenvironment level

Recent research has highlighted the role of hypoxia signaling and its interplay with microenvironmental factors such as oxidative stress and microbiota in modulating the development and progression of IBD (Table 2). Understanding these interactions is crucial for elucidating the underlying mechanisms and exploring potential therapeutic avenues.

Table 2.

Microenvironment and its impact on HIF proteins

Microenvironmental factors regulating HIFs	Mechanism of impact
Oxidative stress (ROS)	ROS directly inhibit PHD, stabilizing HIFs. ROS induces stabilization of other proteins such as NRF2, which upregulates HIFs.
Microbiota	Microbial metabolites stabilize HIF-α subunits and modulate HIF-mediated immune responses. Facultative anaerobes consume oxygen, further increasing hypoxic regions in colon.

 

Hypoxia and oxidative stress

Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the cellular antioxidant defense mechanisms, is a critical modulator of HIFs and hypoxia signaling. ROS are highly reactive molecules that can damage cellular components, including lipids, proteins, and DNA, leading to cellular dysfunction and injury. Under normoxic conditions, ROS levels are typically maintained at low levels through the action of antioxidant enzymes and molecules, which scavenge ROS to protect cells from oxidative damage. Oxidative stress occurs when ROS production exceeds the cellular antioxidant capacity, such as during inflammatory processes or exposure to environmental toxins.

Eukaryotic cells heavily depend on oxidative phosphorylation for maintaining high-energy phosphates, where mitochondrial oxygen consumption is crucial for ATP generation. In conditions of oxygen deprivation, cells activate adaptive processes to enhance survival. The electron transport chain (ETC), particularly complex III, has been proposed as an oxygen sensor, releasing ROS during hypoxia (Guzy et al., 2005; Guzy and Schumacker, 2006; Muller et al., 2004). Under normal oxygen conditions, electrons efficiently traverse the mitochondrial ETC to oxygen. However, during hypoxia, electron transfer becomes less efficient, leading to the partial reduction of oxygen and the formation of superoxide anion (Fukuda et al., 2007). Thus, the paradoxical increase in the product ROS during hypoxia, despite a drop in substrate availability, may be attributed to various factors, including the effects of oxygen on the ubisemiquinone radical's lifetime in complex III.

The interaction between ROS and HIF-α

The mechanisms that ROS led to increased HIF stabilization is multifaceted and is impacted by iron and iron containing proteins. Iron is an essential component of the catalytic center of PHDs. This iron center is critical for the enzymatic activity of PHDs, as it facilitates the binding and activation of molecular oxygen during the hydroxylation reaction (Fong and Takeda, 2008). ROS, such as superoxide anion and hydrogen peroxide (H₂O₂), can inhibit the activity of PHD enzymes. ROS oxidize the ferrous (Fe²⁺) form of iron, which is a cofactor for PHDs. This oxidative modification hinders the ability of PHDs to hydroxylate HIF-α subunits effectively, resulting in increased amounts of HIF proteins (Niecknig et al., 2012).

It is widely accepted that HIF activation helps maintain low levels of ROS in hypoxia by suppressing the mitochondrial citric acid cycle. Induction of HIF proteins leads to the transcription of glycolytic genes, shifting energy production from the ETC to glycolysis, thereby mitigating ROS accumulation (Kung-Chun Chiu et al., 2019). However, some studies indicate that HIF accumulation increases ROS generation. HIF-1α stabilization activates gene expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), generating superoxide and resulting in increased ROS generation (Chen et al., 2018). Thus, HIF activation can either reduce or increase ROS formation. In general, HIF activation in hypoxia ensures optimum ATP production and cell integrity by minimizing ROS during hypoxia.

Crosstalk with inflammatory pathways

Oxidative stress is intimately linked to inflammatory processes, and inflammation is a well-known activator of HIFs. Inflammatory signals, including cytokines and toll-like receptor (TLR) activation, can lead to the stabilization of HIF-α subunits and subsequent HIF-dependent gene expression (Cummins et al., 2006; Nizet and Johnson, 2009). Thus, the interplay between oxidative stress and inflammation contributes to the regulation of HIFs and the cellular response to hypoxia in inflamed tissues.

Inflammatory cytokines, such as interleukin-1β (IL-1β) and TNF-α, exert stimulatory effects on HIF activation. These signaling molecules initiate cascades that converge upon HIF regulation, contributing to its activation (Lappano et al., 2020; Zhou et al., 2003; ). Conversely, HIF induction positively regulates these genes, resulting in their increased expression and increase in inflammation. In the context of IBD and cancer this can be detrimental to the pathogenesis of the diseases, leading to more severe inflammation that can lead to tissue destruction, and tumor growth, respectively (Malkov et al., 2021).

A significant result of inflammation and hypoxic induction is the activation of nuclear factor-kappa B (NF-κB), a master transcription factor in inflammation (Oliver et al., 2009). NF-κB activation also induces the expression of HIF-1α, establishing a positive feedback loop that amplifies both inflammatory and hypoxia responses. Crosstalk between HIF-1α and NF-κB further augments their individual activities, underscoring the interconnectedness of these pathways.

Inflammatory conditions are often accompanied by the generation of ROS. ROS, in turn, inhibit PHDs, via the mechanisms discussed in The interaction between ROS and HIF-α section, leading to the stabilization of HIF-α subunits. Stabilized HIF-α subunits translocate to the nucleus, activating HIF-dependent genes and further influencing the inflammatory milieu.

TLRs, key players in recognizing pathogen-associated molecular patterns (PAMPs), also contribute to HIF activation. TLR signaling induces the production of inflammatory mediators, impacting HIF stabilization. Additionally, in 2009, it was demonstrated that ligand-induced activation of TLR7/8 leads to the accumulation of HIF-1α (Nicholas and Sumbayev, 2009). Furthermore, hypoxia-independent activation of HIFs by inflammatory stimuli, such as IL-1β and TNFα involving alterations in cellular processes such as glycolysis and mitochondrial function, has been observed (Zhang et al., 2018).

The dynamic interplay between inflammation and HIF activation is not only crucial for understanding the molecular underpinnings of these processes but also holds implications for therapeutic interventions targeting inflammatory and hypoxic conditions. This intricate relationship underscores the multifaceted role of HIFs in coordinating adaptive cellular responses in the face of dynamic and challenging environments.

In conclusion, oxidative stress serves as a critical regulator of HIFs, influencing their stability and activity. ROS generated during oxidative stress inhibit PHD activity, leading to HIF-α subunit stabilization and the activation of HIF-dependent gene expression. The intricate crosstalk between oxidative stress, inflammation, and HIF signaling contributes to the complex and multifaceted cellular responses to hypoxia in various physiological and pathological contexts.

HIF regulation by the microbiome

The gut microbiome, a vast community of microorganisms residing in the GI tract, has emerged as a critical regulator of various physiological processes, including immune responses, metabolism, and inflammation. Here we will briefly discuss the bidirectional interaction between hypoxia and microbiota in the intestine.

Microbial metabolism and hypoxia

The dynamic interplay between the gut microbiota and colonic hypoxia encompasses specific microbial contributions that shape the oxygenation status of the colon. In the realm of microbial metabolism, certain bacterial strains exhibit pronounced capabilities in oxygen consumption and the generation of short-chain fatty acids (SCFAs) (Koh et al., 2016), thus influencing the local oxygen milieu.

Several anaerobic bacterial species, such as Bacteroides, Prevotella, and Firmicutes, are recognized for their involvement in fermentative processes (Roediger, 1980). These bacteria actively consume oxygen during metabolic pathways, creating microenvironments within the colon characterized by reduced oxygen levels. Notably, specific strains within these bacterial groups may exhibit varying capacities for oxygen consumption, contributing to the establishment of hypoxic niches (Mohammadi et al., 2022).

In the generation of SCFAs, Firmicutes, in particular, play a pivotal role. Within this phylum, certain species like Faecalibacterium prausnitzii and Eubacterium rectale are well-known butyrate producers (Rath et al., 2020; Singh et al., 2014). Butyrate, a significant SCFA, not only serves as an energy source for colonocytes but has also been implicated in influencing oxygen consumption within the colon. The ability of these specific strains to produce butyrate impacts the overall oxygenation status in the colonic microenvironment (Liu et al., 2018).

Moreover, Bifidobacterium, a common inhabitant of the gut microbiota, has been associated with the production of acetate (Singh et al., 2014). Acetate, along with propionate and butyrate, constitutes a major SCFA. The presence and activity of Bifidobacterium species contribute to the pool of SCFAs, potentially influencing the intricate balance of oxygen levels in the colon (Sahuri-Arisoylu et al., 2021).

In the context of dysbiosis and IBD, specific shifts in microbial composition have been identified. For example, a decrease in the abundance of Faecalibacterium prausnitzii, a butyrate-producing bacterium, has been observed in individuals with IBD. This dysbiosis not only alters the SCFA profile but also impacts oxygen consumption dynamics, contributing to the hypoxic conditions associated with inflammatory states (Santana et al., 2022).

The intricate relationship between the gut microbiota and host cellular responses involves the production of microbial metabolites that can exert specific regulatory effects on key molecular pathways. 1,3-diaminopropane, a diamine compound produced by certain gut bacteria, has emerged as a regulator of HIF-2α activity (Das et al., 2020). The metabolite exhibits inhibitory effects by specifically targeting the heterodimerization process, a crucial step in the formation of functional HIF-2α complexes. This interference disrupts the ability of HIF-2α to form active transcriptional complexes, thereby modulating the downstream effects on gene expression related to oxygen sensing and cellular adaptation.

Similarly, reuterin, a bioactive compound generated by Lactobacillus reuteri, has been identified as another microbial metabolite with inhibitory effects on HIF-2α (Das et al, 2020). Reuterin has been shown to interfere with the heterodimerization of HIF-2α, thereby influencing the transcriptional activity of HIF-2α-dependent genes. This inhibition represents a unique mechanism through which a microbial metabolite can directly impact the host’s oxygen-sensing machinery.

The relationship between specific bacterial strains and oxygenation status in the colon is a burgeoning area of research. Understanding the nuances of microbial contributions to hypoxia involves unraveling the distinct metabolic capacities of microbial species and strains within the complex ecosystem of the gut. As our knowledge deepens, targeting specific microbial contributors may hold therapeutic potential for modulating the oxygenation status of the colon in health and disease.

Hypoxia and the gut microbiome

The intricate relationship between hypoxia in the colon and the gut microbiota involves a dynamic interplay that extends from the compositional dynamics of microbial communities to their functional impact on host physiology. Specific microbial strains within the gut microbiota exhibit distinct responses to varying oxygen levels. Obligate anaerobes, including various strains of Bacteroides and Clostridium, thrive in anaerobic conditions, whereas facultative anaerobes, such as Escherichia coli, may exploit microaerophilic environments. Intermittent hypoxia-exposed mice show a higher abundance of Firmicutes and a smaller abundance of Bacteroidetes and Proteobacteria phyla than controls (Moreno-Indias et al., 2015). These alterations in the gut microbiome composition can, in turn, affect local oxygen levels and hypoxia signaling, creating a complex feedback loop between hypoxia and the gut microbiome.

In the context of inflammatory conditions associated with hypoxia, dysbiosis often ensues, characterized by shifts in the abundance of specific microbial strains (Santana et al., 2022). Notably, reductions in anti-inflammatory strains like Faecalibacterium prausnitzii have been observed in conditions such as IBD. Dysregulation of these strains can impact the metabolic output of the microbiota, influencing the production of key metabolites (Davies and Abreu, 2015).

As hypoxia-induced alterations in microbial metabolism unfold, they have downstream effects on host-microbiome crosstalk. Dysbiosis and changes in microbial composition can modulate host immune responses, influencing the inflammatory milieu in the colon and the host’s ability to respond to hypoxic conditions (Levy et al., 2017). Microbial products, including SCFAs, act as signaling molecules, influencing immune and metabolic pathways in the host.

At the strain level, specific microbial dysregulations may contribute to host pathology. Certain strains of Escherichia coli, for instance, have been implicated in the pathogenesis of CD (Lapaquette et al., 2010). Dysregulation of these strains can lead to the production of virulence factors, contributing to the inflammatory environment in the colon.

Understanding the strain-level responses to hypoxia has therapeutic implications. Precision interventions that consider the specific strains involved in dysbiosis could offer targeted strategies to restore microbial balance and mitigate the impact of hypoxia-associated dysbiosis on host health.

In conclusion, the gut microbiome influences HIF signaling in the intestines through microbial metabolites, such as SCFAs, that stabilize HIF-α subunits. Additionally, the microbiome can modulate HIF-mediated immune responses, contributing to the regulation of inflammation and immune-related diseases. Conversely, hypoxia in the gut microenvironment can impact the gut microbiome composition, establishing a bidirectional relationship between hypoxia and the gut microbiome. The nexus between hypoxia and the gut microbiota involves a sophisticated interplay of strain-specific responses, metabolic dynamics, and host interactions. These findings underscore the intricate interplay between the gut microbiome and HIF signaling, which has far-reaching implications for gut homeostasis, inflammation, and diseases such as IBD.

Hypoxia signaling regulation at the environment level

Environmental factors have emerged as important players in IBD pathogenesis (Table 3). Microplastics, pervasive pollutants in the environment, have been found to induce inflammation and disrupt the intestinal barrier, potentially exacerbating IBD symptoms (Frolkis et al., 2013). Air pollution, characterized by a complex mixture of particulate matter and chemical pollutants, has also been implicated in the development and progression of IBD (Ananthakrishnan et al., 2011). In addition, diet-induced inflammation has been shown to impact IBD (Knight-Sepulveda et al., 2015). The complex interactions between dietary factors, gut microbiota, and immune responses contribute to the inflammatory milieu in the gut. Diet-induced inflammation may lead to hypoxia within the gut microenvironment, further exacerbating the progression of IBD.

Table 3.

Environmental factors and impact on IBD

Environmental factors influencing IBD	Mechanism of impact
Air pollution	Inflammation, ROS, dysbiosis, dysregulated immune system, and reduce oxygen availability.
Microplastics	Inflammation, dysregulated immune system, dysbiosis, and disrupt gut barrier.
Diet	Inflammation, dysbiosis, and ROS.

 

Microplastics

Microplastics, which are small plastic particles less than 5 mm in size, have become a widespread environmental pollutant (GESAMP, 2016). They can be found in various ecosystems, including oceans, freshwater bodies, and even the air, raising concerns about their potential impacts on human and environmental health (Bergmann et al., 2017; Dris et al., 2016). Although the direct link between microplastics and hypoxia is still under investigation, emerging research suggests that microplastics can indirectly contribute to hypoxia through their effects on inflammation and gut barrier disruption. Animal studies have demonstrated that exposure to microplastics can trigger an inflammatory response in the gut. When microplastic particles accumulate in the GI tract, they can cause irritation and activate immune cells (Wright et al., 2020). This immune activation results in the release of pro-inflammatory molecules, leading to localized inflammation (Browne et al., 2013), that disrupts normal tissue oxygenation and contributes to the development or exacerbation of hypoxic conditions (Comerford and Cummins, 2016). Furthermore, microplastics have been found to disrupt the protective gut barrier. Disruption of this barrier allows harmful substances, such as bacteria or toxins, to cross into the bloodstream and trigger immune responses (Bischoff et al., 2014). Animal studies have shown that exposure to microplastics can compromise the integrity of the gut barrier (Browne et al., 2013). This “leaky gut” condition can result in the permeability of bacteria and other inflammatory substances, contributing to systemic inflammation and potentially exacerbating hypoxia (Bischoff et al., 2014).

To summarize, microplastics have been found to induce inflammation and disrupt the gut barrier in animal studies, which could potentially contribute to the development or exacerbation of inflammatory conditions such as IBD. Although the direct impact of microplastics on hypoxia is still being explored, the inflammation and gut barrier disruption caused by microplastic exposure could indirectly influence hypoxic conditions.

Air pollution

Air pollution, particularly fine particulate matter (PM2.5) and gaseous pollutants, has been recognized as a significant environmental health concern. It is known to have adverse effects on the respiratory and cardiovascular systems, but emerging research suggests that air pollution can also impact the GI tract, including its association with IBD and hypoxia. Studies have indicated that air pollution can contribute to the development and exacerbation of IBD. Exposure to PM2.5 has been linked to increased intestinal inflammation and oxidative stress in animal models (Liu et al., 2021). The inhalation of PM2.5 can result in systemic inflammation and the release of inflammatory mediators that may promote gut inflammation and worsen IBD symptoms (Wu et al., 2021). Additionally, air pollution can impact the composition of the gut microbiota, which plays a crucial role in IBD development and pathogenesis (Cushing et al., 2021; Xu et al., 2021). Furthermore, air pollution-induced systemic inflammation can lead to dysregulation of the immune system, potentially affecting the gut immune response and IBD progression (Lelieveld et al., 2015).

Air pollution can contribute to hypoxia through different mechanisms. High levels of air pollutants, such as nitrogen dioxide (NO₂) and carbon monoxide (CO), can directly reduce the oxygen-carrying capacity of the blood, impairing oxygen delivery to tissues (Cosselman et al., 2015), leading to tissue hypoxia. Notably, the exact mechanisms by which air pollution influences IBD and hypoxia are complex and multiple factors can influence hypoxia and IBD progression. Other factors such as genetic predisposition, diet, and lifestyle may also interact with air pollution exposure, influencing disease development and progression.

In summary, air pollution, particularly PM2.5 and gaseous pollutants, can impact IBD and hypoxia. Exposure to air pollution has been associated with increased intestinal inflammation, oxidative stress, and dysbiosis, which can contribute to the development and exacerbation of IBD. Additionally, air pollutants can directly reduce oxygen availability and induce systemic inflammation, leading to tissue hypoxia. However, further research is needed to fully elucidate the complex interactions between air pollution, IBD, and hypoxia.

Dietary toxicologic factors

Diet plays a significant role in the development and management of IBD. A Western-style diet, characterized by a high intake of refined sugars, saturated fats, and processed foods, has been associated with an increased risk of developing IBD (Ananthakrishnan et al., 2011). This dietary pattern promotes inflammation in the gut through several mechanisms, such as alterations in the gut microbiota composition and increased production of pro-inflammatory cytokines (Martinez-Medina et al., 2014). The chronic inflammation induced by a Western-style diet can potentially exacerbate hypoxic conditions and lead to a feed-forward loop involving the mechanisms discussed earlier in this review worsening the IBD condition.

High intake of pro-inflammatory foods can also impact IBD. Certain foods with pro-inflammatory properties, such as red meat, processed meat, and high-fat dairy products, have been associated with an increased risk of IBD and can worsen disease severity (Ananthakrishnan, 2015; Hou et al., 2019). These foods contain pro-inflammatory compounds, such as heme iron, advanced glycation end products (AGEs), and saturated fats, which can trigger inflammation in the gut and promote the production of ROS (Kalampokis et al., 2019; Kim et al., 2019; Larsson et al., 2018).

Furthermore, the balance between omega-3 and omega-6 fatty acids is crucial for maintaining gut health. Omega-6 fatty acids are pro-inflammatory, whereas omega-3 fatty acids have anti-inflammatory properties. Diets rich in omega-6 fatty acids, commonly found in processed foods and vegetable oils, have been associated with an increased risk of IBD and increased disease activity (Ananthakrishnan, 2015; Kalampokis et al., 2019). Conversely, diets rich in omega-3 fatty acids, found in fatty fish, walnuts, and flaxseeds, have been associated with reduced inflammation and improved outcomes in IBD (Jia et al., 2021; Tjonneland et al., 2010).

Additionally, diet plays a critical role in shaping the composition and function of the gut microbiota, which plays a crucial role in gut homeostasis and immune function. Dysbiosis, an imbalance in the gut microbiota, is commonly observed in individuals with IBD and is associated with increased inflammation (Ni et al., 2017). Diets high in processed foods, low in fiber, and lacking diversity can negatively impact the gut microbiota, contributing to inflammation and IBD progression (Ananthakrishnan, 2015; Kalampokis et al., 2019). Dysbiosis can produce SCFAs, including acetate, propionate, and butyrate, which accumulate in the gut (Santana et al., 2022). These SCFAs can stabilize HIF-α subunits by inhibiting PHDs, even under normoxic conditions (Santana et al., 2022). This stabilization of HIF-α subunits activates HIF signaling pathways, contributing to the perpetuation of inflammation.

Furthermore, water sources contaminated with pollutants pose a significant risk to GI health, as ingestion of contaminated water can introduce toxic compounds into the digestive system. Pollutants such as heavy metals, pesticides, and industrial chemicals can contaminate water supplies (Gupta et al., 2001). When individuals consume water contaminated with these substances over time, it can contribute to the development or exacerbation of IBD. Pollutants in contaminated water sources can increase oxidative stress in the GI tract (Frolkis et al., 2013). For example, heavy metals like lead and cadmium, which are commonly found in contaminated water, are known to induce the generation of ROS. The oxidative stress resulting from exposure to these contaminants can further disrupt the delicate balance of oxidative and antioxidative processes in the gut. Oxidative stress induced by waterborne pollutants can contribute to localized hypoxia within the GI tract (Frolkis et al., 2013). This occurs as oxidative stress leads to increased oxygen consumption while impairing blood flow due to vasoconstriction (Eltzschig and Carmeliet, 2011; Morote-Garcia et al., 2009). The combination of increased oxygen demand and reduced supply can create hypoxic microenvironments within the gut.

Food crops grown in soil contaminated with pollutants can serve as another route of exposure to toxic substances. Contaminated soil may contain heavy metals, pesticides, and persistent organic pollutants, which can be taken up by plants and accumulate in their edible parts (Frolkis et al., 2013). When contaminated crops are consumed, individuals are at risk of ingesting these pollutants, which can contribute to the development of GI disorders. Pollutants absorbed by plants can induce oxidative stress in the digestive system when consumed (Wei et al., 2017). For instance, exposure to pesticides like organophosphates and organochlorines through contaminated food can lead to increased ROS production (Sule et al., 2022). The resultant oxidative stress in the gut can disrupt the oxygen balance and promote hypoxia. Consumption of contaminated food can indirectly contribute to localized hypoxia within the GI tract. The oxidative stress triggered by pollutants in contaminated food can lead to increased oxygen consumption during inflammatory responses, resulting in localized hypoxia (Luttmann-Gibson et al., 2014). Additionally, these contaminants may directly affect blood vessel function, further compromising oxygen delivery to affected tissues.

In conclusion, diet-induced inflammation can impact the development and progression of IBD, potentially exacerbating hypoxic conditions in the gut. Western-style diets, high intake of pro-inflammatory foods, imbalanced omega-3 to omega-6 fatty acid ratios, and alterations in the gut microbiota composition can contribute to chronic inflammation, tissue damage, and dysregulation of oxygen levels. Further, ingestion of toxin-contaminated water and produce grown in contaminated soil and treated with pesticides contribute to the production of ROS and hypoxia that exacerbate IBD.

Hypoxia and intestinal fibrosis

In the intricate landscape of IBD, the emergence of fibrosis as a consequential feature is intimately intertwined with the hypoxic microenvironment that characterizes the inflamed mucosa (Colgan and Taylor, 2010; Triantafyllou et al., 2019). Chronic inflammation, a hallmark of IBD, perpetuates a state of hypoxia (Karhausen et al., 2004; Taylor and Colgan, 2007). This hypoxic milieu becomes a critical determinant in the progression towards fibrosis, orchestrating a cascade of cellular and molecular events that contribute to tissue remodeling and scarring (Cummins and Taylor, 2010).

Central to the hypoxia-induced responses in IBD are the HIFs that play a pivotal role in cellular adaptation to low oxygen levels. In the context of IBD-associated hypoxia, HIFs become activated, driving a transcriptional program that includes the upregulation of genes involved in angiogenesis, metabolism, and tissue repair. Although this adaptive response initially aims to restore oxygen supply and resolve tissue damage, prolonged or excessive activation of HIFs can lead to maladaptive outcomes, including fibrosis (Cummins and Taylor, 2010; Karhausen et al., 2004).

Angiogenesis, a hallmark feature of chronic hypoxia, assumes a dual role in the fibrotic processes within IBD (Corpechot et al., 2002; Kalluri and Sukhatme, 2000). The formation of new blood vessels is intended to restore oxygen supply to hypoxic tissues. However, these newly formed vessels often exhibit aberrant structure and function, contributing to the fibrotic remodeling of the tissue (Corpechot et al., 2002; Kalluri and Sukhatme, 2000). The delicate balance between proangiogenic and antiangiogenic factors in the hypoxic context of IBD influences the angiogenic response and, consequently, the progression of fibrosis.

A pivotal cellular player in fibrosis is the fibroblast, whose activation and transformation into myofibroblasts are potentiated by the hypoxic microenvironment (Thomas, 2018). Myofibroblasts are highly contractile cells responsible for excessive production and deposition of extracellular matrix (ECM) components, particularly collagen. The augmented ECM deposition, coupled with persistent inflammation, forms the structural basis for fibrotic scarring observed in IBD (Alkim et al., 2015; Cummins and Crean, 2017).

The dysregulated wound healing response in the hypoxic setting of IBD contributes to the perpetuation of fibrosis (Alkim et al., 2015). Excessive collagen deposition disrupts tissue architecture, impairs organ function, and sets the stage for severe outcomes associated with fibrosis. The intricate crosstalk between hypoxia, inflammation, and fibrosis creates a self-reinforcing loop, amplifying tissue damage and remodeling (Pousa et al., 2008).

Under hypoxic conditions, HIFs activation promotes genes involved in extracellular matrix remodeling, including collagen synthesis (Cummins and Taylor, 2010). TGF-β, a profibrotic cytokine, is induced by hypoxia, further stimulating fibrosis (Eltzschig and Carmeliet, 2011).

HIF-1α and HIF-2α have distinct roles in fibrosis development. HIF-1α enhances TGF-β signaling and collagen production, whereas HIF-2α may have a protective role by inhibiting TGF-β signaling (Günther et al., 2013; Higgins et al., 2007). Hypoxia-induced fibrosis perpetuates inflammation, exacerbating tissue damage in a feedback loop (Pastorelli et al., 2013). Exposure to toxic chemicals, such as heavy metals or environmental pollutants, can lead to cellular damage in the gut lining. These toxicological factors can disrupt blood vessel function, impair oxygen transport, and promote oxidative stress (Gupta et al., 2001). Oxidative stress induces inflammation and endothelial dysfunction, contributing to local hypoxia within the gut microenvironment (Zhang and Li, 2014). Understanding hypoxia’s role is crucial for developing targeted therapies to limit fibrosis and improve outcomes in IBD (Denko, 2008).

Therapeutically, understanding the specific details of the interplay between hypoxia and fibrosis in IBD offers potential avenues for intervention. Targeted strategies may involve modulating the HIF pathway, mitigating aberrant angiogenesis, or disrupting the fibroblast-to-myofibroblast transition. By unraveling the molecular intricacies of this complex interplay, researchers and clinicians may pave the way for more effective therapies aimed at alleviating fibrosis in patients with IBD, ultimately improving patient outcomes.

Environmental factors, hypoxia, and colorectal cancer

The intricate relationship between environmental toxicologic factors such as microplastics, air pollution, and diet on the activation of HIFs in CRC, sheds light on the dual implications for human health and environmental toxicology. Microplastics, ubiquitous environmental contaminants, have been associated with chronic inflammation, gut dysbiosis, and oxidative stress in the human GI tract (Tamargo et al., 2022). These factors, in turn, can activate HIF-1 and HIF-2, thereby potentially promoting CRC progression (Caputi et al., 2022). Additionally, the environmental impact of microplastics on aquatic and terrestrial ecosystems is discussed, highlighting their potential to disrupt wildlife and enter the human food chain.

Microplastics are now prevalent in various environmental settings, including oceans, freshwater systems, and soil, and their presence in the human GI tract raises significant concerns (GESAMP, 2016). One of the primary concerns regarding microplastics is their ability to contribute to chronic inflammation in the human gut (Ananthakrishnan et al., 2011). The ingestion of microplastics may irritate the intestinal lining, triggering an immune response. Persistent inflammation can lead to the release of pro-inflammatory cytokines and growth factors, promoting cell proliferation, survival, and angiogenesis, all of which are hallmarks of CRC (Ananthakrishnan et al., 2011).

Microplastics can disrupt the balance of the gut microbiota (Ni et al., 2017). Dysbiosis, characterized by an imbalance in gut microbial communities, can result in the production of harmful metabolites and inflammatory responses that are implicated in CRC development (Ni et al., 2017). Dysbiosis-induced inflammation can enhance the progression of early-stage CRC to more advanced stages (Artemev et al., 2022).

Microplastics have been associated with oxidative stress (Dris et al., 2016). Oxidative stress can activate various signaling pathways, including those regulated by HIFs (Chandel et al., 2000; Cummins, 2012). HIFs are known to promote angiogenesis, cell survival, and tumor growth in CRC (Corpechot et al., 2002; Semenza, 2012b). Microplastics-induced oxidative stress may contribute to the progression of CRC via HIF-mediated mechanisms. Oxidative stress in the tumor microenvironment can confer resistance to certain cancer therapies, including radiation and chemotherapy (Cummins, 2012). Microplastics-induced oxidative stress may enhance the adaptive response of CRC cells to therapy, reducing treatment efficacy.

The relationship between microplastics and CRC extends to the broader field of environmental toxicology. The accumulation of microplastics in the environment poses risks to aquatic life and may lead to the transfer of these particles and associated chemicals up the food chain to humans (GESAMP, 2016). Elevated microplastic exposure could translate into a higher risk of CRC, given the inflammatory and oxidative stress pathways discussed earlier.

Although research into the direct link between microplastics and CRC is ongoing, the potential mechanisms involving chronic inflammation, dysbiosis, oxidative stress, and environmental toxicology suggest a plausible association. Further investigations are needed to comprehensively understand the impact of microplastics on CRC risk, especially considering the growing prevalence of microplastics in our environment.

Air pollution is widely recognized for its adverse effects on respiratory health and its link to conditions such as lung cancer, its impact on CRC is a relatively newer area of research within environmental toxicology. Air pollution contains a mix of harmful substances, including fine PM2.5, volatile organic compounds (VOCs), heavy metals, and polycyclic aromatic hydrocarbons (PAHs). Individuals living in areas with high levels of air pollution are exposed to these pollutants through inhalation.

Numerous epidemiological studies have examined the link between air pollution and CRC. A study conducted by Ku and company in 2021 (Ku et al., 2021) indicated a positive association between long-term exposure to air pollutants such as PM2.5 and CRC incidence. Additionally, Jones et al. (2019) reported an increased risk of CRC in individuals residing in areas with elevated levels of NO₂, a common air pollutant. These findings underscore the need to investigate the toxicological mechanisms that underlie this association.

Several mechanisms have been proposed to explain the link between air pollution and CRC: Air pollutants, including PM2.5 and PAHs, are known to induce chronic inflammation in the respiratory system (Kelly and Fussell, 2020). This systemic inflammation may lead to increased levels of pro-inflammatory cytokines, which can promote CRC development and progression (Sui et al., 2022).

Air pollutants contain ROS and oxidative stress-inducing agents (Lodovici and Bigagli, 2011). Prolonged exposure to these pollutants can overwhelm the body’s antioxidant defenses, resulting in oxidative stress (Lodovici and Bigagli, 2011). Oxidative DNA damage and mutations may contribute to CRC initiation as well as progression through HIF induction and signaling as we discussed earlier.

Emerging evidence suggests that air pollution may alter the composition and diversity of gut microbiota (Frolkis et al., 2013). Dysbiosis of the gut microbiome has been linked to CRC development (Sui et al., 2022). Air pollution-induced dysbiosis may facilitate the progression of precancerous lesions to malignancy.

The association between air pollution and CRC highlights the role of environmental toxicology in understanding the impact of pollutants on human health. Investigating the chemical constituents and toxic properties of air pollutants is crucial for elucidating their mechanisms of action in CRC development. Additionally, toxicological assessments can aid in setting exposure limits and implementing regulations to mitigate the health risks associated with air pollution.

Air pollution represents a significant environmental factor that may contribute to the etiology of CRC. Understanding the toxicological mechanisms linking air pollution to CRC is essential for public health efforts aimed at reducing CRC incidence and improving air quality standards. This interdisciplinary approach underscores the importance of environmental toxicology in addressing the complex interplay between environmental pollutants and human health.

CAC, arising in individuals with chronic IBD, is influenced by a myriad of factors such as genetics, environmental factors, and tissue hypoxia (Maryńczak et al., 2022). Chronic inflammation and fibrosis provide a conducive microenvironment for CRC initiation and progression (Munkholm, 2003). The interplay between hypoxia, inflammation, and fibrosis can contribute to CRC’s aggressive behavior and poorer prognosis (Pastorelli et al., 2013). HIF-1α, HIF-2α, and HIF-3α contribute significantly to colon cancer progression (Figure 2). HIF-1α promotes angiogenesis, cell survival, and energy metabolism, whereas HIF-2α directly activates genes involved in pro-inflammatory cytokines (Xue et al., 2013), iron metabolism (Xue et al., 2012; 2017), and cell survival, such as platelet-derived growth factor receptor-beta (Tazzyman et al., 2010). These factors enhance PDGF signaling and angiogenesis, fueling tumor growth in CAC. HIF-3α overexpression promoted CRC cell growth and invasion through STAT3 signaling (Xue et al., 2016) as well as increasing EMT and metastasis to the liver through interaction with zinc-finger E-box binding homeobox 2 (ZEB2) (Villareal et al., 2023).

Figure 2.

Colitis-associated colorectal cancer progression. A schematic representation illustrates the contribution of environmental factors, including air pollution and microplastics, along with a pro-inflammatory diet, dysbiosis, and genetic predisposition to the development of IBD. These factors directly contribute to inflammation and reactive oxygen species (ROS), exacerbating IBD symptoms. Additionally, they activate hypoxic signaling (HIF-1α, HIF-2α, and HIF-3α), further contributing to inflammation, ROS accumulation, and genetic mutations that can lead to cancer development. Continued exposure to these factors potentiates cancer progression and creates barriers for effective treatment.

In addition to angiogenesis, hypoxia induces EMT in colonic epithelial cells, making them more invasive and promoting metastasis (Naidoo et al., 2017). HIF-1α and HIF-2α contribute to EMT induction through the upregulation of transcription factors like Snail, Slug, Twist, and ZEB1 (Comijn et al., 2001), HIF-3α promotes EMT by increasing iron loading and increasing ZEB2 (Villareal et al., 2023). Moreover, hypoxia promotes immune evasion and resistance to therapies in the tumor microenvironment. Both HIF-1α and HIF-2α regulate the expression of immune checkpoint molecules, particularly programmed death-ligand 1 (PD-L1), to suppress the immune response and facilitate tumor growth (Barsoum et al., 2014). Additionally, hypoxic tumor cells exhibit altered gene expression patterns and enhanced DNA repair mechanisms, leading to therapy resistance (Cummins, 2012).

Understanding the specific roles of HIF-1α, HIF-2α, and the largely unexplored HIF-3α in CAC is essential for developing targeted therapies that address the hypoxic regions within the tumor microenvironment. The interplay between hypoxia and chronic inflammation in CAC provides valuable insights into potential strategies for intervention and treatment.

Conclusion

In this concise review, we explored the intricate interplay between IBD, hypoxia signaling, and various environmental factors, shedding light on their impact on disease progression. The pathology of IBD remains multifaceted and not fully understood, but our analysis provided valuable insights into its complex nature and association with hypoxia and environmental factors.

Regulation of HIFs involves a complex interplay of factors, including ncRNAs, cofactors, coactivators, and oxidative stress. ncRNAs modulate HIF stability and activity, with specific ncRNAs targeting HIF-α for degradation under normoxic conditions, while also helping to exert their effects under conditions of HIF activation. Cofactors and coactivators like p300/CBP and the Mediator complex facilitate HIF-dependent gene expression, whereas the oxygen sensor, FIH, acts as a transcriptional coactivator.

We also discussed the impact of environmental factors like microplastics and air pollution on IBD. Microplastics induce inflammation and disrupt the gut barrier, potentially worsening IBD symptoms. Air pollution has been linked to IBD development and progression, likely due to chronic inflammation and oxidative stress. Furthermore, diet-induced inflammation can affect IBD pathogenesis and contribute to hypoxia. The complex interactions between diet, gut microbiota, and immune cells may lead to inflammatory responses and hypoxia within the gut microenvironment.

Regarding intestinal fibrosis and cancer associated with IBD, hypoxia plays a significant role in disease progression, activating HIF-1α and HIF-2α, promoting angiogenesis, immune evasion, and therapy resistance. Additionally, fibrosis plays a role in IBD and is influenced by hypoxia-induced fibroblast activation and collagen deposition, further impacting disease outcomes.

This review has highlighted the intricate connections between IBD, hypoxia signaling, and environmental factors. Further research is needed to fully understand the underlying mechanisms and identify targeted therapeutic interventions to mitigate hypoxia and environmental effects in IBD and CAC. The current literature provides insights into HIF-1α and HIF-2α’s involvement in IBD. However, the role of HIF-3α and its isoforms remains less defined, warranting further investigation. There is still much to explore in this disease, but recent studies referenced in this review offer promising potential to uncover valuable knowledge in the future.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Author contributions

L.V. drafted the manuscript and the figures. X.X. designed the topic and edited the final manuscript.

Funding

L.V. was partially supported by a Predoctoral Fellowship from the NIAID-funded Biology of Infectious Disease and Inflammation program (T32AI007538). X.X. received partial support from the National Institutes of Health (P20 GM130422), a Research Scholar Grant from the American Cancer Society (RSG-18-050-01-NEC), Environmental Health and Toxicology Pilot Awards from UNM Center for Native Environmental Health Equity Research (P50 MD015706), and New Mexico Integrative Science Program Incorporating Research in Environmental Sciences (NM-INSPIRES, 1P30ES032755). X.X. also acknowledges support from the Cardiovascular and Metabolic Disease Research Program Pilot Project Grant from UNMHSC Office of Research Signature Programs.

Data availability

All data are available through the cited literatures.