Endoplasmic reticulum stress in gut inflammation: Implications for ulcerative colitis and Crohn’s disease

Abstract

Eukaryotic cells contain the endoplasmic reticulum (ER), a prevalent and intricate membranous structural system. During the development of inflammatory bowel disease (IBD), the stress on the ER and the start of the unfolded protein response are very important. Some chemicals, including 4μ8C, small molecule agonists of X-box binding protein 1, and ISRIB, work on the inositol-requiring enzyme 1, turn on transcription factor 6, and activate protein kinase RNA-like ER kinase pathways. This may help ease the symptoms of IBD. Researchers investigating the gut microbiota have discovered a correlation between ER stress and it. This suggests that changing the gut microbiota could help make new medicines for IBD. This study looks at how ER stress works and how it contributes to the emergence of IBD. It also talks about its possible clinical importance as a therapeutic target and looks into new ways to treat this condition.

Key Words: Endoplasmic reticulum stress; Unfolded protein response; Inflammatory bowel disease; Mechanism of action; Clinical treatment

Core Tip: Endoplasmic reticulum stress, as an important cell - responsive protective mechanism, plays a crucial role in maintaining the stability of the intracellular environment of intestinal cells in the highly prevalent inflammatory bowel disease. If the mechanisms by which it plays a key role can be accurately analyzed, there is great hope of opening up a new path for the treatment of inflammatory bowel disease.

INTRODUCTION

Inflammatory bowel disease (IBD) is a collection of chronic, recurrent inflammatory disorders of the intestinal tract[1], primarily encompassing Crohn’s disease (CD) and ulcerative colitis (UC)[2], characterized by a complex pathogenesis involving genetic predisposition, environmental influences, dysbiosis of intestinal flora, and abnormal immune responses. Although CD can impact any segment of the gastrointestinal system, it predominantly involves the colon and terminal ileum[3-6]. Conversely, UC primarily impacts the mucosal layers of the colon and rectum, characterized by widespread and chronic inflammation. It generally manifests as segmental jumping inflammation of the intestinal wall in the colon and terminal ileum. The severity should not be underestimated, as epidemiological studies indicate that the prevalence of IBD is higher in North America and Europe, frequently linked to a familial history. Despite its rapid development and lack of familial history, the incidence of IBD in Asia is significantly lower than in Western countries. Research indicates that the prevalence of UC in Asia is around double that of CD, although this ratio is progressively diminishing due to the increasing incidence of CD. In developed countries, the incidence of CD is higher than that of UC (Figures 1 and 2)[7]. The incidence is increasing each year. Clinically, UC is often associated with diarrhea, abdominal pain, fever, alterations in bowel habits, and weight loss[8]. Medications can efficiently manage the symptoms, which are relatively stable. Conversely, CD may lead to anemia, diminished appetite, and other complications. In certain instances, it may lead to intestinal obstruction and stricture, necessitating surgical intervention in more advanced stages[9].

Figure 1 Incidence of inflammatory bowel disease per 100000 person-years. The incidence of inflammatory bowel disease varies markedly across the globe with annual incidence rates of approximately 27 per 100000 in Northern Europe; a total of 20 per 100000 in the United Kingdom; a total of 19 per 100000 in the United States; the incidence rate in Asia is about 3 per 100000 people; in Latin American countries such as Brazil and Argentina, the annual incidence rate is roughly 5 per 100000 people.

Figure 2 Incidence of Crohn’s disease and ulcerative colitis per 100000 person-years. The greatest incidence of Crohn’s disease occurs in North America, approximately 21 per 100000, followed by Europe at approximately 16 per 100000, Australia at about 14 per 100000, Asia at roughly 4 per 100000, South America at around 2 per 100000; the highest yearly incidence of ulcerative colitis occurs in several European locations roughly 24 per 100000, followed by North America at 14 per 100000, in China, the annual incidence of ulcerative colitis is roughly 11 per 100000, while in Australia, it is about 8 per 100000.

Pro-inflammatory cytokines like tumor necrosis factor (TNF)-α and interleukin (IL)-1β[10] are produced in significant quantities by persistent inflammation in IBD. These cytokines not only worsen local inflammation but also raise the metabolic load on intestinal cells and cause endoplasmic reticulum (ER) stress (ERS). By activating signaling pathways such inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6), ERS further encourages the release of pro-inflammatory cytokines, resulting in a vicious loop in the intestine[11]. ERS in this process not only causes intestinal epithelial cells to undergo apoptosis and autophagy dysfunction, which destroys the intestinal barrier and permits bacteria and toxins to enter the intestinal wall, exacerbating inflammation; it also alters the diversity and composition of the intestinal microbiota, upsetting the biota’s equilibrium, lowering intestinal immune tolerance, and encouraging chronic and persistent inflammatory responses in IBD[12-14]. ERS induced cell death and impaired autophagy cause damage to the mucosal layer and immune cell activation in UC, which results in a persistent immunological response[15]. And ERS in CD worsens the immunological response by encouraging intestinal inflammation at the whole-layer level, which results in the formation of a discontinuous ulcerated zone. Thus, throughout the inflammatory process, ERS produces a complicated pattern of immunological dysregulation that regulates the contacts between immune cells and intestinal epithelial cells, resulting in distinct immunopathologic aspects of CD and UC. Additionally, addressing the main mechanisms of ERS in conjunction with immune regulation and microbiota restoration is probably going to be a successful tactic for reducing persistent inflammation and repairing the intestinal barrier in IBD[16].

In conclusion, ERS plays a big role in the development of IBD by activating related signaling pathways. This leads to adverse effects like the death of intestinal epithelial cells, impaired autophagic function, and changes in the gut microbiota. These processes yield unique immunopathological characteristics in CD and UC. In spite of this, there isn’t enough thorough and extensive research on how to combine immune regulation with gut microbiota restoration. We have inadequately investigated the mechanisms by which ERS leads to IBD at both micro and macro levels. The research for this study mostly uses papers from the last five years. It did this by searching carefully in databases like PubMed, Google Scholar, and Web of Science for papers that talk about ERS, gut inflammation, UC, and CD. A lot of attention is being paid to high-quality studies that include mechanistic research, clinical trials, and systematic reviews. The goal is to figure out how ERS affects intestinal epithelial cells, immune responses, and the gut microbiota. The review also looks at the immunopathological differences between UC and CD. This makes sure that this research gap is filled in a systematic, thorough, and targeted way.

BASIC MECHANISMS OF ERS

ERS is a cellular stress response that happens when too many unfolded or misfolded proteins build up in the ER because the ER isn’t working right or because proteins are folding too much[17,18]. It sets off the cellular stress response. This stress response triggers the unfolded protein response (UPR), which aims to restore the normal function of the ER. IRE1, PERK, and ATF6 are the three main signaling pathways that enable UPR (Figure 3)[19].

Figure 3 Unfolded protein response pathways in endoplasmic reticulum stress. Endoplasmic reticulum stress is triggered when protein folding in the endoplasmic reticulum goes awry and unfolded or misfolded proteins aggregate abnormally in the endoplasmic reticulum, followed by unfolded protein response to correct the situation, including inositol-requiring enzyme 1, protein kinase R-like endoplasmic reticulum kinase, and activating transcription factor 6. IRE1: Inositol-requiring enzyme 1; PERK: Protein kinase R-like endoplasmic reticulum kinase; ATF6: Activating transcription factor 6; ER: Endoplasmic reticulum; TRAF2: Tumor necrosis factor receptor associated factor 2; ASK1: Apoptosis signal-regulating kinase 1; JNK: c-Jun N-terminal kinase; XBP1: X-box binding protein 1; NF-κB: Nuclear factor kappa B; RIDD: Regulated inositol-requiring enzyme 1 alpha-dependent decay; ERAD: Endoplasmic reticulum-associated degradation.

IRE1 is an important sensor in the ERS[20]. Its job is to find protein folding stress and set off a chain in response to this stress. IRE1 carries out its primary function through two mechanisms: First, it generates active X-box binding protein 1 (XBP1) transcription factors by splicing XBP1 mRNA through its RNase activity, thereby regulating genes associated with protein folding and degradation; second, it facilitates the release of pro-inflammatory cytokines by activating the c-Jun N-terminal kinase signaling pathway, which intensifies local inflammatory responses. New research shows that IRE1 does more in the immune system than just control pro-inflammatory cytokines. It also changes immune tolerance by interacting with the microbiota in the gut, which is a key part of how chronic inflammatory diseases like IBD develop[21]. IRE1 specifically boosts immune responses and inflammation by changing the balance and make-up of the gut microbiota and the way immune cells interact with microbes. This discovery expands the functional scope of IRE1, positioning it as a possible therapeutic target for various clinical situations, including immunological disorders and metabolic illnesses[22,23].

PERK lowers the production of proteins around the cell and reduces stress in the ER by phosphorylating eIF2α, activating ATF4, and changing the expression of genes related to the stress response. A new study found that PERK is important for maintaining metabolic homeostasis and changing the immune system[24]. It is also involved in the ERS. When it comes to glycolipid metabolism, PERK helps cells adjust to changes in their nutritional status by changing how fat tissue’s metabolism works[25]. PERK modulates immune cell function, such as that of macrophages and T cells, and promotes the release of pro-inflammatory cytokines; hence, it regulates chronic inflammatory responses in the immune system. The recent studies indicate that PERK activation significantly influences diabetes, obesity, and several metabolic disorders, intimately linked to its regulation of lipid metabolism. In contrast to IRE1, which promotes the regulation of immunological tolerance, PERK emphasizes the interplay between cellular metabolism, immune responses, and metabolic disorders[26,27].

ATF6 is a key transcription factor in the ERS[28]. It starts the expression of several genes and makes it easier for proteins to fold and break down when they move into the nucleus after being cut by enzymes in the ER. ATF6 traditionally functions to sustain ER homeostasis; however, recent research indicates that ATF6 also plays significant roles in immune system function and metabolic control. The recent findings indicate that ATF6 not only modulates anti-inflammatory responses and mitigates chronic inflammation but also enhances immunological tolerance and facilitates remission of autoimmune disorders[29]. In experimental autoimmune disorders, the activation of ATF6 mitigates the hyperactivation of immune cells and lessens pathogenic damage. Moreover, ATF6 intricately links to lipid metabolism and apoptosis, significantly influencing cell survival[30] death, and fatty acid production. ATF6 is different from IRE1 and PERK because it helps keep cells in balance by controlling immune tolerance and anti-inflammatory responses. This makes it a very interesting area of study for metabolic and immune diseases, especially when it comes to treating long-term inflammatory and autoimmune conditions[31].

SPECIFIC MECHANISMS OF ACTION OF IBD IN THE ERS PATHWAY

IBD and IRE1 signaling

IRE1 signaling in CD: In the etiology of CD, the aberrant activation and malfunctioning of immune cells is a primary element in disease progression. Research indicates the signaling pathway is crucial in CD. IRE1 increases IL-2, interferon-γ[32]. This directly affects the activation and proliferation of T cells, as well as their ability to differentiate and do their job through the activation of transcription factors XBP1 and nuclear factor kappa B (NF-κB), especially in T helper cell 1 (Th1) and Th17 cell-mediated immune responses. Th1 and Th17 cells are important pro-inflammatory immune cell types in CD. They release many pro-inflammatory cytokines, which make the intestines inflamed. The IRE1 signaling pathway amplifies the activation of Th1 and Th17 cells by this mechanism; hence, it intensifies inflammatory responses in CD. Moreover, IRE1 also affects macrophage function indirectly by controlling the production of cytokines and chemokines. It also changes the antiviral and antimicrobial activity of macrophages by changing their polarization state, which breaks down immune tolerance and makes chronic inflammation worse.

IRE1 also enhances autophagy and cell death in intestinal epithelial cells by turning on molecules that work downstream[33,34], such as c-Jun N-terminal kinase and caspase-12[35]. Autophagy is an intracellular breakdown mechanism that eliminates damaged organelles and misfolded proteins; hence, it contributes to the maintenance of cellular homeostasis. Still, an overactive autophagic response makes inflammation worse, especially when it happens in the intestines[36], where increased autophagy may make local immune responses and inflammation worse. Excessive apoptosis directly damages the intestinal mucosa and undermines the integrity of the intestinal barrier’s function. When the intestinal barrier doesn’t work right, it’s easier for things like bacteria, viruses, and toxins to get through the epithelial cells of the gut and into the wall of the gut[37]. This not only increases the risk of intestinal infection but also triggers the immune system, thereby intensifying the inflammatory phase of CD. To sum up, the IRE1 plays a part in the CD by increasing the production of pro-inflammatory cytokines, changing the activities of T cells and macrophages, and causing intestinal epithelial cells to die and undergo autophagy. New research shows that IRE1 not only does what it’s supposed to do in the ERS[38,39], but it also controls the immune system and the integrity of the intestinal barrier in a big way. This makes it a possible target for treating CD.

IRE1 signaling in UC: IRE1β, an isoenzyme of IRE1, is crucial in intestinal epithelial cells. Mucus is an essential element of the intestinal barrier, mostly consisting of mucin, a glycoprotein, and serves to safeguard the intestinal tract from bacteria, viruses, and toxins[40]. That’s why IRE1β controls the production and release of mucin, which protects the digestive tract from harmful substances and keeps the barrier integrity. When IRE1β function is impaired, mucin secretion in intestinal epithelial cells is greatly reduced. This makes the intestinal barrier less effective at protecting against invasions by toxins, raises the risk of intestinal inflammation. Dysfunction of IRE1β in individuals with UC is intimately linked to compromised intestinal barrier function and pathophysiology of the disease[41].

Furthermore, recent findings indicate that abnormal activation of the IRE1-XBP1 signaling pathway significantly contributes to the progression of UC. IRE1 initiates a cascade of downstream signaling molecules via XBP1 splicing[42], a mechanism that regulates protein folding and degradation while also enhancing the overexpression of pro-inflammatory cytokines (e.g., TNF-α and IL-6) through the activation of the NF-κB transcription factor. These cytokines are pivotal in the inflammatory response associated with UC.

Differences in the mechanism of action of CD and UC in the ire1 signaling pathway: Both CD and UC belong to IBD, and their pathogenesis involves complex immune responses and genetic factors. The IRE1 signaling pathway, in turn, is a cytoprotective mechanism that belongs to a part of the UPR initiated under ERS conditions, and it has a key role in maintaining ER homeostasis, dealing with protein misfolding, and in the inflammatory process. We can directly compare the specific differences in the mechanism of action of the IRE1 signaling pathway in CD and UC from the pathophysiological perspective of IBD, providing potential targets for personalized treatment of IBD and further focusing on improving the disease prognosis of patients[43,44].

Specifically, in terms of the site of inflammation, UC mainly affects the mucosal layer of the colon and is an inflammatory disease that begins in the rectum and spreads proximally and is limited to the mucosal layer of the colon. On the other hand, CD can affect any part of the gastrointestinal tract and the lesions are segmentally distributed. This means that in UC, IRE1 activation and downstream effects are more concentrated in the colon in UC, whereas in CD, these processes may be more widespread and discontinuous[45]. In terms of immune response, CD is associated with Th1 and Th17 cell-mediated immune responses, whereas UC is more involved in Th2 immune responses, suggesting that the IRE1 signaling pathway affects T-cell activation and macrophage antimicrobial capacity through different immune cells in order to modulate the immune cell response to intestinal microbes[46], indirectly influencing the different disease progression in UC and CD[47].

In conclusion, the IRE1 signaling pathway will further regulate the expression of inflammation by affecting the generation of XBP1s, leading to increased apoptosis, and easier invasion of pathogens and toxins into the colonic wall, which exacerbates local inflammatory responses. Therefore, given the study of the mechanism of action of IBD in the IRE1 signaling pathway[48], IBD can be treated directly with IRE1 inhibitors, such as APY29 or 4μ8C that block IRE1 autophosphorylation, reduce IRE1 activity, indirectly affect XBP1 maturation and downstream signaling activation, reduce the production of inflammatory mediators, and improve intestinal barrier function, thus continuing to alleviate intestinal inflammation[49,50].

IBD and ATF6 signaling pathway

ATF6 signaling in CD: The ATF6 is very important for controlling inflammatory mediators in people with CD, some of which are directly or indirectly related to CD. When ATF6 is activated, it makes localized inflammation in the gut worse and helps systemic inflammation spread by controlling pro-inflammatory cytokines. This not only facilitates the recruitment and activation of inflammatory cells but also sustains the inflammatory cascade, thereby worsening disease development. In particular, IL-6 makes the inflammatory response in the gut stronger by encouraging the production of acute-phase proteins[51,52]. On the other hand, TNF-α is a strong inflammatory mediator that sets off a series of inflammatory cascades that include cell death and immune cell activation. This keeps the inflammation going and weakens the intestinal barrier, creating a harmful cycle. Moreover, the activation of ATF6 enhances the expression of tight junction proteins, including claudins and occludins, which preserve tight junctions between epithelial cells while safeguarding against pathogens and deleterious chemicals[53,54]. This mechanism is essential for preserving the integrity of the intestinal barrier, thwarting the infiltration of exogenous deleterious chemicals. Nonetheless, under situations of ERS, the ATF6 signaling pathway may exert detrimental consequences. ATF6 may compromise intestinal barrier function by modulating the expression of genes associated with tight junction protein degradation, leading to a decrease in tight junction proteins and an increase in their dephosphorylation. This, in turn, contributes to the disassembly of tight junctions and heightened intestinal permeability, ultimately undermining the physical barrier function[55].

Consequently, ATF6 serves as both a pivotal pro-inflammatory factor and an essential regulator of intestinal immunological equilibrium. Both overactivation and under activation of ATF6 can result in the deregulation of intestinal immune responses, perpetuating a detrimental cycle that exacerbates disease progression. Putting more attention on the ATF6 signaling system and finding ways to stop it from being overactive or get it to work normally could lead to new ways to treat CD. By carefully controlling ATF6 activity, it might be possible to lower the heightened immune response and the resulting intestinal inflammation while also improving the repair and maintenance of the intestinal barrier. This would slow the progression of the disease and reduce the damage to intestinal tissues caused by long-term chronic inflammation.

ATF6 signaling in UC: ATF6 is very important for improving local immune responses because it changes the levels of several pro-inflammatory cytokines and, to some extent, makes systemic inflammation spread. The NF-κB signaling system, a crucial regulatory route in the development of UC, intricately associates with this effect, which extends beyond the unilateral action of inflammatory cytokines[56]. ATF6 not only activates intestinal immune cells but also directly or indirectly influences their survival, development, and functionality, hence augmenting their contribution. ATF6 also plays a role in controlling the immune system in the gut by releasing cytokines that cause inflammation and changing the way cells die, which affects the body’s internal balance[57]. In UC, ATF6 governs the transcription of autophagy-related genes, modulating immune cell activation and suppression; hence, it influences immunological tolerance and the advancement of inflammation. ATF6 facilitates the maturation of autophagosomes, aiding in the elimination of intracellular free radicals and reactive oxygen species while potentially modulating cell death and repair processes in response to severe stress[58,59].

In people with UC[60], gut inflammation that doesn’t go away causes ERS[61], which then changes the activity of antioxidant enzymes like superoxide dismutase, glutathione peroxidase[62], and catalase[63]. These enzymes collaborate to alleviate oxidative stress induced by intestinal inflammation in people with UC. If ATF6 is activated too much or too little, it can mess up this regulatory process. This can make oxidative damage in cells worse. This imbalance may compromise the intestinal barrier and induce oxidative injury in the intestinal epithelium, exacerbating inflammation and tissue damage. So, ATF6 does two things in UC: It makes inflammation worse and makes it harder for the gut’s immune system and tissue repair systems to work properly[64]. By modulating ATF6 activity, we can reduce the overactive immune response in UC and aid in restoring the intestinal barrier, thereby reducing the long-term damage to the gut that chronic inflammation causes. Also, the way ATF6 and antioxidant enzymes work together might lead to new ways to treat oxidative stress in UC.

Differences in the mechanism of action of CD and UC in the ATF6 signaling pathway: In CD, ERS is primarily caused by inflammation of the more widely affected intestinal region resulting from a combination of alterations in the intestinal microbial community, aberrant activation of the immune system, and more severe cellular damage. UC, inflammatory disease primarily confined to the colon, particularly the rectal region, resulting from mucosal barrier dysfunction and localized oxidative stress. ATF6 is the modulation of inflammatory mediators in both CD and UC, but the specific mechanisms and outcomes of its actions will vary depending on the type of disease, with ATF6 in CD associated with a broader pattern of inflammation and tissue injury, whereas in UC ATF6 is more focused on localized inflammation and mucosal repair[65].

Specifically, in terms of inflammatory mediator regulation, ATF6 regulation in CD including Th1 and Th17 cytokines, which are closely associated with the activation of intestinal immune cells and the spread of inflammation[66]. In UC, ATF6 may be more involved in the regulation of Th2 cytokines, which in turn are associated with mucosal repair and confinement of inflammation. Moreover, tissue injury in CD usually manifests as jumping lesions that can deep penetrating injuries and granuloma formation, and ATF6 is more associated with aberrant tissue repair, fistula and stricture formation in CD. Tissue injury in UC is confined to the mucosal layer of the colon, which manifests as a continuous inflammation, and thus ATF6 will be more involved in the regulation of the mucosa in UC, which includes the promotion of epithelial cell proliferation and differentiation. Therefore, ATF6 in UC will be more involved in the repair of the mucosal layer and the maintenance of intestinal barrier function[67].

IBD and the PERK signaling pathway

PERK signaling in CD: When the PERK pathway is activated in people with CD, it changes how antigen-presenting cells absorb, process, and present antigens. This changes T cell polarization[68]. These antigen-presenting cells function as essential intermediaries between external antigens and the immune system’s reaction. Their job is to find foreign antigens in the digestive tract, such as those made by bacteria, viruses, or food, and to process these antigens before they are presented to T cells. This process turns on T cells, which makes them multiply and make a number of cytokines. These cytokines start immune system responses in the area and make the inflammatory response stronger by spreading throughout the body[69]. In CD, the immune response is usually localized and segmental. This means that different parts of the intestine make different amounts, which make the inflammation and damage in the intestine worse and lead to ongoing immune attacks[70,71].

Also, when there is sustained ERS, the PERK pathway selectively increases the translation of ATF4, redox homeostasis, autophagy, apoptosis. The overexpression of ATF4 influences the survival and function of immune cells, especially under stressful conditions. In CD, ATF4 raises the expression of the stress-induced transcription factor CHOP. This then causes the production of pro-inflammatory mediators, which makes both local and systemic inflammatory responses stronger. This procedure also improves the recruitment and activation of immune cells, creating a detrimental cycle that exacerbates inflammation. This cycle exacerbates immunological damage in the intestine, particularly by compromising the intestinal barrier, resulting in significant pathological alterations, such as intestinal perforation and fistula formation. The PERK pathway controls immune responses by releasing cytokines[72]. It also affects the pathways for immune cell survival and apoptosis, which in turn changes how long immune cells live and how well they work. So, the PERK pathway control point in the immune system’s response to CD and could be used as a target for immunotherapeutic treatments[73].

PERK signaling in UC: When inflammatory and intestinal epithelial cells generate excessive reactive oxygen species in UC, they induce ERS. Oxidative stress is a typical cellular reaction to external or internal stimuli; nevertheless, when it surpasses the limits of the cell’s antioxidant mechanisms, cellular function is significantly impaired. In these situations, the PERK signaling pathway raises the production of CHOP through ATF4. This starts pro-apoptotic pathways that kill cells during prolonged ERS. This apoptosis directly increasing the gut’s vulnerability to foreign pathogens and immune system assaults and hence intensifying the inflammatory response. Furthermore, the PERK pathway can activate transcription factors, including AP-1, thereby augmenting the synthesis of pro-inflammatory cytokines. These cytokines make it easier for local immune cells to join the immune response and make it stronger when they do. This creates a persistent immune response network that makes the inflammatory reaction worse, making it harder for people with UC to get better from their chronic inflammatory condition and damaging more intestinal tissue.

PERK indirectly affects T cell activity by regulating the synthesis of cytokines, including IL-2, IL-22, and interferon-γ[74]. Specifically, by augmenting the activity of Th2 cells, PERK intensifies the inflammatory response. Th2 cells produce cytokines such as IL-2, which facilitate inflammation and tissue injury. Concurrently, PERK influences the functionality of regulatory T cells, diminishing their capacity to inhibit immunological responses and resulting in heightened immune reactivity in the gut; hence, it exacerbates the pathological course of UC[75,76]. The purpose of regulatory T cells is to maintain immunological balance in the gut, but compromising their activity can trigger increased inflammation and autoimmune reactions[77], also changes the level of activation of macrophages and dendritic cells, which makes it easier for M1-type macrophages to become polarized. By finding pathogens, these cells help the immune system start responding, which sets off the inflammatory cascade and makes the disease worse in people with UC. The PERK pathway controls the function of intestinal epithelial cells and has a big effect on immune cell[78,79].

Differences in the mechanism of action of CD and UC in the PERK signaling pathway: The mechanisms among CD and UC display both parallels and notable variation. CD causes segmental inflammation, affecting multiple regions of the gastrointestinal tract, while UC primarily localizes inflammation to the colon and rectum, displaying a continuous pattern. The disparity indicates that PERK activation in various parts of the gastrointestinal tract has unique influences on the local immune milieu and inflammatory response[80]. So, the main goal of treatment for CD should be to control segmental inflammation and any possible symptoms outside of the intestines. On the other hand, the main goal of treatment for UC should be to control chronic inflammation and help the mucosa heal through a more targeted and personalized approach[81].

The PERK pathway in CD patients plays a role in the impairment and the compromise of mucosal, hence, it affects the progression of inflammation. PERK is essential in modulating the equilibrium between pro-inflammatory and anti-inflammatory cytokines, which is fundamental to the inflammatory response[82,83]. So, therapeutic efforts should focus on both improving PERK’s anti-inflammatory effects to control inflammation and helping the mucosa heal by differentiating and surviving epithelial cells. The effect of PERK on immune cells, makes the inflammatory response in CD more complicated. This shows how important it is to make immunomodulators and biologics that can accurately control immune cell function and boost the immune response for better disease management[84-86].

In particular, small molecules like ISRIB may affect PERK’s effects on inflammation in a roundabout way. They do this by blocking the phosphorylation of eIF2a and the integrated stress response. This technique, in contrast to conventional immunosuppressive medicines, would specifically target stress response systems, thus diminishing nonspecific immune system suppression and lowering potential side effects[87]. Furthermore, given the intricate role of PERK in inflammation, further research into the precise regulation of its activity in clinical settings is crucial to improve the treatment of IBD[88]. Using small molecule inhibitors giving IBD patients a more personalized and targeted treatment plan (Table 1, Figures 4 and 5).

Figure 4 Comparison of normal intestine and intestine of inflammatory bowel disease patients. A and B: The predominant symptoms of inflammatory bowel disease include abdominal discomfort, diarrhea, and rectal bleeding; additional symptoms may encompass urgency to defecate, weight loss, anorexia, nausea, and anal pain, which, although manageable, exhibit a high recurrence rate. Te: Effector T cell; Tm: Memory T cell; DC: Dendritic cell; ERS: Endoplasmic reticulum stress; IBD: Inflammatory bowel disease; TNF: Tumor necrosis factor; IL: Interleukin; Th1: T helper cell 1; Th2: T helper cell 2; Th17: T helper cell 17.

Figure 5 Comparison of ulcerative colitis and Crohn’s disease in three pathways. A: Crohn’s disease can happen anywhere, from the mouth to the anal area, and it can affect the plasma membrane layer, it can also cause the intestinal wall to thicken, strictures to form, and fistulas to form; B: Crohn’s disease may exhibit dysfunction in the regulation of T- and B-cells, which has been associated with immune cell functional abnormalities due to endoplasmic reticulum stress. CD: Crohn’s disease; UC: Ulcerative colitis; ERS: Endoplasmic reticulum stress; TNF: Tumor necrosis factor; IL: Interleukin; NF-κB: Nuclear factor kappa B; XBP1: X-box binding protein 1; IRE1: Inositol-requiring enzyme 1; PERK: Protein kinase RNA-like endoplasmic reticulum kinase; Th1: T helper cell 1; ATF6: Activating transcription factor 6; ATF4: Activating transcription factor 4.

Table 1 Differences in ulcerative colitis and Crohn’s disease between the three pathways.

Access	Mechanism of action	UC	CD
PERK	Inhibiting the start of mRNA translation reduces protein synthesis, whereas activating ATF4 increases the expression of antioxidant enzymes	PERK affects the integrity of the mucosal barrier and the proper functioning of intestinal epithelial cells. It also changes the course of inflammation by controlling the levels of pro- and anti-inflammatory cytokines	PERK in CD affects disease progression primarily by modulating the activity of immune cells, including T cells and macrophages, that participate in the inflammatory response
IRE1	It facilitates mRNA splicing, augments protein folding ability, and supports ER adaptation	The mucosal layer of the colon is the only area where UC occurs, with IRE1 activation and its subsequent effects primarily localized there and associated with Th2 cell-mediated immune responses	CD can affect any part of the digestive tract, causing lesions to spread out in different areas and mostly triggering a Th1 and Th17 immune response
ATF6	The regulation of ER related gene expression and enhancement of protein folding capability are being discussed	ATF6 is a key player in fixing the mucosal layer and keeping the intestinal barrier working well in UC. It does this by improving the growth and differentiation of epithelial cells	A discontinuous lesion characterizes tissue damage in CD, and ATF6 frequently plays a role in aberrant tissue repair as well as the formation of fistulas and strictures

PERK: Protein kinase RNA-like endoplasmic reticulum kinase; IRE1: Inositol-requiring enzyme 1; ATF6: Activating transcription factor 6; ATF4: Activating transcription factor 4; ER: Endoplasmic reticulum; UC: Ulcerative colitis; CD: Crohn’s disease; Th2: T helper 2 cell; Th17: T helper cell 17; Th1: T helper cell 1.

EXPLORING STRATEGIES FOR ERS IN THE TREATMENT OF IBD

Amino salicylic acid

The management of IBD, particularly UC, extensively utilizes amino salicylic acid. The main way these medicines work is by stopping cyclooxygenase and lipoxygenase from working. This lowers the production of prostaglandins and leukotrienes, which reduces inflammation in the area. In addition, they change how the ERS by blocking the IRE1 and PERK signaling pathways. This lowers the apoptosis caused by ERS, protecting intestinal epithelial cells, increasing cell survival, and restoring ER homeostasis. Mesalamine, the main aminosalicylate, helps proteins fold correctly in the ER and stops the buildup of misfolded proteins. It also effectively reduces ERS, slows down acute inflammatory reactions, and stops intestinal epithelial cells from dying. The intestines metabolize balsalazide into 5-aminosalicylic acid (5-ASA), which directly affects the intestinal mucosa, reduces oxidative stress, and reduces inflammation. These pharmaceuticals have anti-inflammatory and antioxidant characteristics while also safeguarding the intestinal barrier and mitigating intestinal damage[89].

We choose aminosalicylate medications based on the patient’s condition. During the acute period, particularly for mild to moderate UC patients exhibiting more pronounced symptoms, mesalamine and balsalazide serve as the principal agents for induction therapy. Mesalamine is especially appropriate for individuals with localized colonic and rectal illness, since it can successfully diminish inflammation and restore intestinal barrier function by oral or local administration (e.g., suppositories)[90]. Balsalazide is a prodrug of 5-ASA[91] that breaks down in the intestines and acts directly on the intestinal mucosa. This makes it a great choice for people who can’t handle mesalamine. Patients exhibiting more severe acute symptoms may utilize oxalazine for induction therapy; however, its side effects, particularly gastrointestinal pain, necessitate vigilant monitoring.

During the maintenance phase, mesalamine and olsalazine (a disulfide derivative of 5-ASA) are the preferred medications. Mesalamine is appropriate for patients with stable symptoms, and prolonged maintenance therapy aids in postponing recurrence, particularly in those with confined intestinal involvement. Long-term maintenance therapy of UC largely utilizes olsalazine, which persists in modulating ERS and diminishing the recurrence of chronic inflammation. Selecting a suitable aminosalicylate for various individuals not only alleviates symptoms but also enhances intestinal barrier function by modulating ER homeostasis, thereby decreasing disease relapse rates. During treatment, it is essential to examine crucial criteria such as patient tolerance, disease location, disease duration, and inflammation severity to select the proper medication and provide long-term monitoring[92].

Corticosteroids

Corticosteroids such as prednisone and budesonide are crucial in managing IBD, particularly during acute exacerbations, as their strong anti-inflammatory properties offer swift symptom alleviation. Prednisone does its job by attaching to the glucocorticoid receptor, going into the cell nucleus, controlling gene expression, stopping the production of cytokines that cause inflammation. This diminishes both systemic and localized inflammation. Furthermore, prednisone suppresses phospholipase A2, diminishing the synthesis of prostaglandins and leukotrienes and thus contributing to the mitigation of the inflammatory response. It is particularly efficacious in moderate-to-severe IBD, especially in steroid-dependent individuals, by swiftly managing symptoms and inflammation. Budesonide, a glucocorticoid characterized by significant local efficacy and minimal systemic absorption, primarily targets the gastrointestinal tract to regulate inflammation and hence reduce systemic adverse effects. It is notably appropriate for mild to severe CD, particularly in instances involving the ileocecal region and right-sided colon.

Clinical practice must customize the administration of corticosteroids based on the specific state and severity of each patient’s disease. In cases of acute flare-ups, particularly for patients needing swift symptom alleviation, prednisone is the preferred medication, which can be taken either orally or intravenously, with dosage modifications contingent upon patient tolerance. Once acute symptoms stabilize, systematically reduce the dosage or transition patients to localized treatments like budesonide to mitigate the adverse effects of corticosteroids, osteoporosis, diabetes, hypertension. Budesonide is the recommended option for maintenance therapy in mild to moderate CD for steroid-dependent patients, due to its reduced systemic side effects. We must base the treatment strategy on the disease activity, the specific regions involved, the patient’s therapeutic response, and the risk of corticosteroid-related adverse effects, while continuously monitoring the patient’s overall health and disease progression[93].

Immunosuppressants

Immunosuppressive agents are essential in IBD, particularly for individuals who are reliant on steroids or have inadequate responses to standard therapies. Common immunosuppressive agents comprise azathioprine, 6-mercaptopurine, methotrexate, and cyclosporine. By stopping the production of purines, azathioprine and 6-mercaptopurine slow down the growth of lymphocytes. This lowers immune responses and inflammation. By inhibiting T-cell growth, they facilitate immunological tolerance and are crucial in maintenance therapy. Specifically, azathioprine aids in diminishing long-term steroid dependence in patients reliant on steroids and can extend durations of illness remission. Methotrexate inhibits dihydrofolate reductase[94], which obstructs DNA synthesis and attenuates immune cell proliferation, resulting in significant anti-inflammatory effects. Individuals with CD who exhibit inadequate responses to conventional treatments, particularly those intolerant to steroids or immunosuppressants, frequently utilize it. For induction therapy in severe acute IBD, cyclosporine extensively blocks T-cell activation and cytokine generation, especially in individuals whose symptoms remain unmanageable with alternative medications[95].

Clinical treatment typically tailors the administration of immunosuppressive medicines based on the patient’s disease type, progression, response to alternative therapies. In steroid-dependent patients or those with inadequate responses to steroids, azathioprine or 6-mercaptopurine serves as primary maintenance therapy. These medications facilitate the preservation of remission and diminish reliance on steroids. We may administer methotrexate as induction therapy to exhibiting symptoms, especially those unresponsive to alternative treatments. Patients unresponsive to standard therapies often utilize methotrexate for prolonged maintenance therapy. Cyclosporine is effective for managing severe acute exacerbations due to its powerful immunosuppressive properties. Administration of immunosuppressive drugs necessitates consistent monitoring of patient tolerance, hepatic and renal function, and hematological parameters to mitigate potential adverse effects. Moreover, while using immunosuppressive medications, it is crucial to evaluate the infection risk, as these agents can heighten susceptibility to infections by inhibiting the immune response.

Biological agents

Biologic drugs are essential for patients unresponsive to conventional therapy or those with inadequate tolerance. TNF-α monoclonal antibodies (like infliximab and adalimumab), anti-IL-12/23 antibodies (like ustekinumab), and anti-integrin antibodies (like vedolizumab) are some of the most common biologic medicines. These medications primarily function by targeting specific cytokines or receptors to inhibit immune responses. Infliximab inhibits TNF-α by obstructing its attachment to cell surface receptors; hence, it suppresses TNF-α induced inflammatory reactions. Adalimumab, similar to infliximab, is suitable for long-term management and typically administered through subcutaneous injection, making it a viable option for individuals who are intolerant to intravenous infusions or insensitive to infliximab. Ustekinumab inhibits IL-12 and IL-23, primarily diminishing the activation of T cells and attenuating the inflammatory response. Patients who show inadequate responses to TNF inhibitors frequently utilize it, particularly for managing CD and UC[96,97].

Disease activity, patient tolerance, medical history, and responses to previous drugs must all be considered when tailoring the biologic therapy strategy. It is best to use anti-TNF biologics as an induction therapy for people with severe acute symptoms who have not responded to or can’t tolerate conventional medications. Long-term treatment frequently employs adalimumab and ustekinumab for maintenance therapy. Ustekinumab is especially appropriate for people who have not responded to or have had negative reactions to TNF inhibitors. Anti-integrin antibodies, like vedolizumab, can also target gut integrins specifically, which makes it harder for leukocytes to get into the digestive tract. Patients experiencing gut-specific inflammation can benefit greatly from these antibodies, especially when conventional immunosuppressants and TNF inhibitors have proven ineffective. In clinical practice, giving biologic medicines requires constant monitoring of the drug’s effectiveness and side effects[98], along with checking on the patient’s immune system and figuring out the risk of infection so that the treatment plan can be changed as needed to keep the patient in remission (Table 2).

Table 2 Commonly used drugs for the treatment of inflammatory bowel disease.

Drugs	Mechanism of action	Clinical application	Adverse reaction
Mesalamine	Decreased synthesis of prostaglandins and leukotrienes	Patients with mild to moderate UC should maintain remission	Gastrointestinal upset, headaches, and kidney damage
Prednisone	It reduces leukocyte migration and suppresses the immune response	Short-term induced remission in moderately to severely active CD and UC is possible	Weight gain osteoporosis diabetes
Budesonide	Inhibits multiple inflammatory mediators	There was an induced remission of moderate to mild CD	Gastrointestinal distress and mild hypertension
Azathioprine	It inhibits purine synthesis and reduces leukocyte activation	We maintain the remission of CD and UC while reducing our reliance on hormones	Bone marrow suppression, hepatotoxicity, and nausea
Infliximab	Anti-TNF-α inhibits inflammatory response	Both of these therapies are either ineffective or poorly tolerated	Infusion reactions and drug resistance
Ustekinumab	Anti-IL-12/23 inhibits activation of Th1 and Th17 cells	CD and UC are moderately to severely active	Injection site reactions: Risk of infection

IL: Interleukin; TNF: Tumor necrosis factor; UC: Ulcerative colitis; CD: Crohn’s disease; Th17: T helper cell 17; Th1: T helper cell 1.

CONCLUSION

An important factor in the development of IBD is ERS. People increasingly recognize its significance in regulating immune responses, intestinal barrier integrity, and cellular survival through the IRE1, PERK, and ATF6 signaling pathways, which operate through various mechanisms with distinct pharmacological agents. Aminosalicylic acid safeguards the intestinal epithelium by obstructing the ERS pathway and diminishing cellular apoptosis; corticosteroids mitigate inflammation during acute exacerbations by swiftly alleviating symptoms and are appropriate for mild-to-moderate CD; immunosuppressants shield the intestinal epithelium by reducing the ER burden, particularly benefiting hormone-dependent patients; and biologics inhibit cytokines, such as TNF-α, through targeted suppression, thereby decreasing inflammation and tissue damage, and those whose IBD is moderately to severely active and has not responded to standard therapies may benefit from this[99]. Nevertheless, the current pharmacological treatment inadequately addresses the intrinsic mechanisms of several ERS pathways. In the future, IBD should focus on the meticulous management of ERS pathways to enhance the long-term prognosis of patients by targeting these signaling pathways[100].

The small molecule compound 4m8C can slow down the IRE1 pathway in people whose immune systems are overactive. This reduces the damage to the ER that leads to immune system dysfunction and cell death during high levels of inflammation. Giving ATF6 activators, like XBP1 small molecule agonists, to people with IBD whose intestinal barrier function is already inadequate may reduce intestinal permeability and stop further immune system damage[101]. Therapies that target PERK, like ISRIB, can help IBD patients with abnormal apoptosis and chronic inflammation keep the integrity of the intestinal epithelium and make it easier for the intestines to work again. The mechanisms of action of the three signaling pathways are intricate and interconnected, necessitating a therapeutic strategy that considers the unique pathological characteristics of each patient and implements a multifaceted therapy plan.

Research on intestinal microecology has progressed, revealing a connection between ERS and intestinal flora. Changing intestinal microecology can help us learn new ways to treat IBD. For better intestinal barrier function, active Akk bacteria make more and thicker intestinal mucus. This stops pathogens and harmful substances from directly interacting with the intestinal wall. When intestinal mucus breaks down, they create short-chain fatty acids. These bacteria supply energy to ensure the integrity of the intestinal wall remains intact. The intestinal wall offers a novel approach for the treatment of intestinal microbial agents. Future researchers should study how ERS affects the microbiome and immune system and use probiotics, prebiotics, and other microbiome regulators to avoid single-therapy issues. ERS is very important for intestinal epithelial cells, and it may also change the balance of microbes in the gut, which could affect immune responses. Prebiotics and probiotics are believed to modify gut microbiota, enhance gut barrier integrity, augment immunological tolerance. These effects are closely connected to managing ERS. So, future research should focus on the interactions among ERS, the immune system and gut microbiota. It should also look into multi-targeted, personalized treatment approaches to get around the limitations of single therapies and improve IBD patients’ long-term outcomes and quality of life.

The management of IBD should transition toward multi-targeted, personalized, and precise interventions. ERS is a new target for IBD therapy that will focus more on fine-tuning three signaling pathways based on the specifics of each patient’s disease. Future efforts will aim to enhance the understanding of these three signaling pathways, investigate multi-targeted, multi-level therapeutic strategies, and comprehensively regulate the signaling pathways to enhance patients’ long-term health outcomes. We aim to modulate signaling pathways, enhance the long-term prognosis of patients, and provide more tailored and efficacious therapeutic alternatives for individuals with IBD.

ACKNOWLEDGEMENTS

I would like to express my sincere gratitude to all those who have supported and helped me in this endeavor for their invaluable guidance and assistance.