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## Meet the editor

Dr. Partha Pal is a consultant gastroenterologist at the Asian Institute of Gastroenterology. He achieved high honors in his medical school and internal medicine training, receiving awards as the best student at the undergraduate and postgraduate levels. He has published over 60 peer-reviewed articles, mainly on interventional and clinical IBD, small bowel disease, interventional endoscopy, and pancreatic disease. He gained the

National Young Scholar Award in 2017. Most recently he received the Endoscopic Training Award for the year 2021 from the American Society of GI endoscopy (ASGE) for his training work on interventional IBD and small bowel endoscopy.

### Contents



## Preface

Ulcerative colitis (UC), together with Crohn's disease (CD), is one of the major forms of inflammatory bowel disease (IBD). UC affects only the colon and rectum, while CD can affect any part of the bowel. Epidemiological trends suggest that in a region where IBD incidence is increasing, UC is the predominant subtype in the early years of increased industrialization, followed by a rise in the incidence of CD. This book covers various aspects of UC: etiology, clinical manifestation, histopathologic diagnosis, the role of anti-inflammatory dietary components such as fermented rice bran, special populations such as children and expectant mothers, the emerging role of interventional endoscopy in colitis-associated neoplasia, and the management of postoperative complications.

The etiology of UC is still unknown but it is multifactorial. In a genetically susceptible host, the combination of altered gut microbiome and environmental factors ultimately triggers the common pathway of dysregulated immune activation. First chapter, "Etiology of Ulcerative Colitis", discusses the well-known etiological factors that are unique to UC. The chapter "Platelets in Ulcerative Colitis: From Pathophysiology to Therapy" highlights the unique role of platelet activation in amplifying immune response in UC, and summarizes current evidence to support the role of anti-platelet therapy in UC.

Intestinal and extra-intestinal complications and manifestations are summarized with specific reference to pediatric patients in "Complications of Ulcerative Colitis in Children".

The two chapters "Histomorphological Diagnosis of Ulcerative Colitis and Associated Conditions" and "The Role of the Pathologist in Ulcerative Colitis" provide a concise illustrated review of all aspects of histopathology in UC. Histologic diagnosis of UC and histology in different stages of the disease are covered, together with histological scoring systems, histologic remission, differential diagnosis (from infective or Crohn's colitis), histopathological changes in special conditions (e.g., post-operative status, acute severe colitis), diagnosis of co-existent cytomegalovirus infection, and colitis-associated neoplasia.

Pediatric ulcerative colitis is a distinct subset of UC. Differences between pediatric and adult UC, natural history, diagnostic algorithms, and overall management, including acute severe UC and very early onset IBD (VEOIBD), are highlighted in the chapter "Pediatric Ulcerative Colitis".

Another special population in UC is pregnant women, a group that poses unique clinical challenges to the treating physician. Pre-conception planning (fertility, counseling, contraception, inducing remission), pregnancy care (obstetric, nutritional and drug therapy, management of flare and acute severe colitis, the role of endoscopy), and postpartum care (lactation, thromboprophylaxis, and contraception) are discussed in detail in the chapter "Ulcerative Colitis and Pregnancy".

As in Crohn's disease, anti-inflammatory diets are being explored in UC. "Dietary Fermented Rice Bran Is an Effective Modulator of Ulcerative Colitis in Experimental Animals" highlights the potential role of anti-inflammatory dietary components in reducing gut permeability.

Finally, there is the emerging role of interventional endoscopy as a potential bridge between endoscopic and surgical therapy. The main indications in UC are endoscopic detection (using advanced endoscopic imaging) and resection of colitis-associated neoplasia, along with management of postoperative pouch complications. The chapter, "Role of Interventional IBD in Role of Interventional IBD in Management of Ulcerative Colitis(UC)-Associated Neoplasia and Post-Operative Pouch Complications in UC: A Systematic Review", is the first review of its kind and includes all currently available evidence for the role of interventional endoscopy in UC.

*Ulcerative Colitis - Etiology, Diagnosis, Diet, Special Populations, and the Role of Interventional Endoscopy* aims to act as a ready reference for the clinician treating ulcerative colitis. It provides indispensable updates on several relevant issues in the diagnosis and management of ulcerative colitis and has benefited from the collaboration of leading experts in various aspects of the disease. It aims to facilitate decision-making by gastroenterologists, IBD specialists, interventional endoscopists, dieticians, pathologists, surgeons, and pediatricians treating UC patients in their clinical practice.

> **Partha Pal**  Asian Institute of Gastroenterology, Department of Gastroenterology, Hyderabad, India

Section 1

Ulcerative Colitis - Etiology

## Section 1 Ulcerative Colitis - Etiology

### **Chapter 1** Etiology of Ulcerative Colitis

*Carmen-Monica Preda and Doina Istrătescu*

#### **Abstract**

Ulcerative colitis (UC) is a chronic immune-mediated inflammatory disorder of the colon, related to a complex contribution of environmental and host factors that increase the susceptibility of individuals. Genetics, environmental factors, dysbiosis, and dysregulated immune system: all these components together are necessary to trigger IBD. The temporal sequence of events leading to UC is unknown. UC is not a classically transmitted genetic affliction. The risk of developing the disease is increased in first-degree relatives but there is no evidence that it is related to genetics or environmental factors exposure early in childhood. The environmental factors associated with ulcerative colitis development are diet, smoking, breastfeeding, use of antibiotics or NSAIDs, urban location, pollution exposure, appendectomy, and hypoxia. In normal intestinal homeostasis environment, both innate and adaptive immune systems are integrated with various mediators and immune cells to maintain tolerance to commensal organisms. In UC patients, the innate immune system is responsible for inducing inflammatory reactions, while the adaptive immune system is crucial in the evolution of chronic inflammatory events. With the shifting global burden of ulcerative colitis, more research is needed to better understand the illness's etiology in order to prevent and find potential novel therapeutic targets or predictors of disease burden in the future.

**Keywords:** ulcerative colitis, inflammatory bowel disease, etiology, genetics, environmental factors, immune response

#### **1. Introduction**

Ulcerative colitis (UC) is a chronic immune-mediated inflammatory disorder of the colon (IBD) that is hypothesized to be related to a complex contribution of environmental and host factors, that increase the susceptibility of individuals and events that damage the mucosal barrier, alter the gut microbiota's healthy balance, and inappropriately enhance gut immune responses, are all known to promote illness onset [1–3].

Despite knowing the pathophysiology of the disease, the exact etiology is not so clear, but it is likely to be multifactorial. Genetics, environmental factors, dysbiosis, and dysregulated immune system: all these components together are necessary to trigger IBD. The temporal sequence of events leading to UC is unknown up to now.

#### **2. Ulcerative colitis etiology**

#### **2.1 The role of genetics in UC**

A number of genetic variables have been associated with ulcerative colitis. There are 163 susceptibility disease-associated loci associated with IBD. Thirty of them are associated with Crohn's disease (CD), 23 with ulcerative colitis and most of the remaining ones are common to both CD and UC, as well as other conditions: psoriasis, celiac disease [4, 5]. The unique genes associated with UC can be divided into genes that affect epithelial barrier (ECM1, HNF4A, CDH1, LAMB1, and GNA12), genes that are immune-mediated (IL8RA / IL8RB, IL2 / IL21, IFNG / IL26, IL7R, TNFRSF9, TNFRSF14, IRF5, LSP1, FCGR2A) and others (OTUD3 / PLA2G2E, PIM3, DAP, CAPN10, JAK2). The genes that overlap with Crohn's can also be divided into those that are immune-mediated: IL10, CARD9, MST1, ICOSLG, IL1R2, YDJC, PRDM1, TNFSF15, SMAD3, PTPN2, TNFRSF6B, HLA: DRB1\*03 and others: ORMDL3, RTEL1/SLC2A4RG, PTGER4, KIF21B, NKX2-3, CREM, CDKAL1, STAT3, ZNF365, PSMG1, IL23R, IL12B, AK2, FUT2, and TYK2 [4, 6–9]. Further details are presented in **Tables 1**–**5** [4, 7, 9].

Recent studies have shown that the genes of the major histocompatibility complex are major genetic determinants of susceptibility to UC. The human leukocyte antigen (HLA) region on chromosome 6 is connected with the greatest genetic signals within UC-specific loci. Sixteen HLA allelic correlations for ulcerative colitis were revealed after further fine mapping genetic study, including HLA DRB1\*01\*03 for IBD colonic involvement [10, 11].

A unique yet rare missense mutation in the adenylate cyclase 7 gene (ADCY7) that doubles the risk of ulcerative colitis was discovered in a recent whole-genome sequencing study of over 2,000 ulcerative colitis patients. The ADCY7 gene has the strongest genetic connection with ulcerative colitis outside of the HLA area. ADCY7 is one of ten enzymes that convert ATP to cAMP. Additionally, numerous ulcerative colitis-specific genes are involved in epithelial barrier function regulation [12].

UC is not a classically transmitted genetic affliction. The risk of developing the disease is increased in first-degree relatives but there is no evidence that it is related to genetics or environmental factors exposure early in childhood or both conditions.


#### **Table 1.** *Genes associated with UC that affect the epithelial barrier.*

*Etiology of Ulcerative Colitis DOI: http://dx.doi.org/10.5772/intechopen.106842*


#### **Table 2.**

*Genes associated with UC—Immune-mediated.*

Twin studies that compared the concordance rates of monozygotic and dizygotic twins backed up this conclusion. Monozygotic twins had a higher concordance (up to 17 percent in UC and up to 55 percent in CD) than dizygotic twins (6 percent in UC and 4 percent in CD), suggesting that the genetic trait is more important in Crohn's disease than ulcerative colitis. Furthermore, in both Crohn's disease and ulcerative colitis, genetic factors appear to differ across Western and Asian locations [13–18].

Another study reported a concordance rate among monozygotic twins of 67% for CD and 13–20% for UC; in one study, a lower rate of concordance for CD has been reported among monozygotic twins [19].

The overall lifetime risk (absolute risk) of developing IBD for first-degree relatives of a UC patient is 1.6% in non-Jews and 5.2% in Jews. Similarly, the risk (age-corrected) for offspring of a UC patient developing IBD is 11 and 2.9–7.4% in non-Jews and Jews, respectively. There is an increased risk (33–52%) in offspring with both affected parents [20].

However, there are many individuals that, when assessed by a polygenic risk score, do not present a genetic predisposition that accounts for all of the susceptibility loci. Despite the significance of genetic predisposition, no single genetic mutation can account for the rapid progression of UC. It is also unclear why some people with


#### **Table 3.**

*Other genes associated with UC.*


*Etiology of Ulcerative Colitis DOI: http://dx.doi.org/10.5772/intechopen.106842*


#### **Table 4.**

*Genes associated with IBD—Immune-mediated.*



#### **Table 5.**

*Other genes associated with IBD.*

UC-associated risk variations remain healthy while others develop UC or perhaps several immune-mediated diseases [21, 22].

IBD susceptibility and progression cannot be explained solely by genetics. This indicates that abnormal adaptive immune responses and epithelial barrier dysfunction play a crucial role in disease development. Nongenetic factors, notably epigenetics, may have a role to play [23, 24]. A summary of the genetic factors that are associated with UC can be seen in **Table 6**.


#### **2.2 Environmental factors in UC**

The rapid growth in the incidence of ulcerative colitis in newly industrialized nations implies that environmental factors have a role in disease initiation [25].

Ulcerative colitis comes initially in urban locations, with a quick rise in incidence followed by a slowing period. After that period, Crohn's disease grows in frequency, finally approaching that of UC. Industrialization is associated with a new urban lifestyle, pollution exposure, dietary changes, antibiotic access, improved cleanliness, and fewer infections, all of which are considered general contributory factors [26, 27]. Urbanization is no longer regarded as a risk factor, according to studies from both Western and developing jurisdictions [28–30].

#### *2.2.1 Early life factors*

Breast milk is often one of the first foods offered to babies. Breastfeeding has been shown in studies to help prevent the development of immune-mediated disorders by preserving the epithelial barrier, avoiding infections, and offering direct immunologic advantages [31–33]. A meta-analysis of 35 studies discovered a link between breastfeeding and the likelihood of developing ulcerative colitis later on [34].

Human milk oligosaccharides (HMOs), which are nondigestible molecules and free competitors to enteric pathogens, highly influence the composition of the infant gut microbiota. Formula-fed children's fecal microbiota is poorer in bifidobacteria and lactobacilli (only 40 to 60%), whereas breastfed children have a higher proportion of bacteria (90%). It demonstrates the important role of breast milk oligosaccharides in the establishment of the infant gut microbiota. HMOs are digested by gut bacteria and produce a variety of metabolites, including short-chain fatty acids (SCFA), which are well-known for their immunomodulatory characteristics. SCFA boosts numerous activities of the epithelial barrier after being absorbed by colonic epithelial cells. The mucus layer that covers epithelial cells is necessary for the epithelial barrier to remain intact. SCFA increases mucus production by upregulating mucin 2 expression, protects against inflammatory insults, and fortifies the tight junction barrier. They also modulate the inflammatory immune response by interacting with DC and T cells [35–38].

Hygiene hypothesis: evidence suggests an inverse relationship between the risk of UC and early childhood exposure to farm animals, pets, larger families, more siblings, and childbirth mode. As an internal environmental component, all of these early exposures are known to be major drivers for more diversified gut microbiota in early life. Although external variables are equally key determinants of health and disease, the positive relationship between the gut microbiota, host genetics, and immune system is an essential environmental factor in disease etiology [39–43].

Several studies have looked into whether antibiotic usage early in life predisposes to IBD in Western countries and have consistently shown this link [44]. According to a Canadian nested case-control study, 58 percent of juvenile IBD patients got antibiotics in their first year of life, compared to 39 percent of healthy controls. The number of antibiotic courses taken and the degree of the elevated risk of ulcerative colitis were also found to have a dose-response relationship [45]. Although the results of these studies are significant, other studies have failed to establish a relationship between the use of antibiotics and the risk of ulcerative colitis [46].

#### *2.2.2 Adolescent influences*

Quitting smoking has been linked to an increased risk of ulcerative colitis [47]. The pathophysiology of how smoking causes ulcerative colitis or protects a person from developing the condition is unknown. Active or passive smoking produces milder forms of the disease in the case of UC, requiring fewer surgeries throughout its development and less need for immunosuppressive drugs. It is unclear whether the rise in ulcerative colitis is related to smoking cessation patterns. Indian research shows that there is no link between quitting smoking and the development of ulcerative colitis. As for the association between active smoking and the incidence of Crohn's disease, there is also no evidence in their studies [30, 48].

Studies proposed the divergent effect of appendectomy on UC suggesting inflammation of appendix might have protective interplay with the disease [49, 50].

The dietary habits of adolescents are characterized by excessive consumption of meat and fat and an insufficient intake of fiber, fruits, and vegetables. There is also a tendency to frequently consume processed food and high sugary or soft drinks that increase the risk of developing IBD [51]. This subject will be further discussed in the Diet chapter.

Stress and distress can cause depression and anxiety. Psychological comorbidity is three times higher in those with IBD than in the general population. More than a quarter of people with IBD will have depression at some point in their lives, and more than a third will experience anxiety. Not only does having this chronic disease cause an increase in anxiety and depression but it is also possible that having these psychiatric disorders makes you more likely to develop IBD. It is unclear how much depression and IBD have in common in terms of gene alterations, epigenetic changes, or immunological responses. When they coexist, it has a detrimental influence on health-related quality of life (HRQOL), regardless of which arrives first: impaired mental health or IBD [52–54].

#### *2.2.3 Other factors*

NSAIDs are among the most commonly used drugs, and their link to ulcers in the stomach or duodenum is well known. They have, however, been associated with the development of IBD. Several theories have been proposed as possible mechanisms for the link between NSAIDs and IBD. A prospective cohort study assessed the link between aspirin and nonsteroidal anti-inflammatory drug (NSAID) use and the occurrence of Crohn's disease and ulcerative colitis. A higher risk of both conditions was observed with the highest frequency of NSAID use [55].

In urban areas, air pollution has been related to a variety of health problems. In mice, acute exposure to high levels of airborne particulate matter increases gut permeability and heightens the innate immune response in the small intestine, while chronic exposure results in increased expression of pro-inflammatory cytokines and changes in colon microbiota composition and function. Long-term exposure also aggravated colitis in an Il10/mouse model [56].

Particulate matter exposure has given inconsistent results in epidemiological studies evaluating the link between air pollution and ulcerative colitis, showing that when there is a link, other components of air pollution may play a role in disease development. People who lived in locations with greater SO2 concentrations were more likely to develop ulcerative colitis than people who lived in areas with lower SO2 concentrations [57]. In a European nested case-control study, airborne particulate


#### **Table 7.**

*Summary of environmental factors in UC.*

matter interaction was found to be inversely related to the incidence of IBD, but not Crohn's disease or ulcerative colitis. In contrast, living near a high-traffic area was linked to a higher risk of disease, and other air pollutants such as nitrous oxides had a trend toward positive relationships with IBD [58].

Hypoxia has been shown to cause inflammatory responses in immune and endothelial cells, with a buildup of inflammatory cells in different organs and increased cytokines in experimental animal models after short-term exposure to low oxygen levels. Levels of circulating IL-6, IL-1ra, and C-reactive protein are elevated in human studies in response to hypobaric hypoxic settings such as high altitudes, and the systemic elevations in these inflammatory markers could reflect local inflammation in the intestine [59, 60].

Hypoxia-inducible factor (HIF), a transcription factor that is dormant when oxygen is available but activated in hypoxic situations, is required for cellular responses to hypoxia. Patients with ulcerative colitis or Crohn's disease have increased expression of HIF-1. Patients with IBD also have increased colonic mRNA expression of glycolytic enzymes, which is triggered by hypoxia through the transcription factor HIF-1 [59, 61].

Based on the hypothesis that hypoxia leads to intestinal inflammation, a small pilot proof-of-concept randomized trial that included 18 patients demonstrated hyperbaric oxygen therapy to be beneficial in moderate-to-severe ulcerative colitis (**Table 7**) [62].

#### **2.3 Diet**

Multiple epidemiological researchers have concluded a link between nutrition and ulcerative colitis. In recent decades, significant changes in food intake have been related to an increase in the incidence of UC. Consumption of soft drinks and sucrose was linked to an increased chance of acquiring the condition. On the other hand, the consumption of fruits and vegetables was related to a decrease in UC development [63–68].

There is a significant association between red meat intake and ulcerative colitis risk [69]. Furthermore, whereas dietary n-3 polyunsaturated fatty acids (PUFAs) were linked to a lower risk of UC (odds ratio: 0.56) [70], dietary arachidonic acid (an n-6 PUFA) assessed in adipose tissue was linked to a higher risk of UC (relative risk: 4.16) [71].

Although there is no evidence of the mechanisms involved in the diet role in IBD development, there are several plausible explanations such as the effects on composition of gut microbiota, the microbial metabolites produced, and alterations in mucosal barrier and immunity [72].

Diet plays a major role in the composition of gut microbiota. Several studies demonstrated that a change in the gut microbiome induced by diet can result in a disease-inducing entity that could either initiate or perpetuate inflammation in patients with IBD. Differences in food patterns between African and European children were related to increased Bacteroidetes and decreased Firmicutes and Enterobacteriaceae [73, 74].

A high fat/high sugar diet can result in intestinal mucosal dysbiosis characterized by an overgrowth of pro-inflammatory proteobacteria and a decrease in protective bacteria. Dietary factors have significant effects on microbial composition and can also affect the metabolic functions of gut microbiota. In both small and large intestines, commensal bacterial fermentation of indigestible food fibers produces short chain fatty acids (SCFA). SCFA changes gene expression, cellular differentiation, chemotaxis, proliferation, and apoptosis in epithelial and/or immunological cells [75]. Some UC patients have a lower amount of SCFA-producing bacteria such as Faecalibacterium prausnitzii, which is inversely connected to disease activity. Furthermore, experimental investigations have linked a western diet high in sugar and fat and low in dietary fiber to lower SCFAs and greater colitis susceptibility [76–78].

There have been demonstrated links between dietary PUFA content and inflammatory processes in IBD. Dietary n-3 polyunsaturated fatty acid (PUFA) intake has been linked to a lower risk of ulcerative colitis, while dietary n-6 PUFA intake has been linked to a higher risk of ulcerative colitis [71, 79, 80]. Dietary n-3 PUFAs reduced the clinical severity of spontaneous and NSAID-induced colitis in rats. Furthermore, TNF generated by splenic CD4+ T cells was inhibited. These findings are consistent with previous reports establishing the preventive impact of n-3 PUFAs on experimental colitis [81], as TNF plays a key role in IBD development.

Dietary variables may have a direct impact on the cells of the host. Some studies have demonstrated that luminal iron may affect the function of intestinal epithelial cells and T cells and also triggers the apoptosis of epithelial cell stress [82]. Zinc deficiency can also decrease the barrier integrity and increase the permeability in IBD patients and vitamin D has a role in reducing inflammation in experimental and human IBD [83, 84].

Several food additives, such as emulsifying agents, maltodextrin, and thickeners including carrageenan, carboxymethyl cellulose, and xanthan gum, have been shown to disrupt intestinal homeostasis [85]. Carrageenan is a type of sulfated polysaccharide derived from seaweed. The US Food and Drug Administration has approved it as "generally regarded as safe," and it is utilized in the food industry for its gelling, thickening, and stabilizing characteristics. Reduced protein and peptide bioaccessibility, disturbance of normal epithelial function, and intestinal inflammation have all been associated with carrageenan [86]. Within one day, carboxymethyl cellulose and polysorbate80 were found to shift the gut microbiota into a pro-inflammatory state by raising bioactive flagellin levels. Changes in gene expression and the development of colitis have been linked to the proinflammatory microbiota [87, 88].

Other studies have found that complete dietary guidance, low FODMAP, or IgG-guided exclusion diets are useful in reducing disease activity in UC patients [89–91]. Although these findings are encouraging, one of the significant limitations of these studies is that they did not disclose their findings separately for patients with active disease and those in remission, making it difficult to make meaningful judgments (**Table 8**).


#### **Table 8.**

*Dietary factors associated with an increased/decreased risk of developing UC.*

#### **2.4 Microbiome**

Early gut microbial colonization is integral to the development of the immune system and intestinal homeostasis, providing a synergistic relationship between defensive and tolerant mechanisms [92]. Different studies from the literature have demonstrated that patients with ulcerative colitis have disturbances in the composition of their gut microbiota, coined "microbial dysbiosis," with a reduction in bacterial diversity with lower proportions of Firmicutes (phylum) and Bacteroides (genus) and higher proportions of Enterobacteriaceae (family) [73, 93–95]. Short-chain fatty acid (SCFA)-producing Ruminococcaceae and Lachnospiraceae have been shown to be depleted, whereas pro-inflammatory microorganisms such as Enterobacteriaceae, especially Escherichia coli and Fusobacteriaceae have grown in number [96, 97].

It is unclear if dysbiosis is a result of or a cause of gut inflammation in ulcerative colitis. In ulcerative colitis, the virome and mycobiome are similarly less varied in this regard [98–101]. There are four controlled positive faecal microbial transplantation clinical studies that confirm the therapeutic effect for ulcerative colitis patients [102–105]. Microbial diversity restoration, particularly the bacterial species responsible for SCFA generation in donor stool, has been indicated as a key factor [102, 106].

In ulcerative colitis, one of the main impacts of dysbiosis is likely to be a decline in the epithelium health or a state of epithelial malfunction, which increases inherent sensitivity to disease. Faecal diversion away from the rectum worsens inflammation, resulting in "diversion colitis" in ulcerative colitis; on the other hand, faecal diversion decreases inflammation in Crohn's disease [107].

The microbiome is the most unstable during childhood, and disturbances to the microbiota in the earliest years of life may alter gut immunity and, therefore,


#### **Table 9.** *Overview of microbiota changes in UC.*

susceptibility to IBD [108]. Before, during, and after a 5-day treatment with oral ciprofloxacin, the variety, richness, and evenness of the faecal microbiota in healthy humans were reduced [109]. Because antibiotics are widely used in both developing and developed countries and are progressively used in poor countries, it is plausible to believe that antibiotic use is a fundamental predisposing factor in IBD etiology. Antibiotic misuse and abuse, as well as their usage in cattle, could aggravate the problem (**Table 9**).

#### **2.5 Epithelial barrier alteration**

An increased population of effector T cells and increased production of proinflammatory cytokines (such as TNF- α, IL-6, and IFN- γ) are thought to be the cause of ulcerative colitis. The balance between proinflammatory and immunosuppressive forces can determine the progression of inflammation that is characteristic of IBD. Disruption of intestinal homeostasis can be determined by an epithelial barrier deficiency. This deficiency has multiple causes: a primary dysbiosis of the intestinal microbiota, a defect in the mucus layer, a primary defect of the epithelium, or an inflamed state of the lamina propria [110].

An epithelial barrier deficiency is seen early in the etiology of UC. For example, in individuals with active UC, the thickness of the mucin-containing mucosal layer of the colon has been demonstrated to be reduced, primarily due to decreased mucin 2 synthesis. In addition, in the early stages of UC, although the epithelium looks normal endoscopically, apoptotic foci can already be observed. This weakened barrier function might be caused by a fundamental genetic deficiency or environmental influences such as changes in the microbiota [111].

Susceptibility polymorphisms in genes producing junctional proteins such as E-cadherin, guanine nucleotide-binding protein alpha 12, and Zonula occludens-1 have been found in genome-wide association studies (GWAS), suggesting that epithelial barrier abnormalities may be a major cause for UC. Furthermore, alterations in the expression of junctional proteins such as E-cadherin, b-catenin, and claudins have been detected in intestinal biopsies from patients with IBD, indicating that barrier disruption plays a role in IBD etiology [112, 113].

#### **2.6 Immune response in UC**

Because the human immune system is responsible for recognizing, responding to, and adapting to a wide range of self and foreign molecules, its integrity is vital for maintaining and recovering health. In the gastrointestinal system, there are two complicated mucosal immune processes that check the luminal contents on a regular basis, recognize microbial or dietary antigens, and activate immune pathways. During the active phase of gut diseases, such as UC, both innate and adaptive immune systems are integrated with various mediators and immune cells to maintain tolerance, manage low-grade inflammation, and upregulate [114].

Antigen-presenting cells (APCs) include dendritic cells, B cells, and macrophages, which are important in both innate and adaptive immunity and immune homeostasis because they can secrete cytokines and activate innate immunity while also presenting antigens to adaptive immune cells, thus linking adaptive and innate immunity pathways [115].

#### *2.6.1 Innate immune response*

Innate immunity consists of defense-related elements that are programmed or automatic, such as the mucosal barrier, epithelial cell tight junctions, and gut permeability control, as well as the secretion of antimicrobial enzymes like defensins and lysozyme to protect the lamina propria from microbial raids. The innate immune system is composed of macrophages, monocytes, neutrophils, and other granulocytes, as well as natural killer cells (NKs), dendritic cells, mast cells, and innate lymphoid cells (ILCs). Non-immune cells involved in the innate immunity system include intestinal epithelial cells (IECs), endothelial cells, transforming growth factor-releasing stromal cells, and mesenchymal cells [116].

Several types of innate immune cells have been implicated in the development of IBD. Neutrophils contribute to the persistence of intestinal inflammation by impairing epithelial barrier function and releasing numerous inflammatory mediators. To maintain homeostasis, dendritic cells (DCs) regulate crosstalk between innate and adaptive immunity. In IBD, however, inappropriate conditioning of DCs has been observed throughout both active and passive disease states as a result of decreased mucosal expression of TGF-b and TSLP, as well as downregulation of the retinoic acid signaling pathway [115].

Macrophages and DCs, as well as epithelial cells and myofibroblasts, maintain gut immunological homeostasis by continuously recognizing microbial antigens. Mucosal DCs and macrophages from IBD patients have higher levels of TLR2, TLR4, CD40, and the chemokine receptor CCR7, all of which contribute to and promote inflammation by stimulating the release of pro-inflammatory cytokines like TNF, IL-1b, IL-6, and IL-18 [114–116].

#### *2.6.2 Adaptive immune response*

Adaptive immunity is characterized by unique immunological responses triggered by antigen-specific activation of B cells or T cells. This immune system includes antibody-secreting B cells, cytotoxic T cells, effector T cells, regulatory T cells (Tregs), and T helper lymphocytes that are all engaged in this process. Peyer's patches of the small intestine, lymphoid follicles of the colon, and mesenteric lymph nodes are the places where adaptive immune cells differentiate. The human immune system's basic function is determined by its interaction with the human microbiome [9].

Several types of innate immune cells have been implicated in the development of IBD. Neutrophils contribute to intestinal inflammation by impairing epithelial barrier function and secreting a variety of inflammatory mediators. To maintain homeostasis, dendritic cells (DCs) regulate crosstalk between innate and adaptive immunity. Intestinal epithelial cells that generate retinoic acid, thymic stromal lymphopoietin (TSLP), and transforming growth factor (TGF)- β impact DCs, increasing the formation of IL-10-producing DCs and thus anti-inflammatory responses and tolerance. In both active and inactive IBD disease stages, decreased mucosal expression of TGF- β and TSLP, as well as downregulation of the retinoic acid signaling pathway, leads to improper conditioning of DCs. [117].

A complex inflammatory process involving innate and adaptive immune cells entering the lamina propria occurs during the active phase of UC. Neutrophils, the short-lived "first responder" cells, are recruited in large numbers with the histology of "crypt abscesses," and they migrate over the epithelium before dying in the crypts. [118].

The survival of neutrophils is aided by the inflammatory environment (potentially via HIF-1 and hypoxia). As a result of this prolonged survivability, its inflammatory impact and tissue damage are intensified (via many means, including the release of serine and matrix metalloproteases, reactive oxygen species, and pro-inflammatory cytokines). Uncontrolled pro-inflammatory cell death (necrosis, necroptosis, and NETosis) occurs in a large proportion of neutrophils, amplifying and potentiating the pro-inflammatory milieu. High quantities of s100a8/9 proteins (or calprotectin) produced in blood and stool, as well as a strong serological response to self perinuclear anti p-neutrophil cytoplasmic antibodies (pANCA), are both likely indirect indications of uncontrolled neutrophil cell death, corroborate this mechanism in UC. Extracellular traps (NETs) on neutrophils can operate as a net for immunogenic chemicals that keep the inflammatory response going. All of these changes support the rational paradigm that, following the onset of the disease, a wave of innate inflammatory neutrophils and monocytes (with their pro-inflammatory cytokine repertoire, such as IL-1 family, IL-6, and TNF- α) creates an inflammatory environment (nutritional, metabolic, and cytokine) that promotes a pathologic adaptive (likely T-cell) immune response [119–121].

All of these parameters will influence the host's ability to resolve inflammation, restore homeostasis, and heal the UC mucosa, as well as newly incoming inflammatory monocytes, monocyte-macrophage activity, survival, and phenotype [122].

Because of UC's significant genetic connections to HLA (mainly class II), defective antigen(s) drive the aberrant T-cell response, which subsequently shapes the pathologic cytokine milieu, and is considered to be a key causal component. The complete mechanism of how HLA affects commensal and/or self-antigen presentation to T cells, and then a downstream pathogenic T-cell response, is yet unknown and difficult to understand. Approaches to studying, screening, and defining T-cell epitopes have vastly improved, and further development is expected [123].

Naïve CD4+ T-cells activated by antigen-specific signals from APCs, influenced by the cytokine milieu, differentiate into effector T-helper cells; T-helper 1 (Th1), T-helper 2 (Th2), T-helper 17 (Th17) cells, T-helper 9 (Th9), or regulatory T-cells (Tregs). Previously, it was thought that the differentiation of naive CD4+ T-cells into effector T-cell lineages was an irreversible process; however, specific cytokine circumstances and stimuli may cause plasticity between T-cell subsets [124]. Treg and Th17 plasticity are most likely triggered by dynamic changes in the inflammatory environment. As a result, pro-inflammatory stimuli may stimulate the conversion of immune-suppressive regulatory T cells into pro-inflammatory Th17 cells, while inflammation resolution may induce or even necessitate the switch from Th17 to Treg [125].

UC is traditionally associated with a Th2 response characterized by high levels of IL-4, IL-5, and IL-13, whereas CD is characterized by a Th1/Th17 response. Previous research has linked UC to a nonclassical Th2 response, with CD1d-restricted natural killer T-cells releasing IL-13. This region has been overwhelmed by subsequent developments. The discovery of IL-23 as a critical driver of Th17 responses, genetic connections with IL-23 and associated genes and the presence of Th17 (and Th9) cells in UC are only a few examples. IL-9 is produced from Th9 cells, a new subtype of Th cells. Th9 cells develop from naïve T cells under the induction of transforming growth factor (TGF)-β and IL-4. IL-9 is thought to disrupt gut barrier function by inhibiting intestinal epithelial cell proliferation and suppressing the expression of many tight-junction proteins such as claudin and occludin. Furthermore, greater IL-9 levels in UC patients with

Pathogenic adaptive (presumably T-cell driven) responses: triggered by innate immune responses (neutrophils/ macrophages)

HLA allelic connections may influence antigen presentation


#### **Table 10.**

*Overview of the immune responses in UC.*

severe disease compared to patients with moderate disease and control patients may represent disease activity, as seen by the higher IL-9 levels reported in UC patients with severe disease compared to patients with mild disease and control patients [126–128].

Multiple pathways occur in the recruitment of mesenchymal cells and the formation of activated myofibroblasts, the major functional unit responsible for excessive extracellular matrix (ECM) deposition, during intestinal injury and repair. Multiple matrix metalloproteinases (MMPs) are significantly expressed in IBD tissues, with interstitial collagenase (MMP1) and MMP2 mediating collagen fiber breakdown, whereas fistula formation in Crohn's disease has been linked to elevated expression of MMP3 and MMP9. A balance between MMPs and tissue inhibitors of metalloproteinase occurs, resulting in excessive deposition of certain ECM components. All of these anomalies are most likely the result of inflammation-derived soluble mediators that regulate ECM deposition.

Primary human intestinal epithelial cells (IECs) from normal mucosa may process and deliver antigens to primed peripheral blood CD8+ T lymphocytes that act as nonspecific suppressor cells. IBD-associated IECs have a reduced ability to induce CD8+ T suppressor cells, implying a deficiency in mucosal immunoregulation that predisposes to IBD [129].

Despite the fact that CD4 T cells are thought to have a larger role in IBD pathogenesis, CD8 T cell transcriptomic patterns have been identified to determine whether UC follows a more aggressive course. The recent discovery of innate lymphoid cells (ILCs) as a further mediator of IL-23-driven inflammatory response in the colon is a further new dimension in UC [130–132].

While the innate immune system is responsible for inducing inflammatory reactions, the adaptive immune system is crucial in the evolution of chronic inflammatory events in UC (**Table 10**).

#### **2.7 New advances in the etiology**

Recent studies suggest that mitochondria have a major role in inflammation. Mitochondrial dysfunction has long been linked to UC, but recent paper released in the last three years has re-emphasized this theory. Earlier colonic microarray investigations in UC revealed such dysregulation of genes that affect mitochondrial activity [133–135].

When mitochondrial homeostasis is disrupted, energy generation is impaired, mitochondrial oxidative stress rises, and mitochondrial products (mitochondrial DNA) are released as pro-inflammatory DAMPs. All of these factors play a role in

core UC themes such as epithelial failure, the pro-inflammatory mucosal environment, and direct inflammatory triggers. As a result of this convergence of facts, novel techniques for targeting pro-inflammatory mitochondria have emerged, such as mitochondrial antioxidant therapy in active UC [136, 137].

Inflammation causes tissue damage and different forms of cell death (apoptosis, necrosis, necroptosis, and pyroptosis), as well as the release of several cytosolic and nuclear products with intrinsic proinflammatory characteristics, as seen in IBD. DAMPs are the term used to describe those items. Proteins and peptides (High mobility group box 1 protein [HMGB1], defensins, heat-shock proteins, S100 proteins, IL1 and IL33, and so on), lipoproteins and fatty acids (such as serum amyloid A and oxidized low-density lipoproteins), ECM degradation products (for example, hyaluronan fragments), and nucleic acids are among the many different types of DAMPs. Through a DAMP-mediated mechanism, any agent, medicine, or virus that damages the epithelium can cause IBD flare-ups and clinical illness recurrence [138].

Exogenous, microbial, stress, and endogenous danger signals trigger inflammasomes, which activate caspase 1 and produce IL1 and IL18. Inflammasomes are members of the NLR or pyrin family, with members of the NOD-like receptor family, such as NLRP1a/b, NLRP3, NLRC4, and AIM2, regulating immunological responses, metabolism, and disease pathogenesis being the best known. The inflammasome's function in regulating interaction between the mucosal immune system and the microbiota makes it particularly appealing and biologically relevant to IBD immunopathogenesis. Inflammasome activity appears to be higher in CD based on circumstantial data, but there is no information available for UC [139].

MicroRNAs (miRNAs) are single-stranded noncoding RNAs with key regulatory activities on gene expression, primarily via suppressing (silencing) genes via degradation of target RNAs or translation inhibition. Long noncoding RNAs and circular RNAs are two more forms of noncoding RNAs that have been discovered. These noncoding RNAs also have important regulatory activities, and how these functions may be involved in IBD pathogenesis is becoming a hot topic. Excessive immunological reactivity and inflammation, both of which are linked to IBD, could be caused by dysregulation or insufficient miRNA-mediated repression [140].

Single-cell profiling of the inflamed UC mucosa allows for a thorough examination and census of the cell populations. New research has discovered new and unusual cell kinds, as well as cell-type-specific expression and deep cell–cell interactions and cell lineage linkages. Mucosal compartments that have gotten less attention in the past, such as the colonic mesenchyme, are now being identified as major mediators of inflammation, but all of this needs to be confirmed in the future (**Table 11**) [141–143].

Novel techniques in active UC: targeting pro-inflammatory mitochondria, (i.e. mitochondrial antioxidant therapy)

Major mediators of inflammation: colonic mesenchyme

Disruption of mitochondrial homeostasis → alteration of energy production →↑ oxidative stress →release of pro-inflammatory damage-associated molecular patterns.

#### **3. Conclusion**

Despite recent advances in our understanding of the role of environmental exposures, genetics, dysbiosis, and dysregulated immunity in disease development, the temporal sequence of events leading to IBD remains unknown. They are all important in triggering IBD/UC because none of the factors alone can cause IBD/UC. Immune system is the effector arm for inflammatory response. With the shifting global burden of ulcerative colitis, more research is needed to better understand the illness's etiology in order to prevent and find potential novel therapeutic targets or predictors of disease burden in the future.

#### **Acknowledgements**

I would like to express my deep and sincere gratitude to my mentors MD, Ph.D. in gastroenterology and internal medicine, Chief of Gastroenterology and Hepatology Department, Fundeni Clinical Institute, Mircea Mihai Diculescu, and MD, Ph.D. in gastroenterology and internal medicine, Ioan-Alexandru Oproiu for their support and helpful feedback throughout the years.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Carmen-Monica Preda\* and Doina Istrătescu Department of Gastroenterology and Hepatology, Fundeni Clinical Institute, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania

\*Address all correspondence to: carmenmonica.preda@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 2**

## Platelets in Ulcerative Colitis: From Pathophysiology to Therapy

*Stanko Petrovic, Slobodan Obradovic, Marijana Petrovic and Nemanja Rancic*

#### **Abstract**

Based on the role of platelets in inflammation and hemostasis it has been assumed that antiplatelet therapy could be beneficial for patients suffering from ulcerative colitis. Platelets present a link between inflammation and coagulation. They have more than 300 active mediators stored in their granules. Upon activation, platelet degranulate and release a lot of microparticles and mediators and interact with other immune and non-immune cells thereby amplifying inflammation. The most important parameters of platelet activation are P-selectin and CD40 ligand expressed on their surface upon activation, and their soluble forms presented in blood. Today, we have potent anti-platelet drugs that can inhibit platelet activation and degranulation, and thereby reduce inflammation. The most important drugs are P2Y12 receptor antagonists such as ticagrelor and clopidogrel and glycoprotein IIbIIIa inhibitors. Ticagrelor is an active drug and besides antiplatelet activity, it has bactericidal activity against Gram-positive strains and *Clostridium difficile*. Clopidogrel is a prodrug with less anti-inflammatory effect than ticagrelor and no proven bactericidal activity. Glycoprotein IIbIIIa inhibitors are very potent in reducing platelet aggregation but have lower anti-inflammatory potential than ticagrelor and clopidogrel.

**Keywords:** ulcerative colitis, platelets, antiplatelet therapy, P-selectin, CD40 ligand, ticagrelor, clopidogrel, glycoprotein inhibitors

#### **1. Introduction**

Ulcerative colitis (UC) is a chronic disease resulting not only from the abnormal immune response but also from the activation of non-immune cells. Both, immune and non-immune cells are inducing inflammation that causes tissue injury [1, 2]. Platelets (Plt) are now recognized as proinflammatory cells, and aside from their primary role in a hemostasis they also enhance inflammation. The hypercoagulable state exists in the UC patients. Inflammation activates coagulation and coagulation amplifies inflammation [3, 4]. Platelets are unique cells without nucleus that have an important role in hemostasis and thrombosis, with a 5–9-day life span. Platelets have four granule types with stored numerous biologically active substances, such as platelet factor 4, fibrinogen, Von Willebrand factor (vWF), protein S, histamine, prostaglandin E2, platelet growth factor, thromboxane A2, transforming growth

factor-beta, coagulation factors, angiogenic and growth factors, β-thromboglobulin, P-selectin (Psel), chemokines, regulated upon activation, normal T cell expressed and presumably secreted (RANTES), monocyte chemotactic protein-1, interleukin (IL) 8 (IL-8), IL-1β, IL-7 [5, 6]. Platelets can interact with many different cells and contribute to vascular inflammation [7]. Platelet factor 4 and β-thromboglobulin are exclusively released from Plt and are increased in the serum of the patients with active UC [8]. Platelet activation is of utmost importance for Plt functioning and is a result of Plt interaction with numerous active molecules. The first step is adhesion to the subendothelial matrix. After that Plt change their shape, resulting in pseudopodia formation [9]. Platelet activation, in the UC patients, takes place in mesenteric microcirculation after exposure to subendothelial collagen, adenosine diphosphate (ADP), arachidonic acid, Plt activating factor, thrombin, fibrinogen, and cytokines from other cells. Upon Plt activation, they degranulate and release a lot of Plt-derived microparticles (PDMP) and preformed mediators and interact with other immune and non-immune cells [10]. The PDMP represent 70–90% of all human cell-derived microparticles and have high procoagulant (due to tissue factor) and proinflammatory potential [11]. They also secrete ADP which in turn bind to the P2Y1 and P2Y12 receptors on the membrane surface of the Plt and amplify initial Plt activation [12].

#### **2. Mechanism of platelets intervention in ulcerative colitis**

Upon activation, Plt express receptors on their surface, the most important being glycoprotein IIbIIIA (GPIIbIIIa), CD40 ligand (CD40L), Psel and receptors for cytokines, chemokines, and complement components [13]. A CD40L is a membrane protein, co-stimulatory molecule, presented mostly on the surface of the activated T lymphocyte (T Ly) and activated Plt. Its receptor is CD40, expressed on the surface of the immune cells, endothelial, epithelial cells, Plt, and other mesenchymal cells [14]. After Plt activation, CD40L and Psel are cleaved from the cell surface and secreted in the blood, being called soluble CD40L (sCD40L) and soluble Psel (sPsel). These soluble forms activate other cells, especially endothelial cells, fibroblasts, T Ly, monocyte, neutrophils, and B cells. The CD40/CD40L signaling pathway is a very important pathogenic mechanism in the UC, it amplifies inflammation and activates numerous immune and non-immune cells, including Plt [15, 16]. Platelets are the main source of sCD40L in UC. The number of CD40L positive T Ly and Plt is increased in colonic mucosa [17]. Also, the CD40L-CD40 signaling pathway is responsible for thromboembolic complications in UC patients and inflammation-induced angiogenesis. Platelet dysfunction exists in UC, meaning that Plt are becoming pro-inflammatory cells, and represent a connection between innate and adaptive immunity and between inflammation and coagulation [18].

#### **3. Role of platelets as biomarkers in UC severity**

P-selectin is expressed on the membrane surface of the activated Plt and endothelial cells. P-selectin has the most important function in leucocyte (Le) recruitment, mostly in the colonic mucosa [19]. The level of tissue expression of Psel is in strong positive correlation with the level of inflammation in colonic mucosa [20]. In severe inflammation, there is abundant Psel expression in colonic mucosa. Soluble Psel and sCD40L are excellent biomarkers of Plt activation [21].

#### *Platelets in Ulcerative Colitis: From Pathophysiology to Therapy DOI: http://dx.doi.org/10.5772/intechopen.102041*

Abnormalities seen in UC are: elevated Plt count (>450,000 × 109 /L), reduction in mean Plt volume (MPV), increased platelet distribution width (PDW) value, increased plateletcrit value (PCT), increase in granular content, increased Plt activation and aggregation, hyperreactivity to agonist stimulation, such as ADP and collagen. These abnormalities are mediated by IL-6, are not seen in a healthy person, and are more pronounced in UC than in other inflammatory diseases like rheumatoid arthritis. The MPV and PCT show a negative correlation with disease activity [22–25]. Spontaneous platelet aggregation is observed in more than 30% of UC patients, a phenomenon that is not seen in healthy persons and rarely seen in other inflammatory disorders [26]. Histopathological studies found mesenteric vascular microthrombi to be the first finding in the mucosa of UC patients. Those microthrombi contribute to ischemia. Microthrombi are not found in mesenteric vessels in healthy persons [27]. Activated Plt form aggregates with Le and other Plt, so-called platelet-leukocyte aggregates (PLA) and Plt-Plt aggregates (PPA), via Psel [28]. Platelet-leukocyte aggregate number is increased in serum and colonic tissue of patients with active UC but does not correlate with disease activity, instead, there is a positive correlation with Plt number and serum sPsel concentration. But it is proven that Le within PLA are more active than free Ly or Plt [29]. Platelet-leukocyte aggregate react with endothelial cells, activate them, activate other free Plt and Le. Also, PLA activate endothelial cells more than free cells, leading to increased expression of adhesion molecules thus contributing to inflammation [30]. Increased Plt activation and aggregation, especially spontaneous platelet aggregation, are very much responsible for thrombosis and thromboembolic complications in UC, particularly arterial thrombosis [31, 32].

Platelet to Ly ratio, with cut off value of 175.9 (sensitivity 90.9%; specificity 78.4%; positive likelihood ratio 4.205, 95% confidence interval (95% CI) 2.214–7.894; area under the curve (AUC) 0.897, 95% CI 0.802–0.992) can serve as a biomarker for disease activity in UC, and can help us distinguish UC from healthy controls, that is, to identify UC patients with active disease [33].

We can also use neutrophil to Plt ratio to identify UC patients with active disease, with cut-off point of 14.94 (sensitivity 87.95%; specificity 63.5%) [34].

#### **4. Antiplatelet drugs types**

With the developments in medicine, especially pharmacology, we have a lot of antiplatelet drugs, and the number is constantly increasing [35]. The most important antiplatelet drugs are:


They are used to prevent or treat arterial thrombosis.

The most important indications are: acute coronary syndrome, after the percutaneous coronary intervention (PCI) with stenting, acute ischemic stroke, after percutaneous intervention of peripheral arterial disease, stable angina, and primary prevention of coronary artery disease [43].

Not all anti-Plt agents are the same. Some of them affect mostly Plt aggregation, and some of them affect Plt aggregation and degranulation. The most significant contraindication for anti-Plt agents is active bleeding [44].

The most important antiplatelet drugs with the possibility to be used in UC are clopidogrel, ticagrelor, and GP inhibitors.

Clopidogrel is a prodrug, has 50% bioavailability. After biotransformation in the liver, its active metabolite binds to P2Y12 on the Plt surface and irreversibly inhibits ADP-mediated Plt aggregation and Plt activity. Due to the necessity of the liver biotransformation of clopidogrel by cytochrome P450 (CYP) enzymes CYP3A4/3A5, there is potential for drug interactions and therapeutic failure. Some genetic alterations in the CYP2C19 gene can lead to a low Plt response to clopidogrel [45].

Ticagrelor is an orally active drug. It is a reversible antagonist of P2Y12 receptor on surface Plt membrane that inhibits ADP induced Plt aggregation. It is given twice daily. After ingestion, maximal Plt inhibition was measured at 2–4 hours. It almost completely inhibits Plt aggregation. It has faster and more profound action on Plt inhibition than clopidogrel. Its half-life is 7 hours. After P2Y12 inhibition there is decreased Plt degranulation and decreased releasing of bioactive mediators from Plt, and low expression of Psel and CD40L on Plt surface. Ultimately it leads to reduced generation of PLA and PPA which is considered to be the major mechanism responsible for anti-inflammatory effect. It also inhibits the reuptake of adenosine which leads to its accumulation in the extracellular matrix. Major adverse events are bleeding, dyspnea and bradycardia [46].

*Platelets in Ulcerative Colitis: From Pathophysiology to Therapy DOI: http://dx.doi.org/10.5772/intechopen.102041*

Glycoprotein inhibitors compete with fibrinogen and VWF for binding to GPIIbIIIa, which represent the final step in Plt aggregation. They are very potent inhibitors of Plt aggregation. Three GP inhibitors are approved in clinical use: abciximab, eptifibatide, and tirofiban. The route of administration for all three drugs is intravenous. Major adverse events are bleeding and thrombocytopenia. They are very potent in inhibiting Plt aggregation but do not have a potent anti-inflammatory effect [47].

#### **5. The role of antiplatelet drugs in the pathogenesis of UC**

Antiplatelet therapy is not a part of standard therapy for treating UC patients, but growing evidence suggest that it is safe in UC and might be useful addition to the standard therapy. I will summarize published results.

This chapter is based on an evaluation of antiplatelet therapy in patients with UC. We defined key questions as our literature searching algorithm. We searched literature from PubMed according to the adequate MESH terms ("ulcerative colitis," "platelets," "antiplatelet therapy," "P-selectin," "CD40 ligand," "ticagrelor," "clopidogrel," and "glycoprotein inhibitors") for the period from 2000 to the present.

#### **5.1 Antiplatelet agents'-ticagrelor and eptifibatide-safety in experimental colitis in mice**

The authors conducted an animal study about the usage of antiplatelet agents ticagrelor and eptifibatide in mice. Forty C57BL/6 mice (inbred females, age: 2–3 months, and average body mass: 20–24 g) were used. The bodyweight of mice was measured every day. Mice were observed for stool consistency and rectal bleeding on a daily basis so that disease activity index (DAI) could be calculated daily as the sum of the weight loss score, the diarrheal score, and the hematochezia score based on the method used by Friedman et al., as shown in **Table 1**. The DAI was used to assess the severity of colitis [48].

Colitis was induced in 30 mice by 5-day drinking water with 3.5% dextran sulfate sodium (DSS) (average molecular weight within the range of 35,000–55,000). All mice developed DSS colitis. After 5 days, DSS-induced mice were divided into three experimental groups, 10 each. The first (I) group, the DSS control group, received no intervention during the subsequent 5 days treatment period. The second (II) group, the ticagrelor treatment (PO) group, received 1 mg (in 0.5 mL) dosages per day of


#### **Table 1.**

*Disease activity index (DAI).*

Brilinta® via gastric tube. The third (III) group, the eptifibatide treatment (IP) group, received 150 μg (in 0.2 mL) dosages per day of Integrilin® via intraperitoneal injection. Group of mice (*n* = 10), experimental control (K) group, received water without DSS during the 5 days period.

The primary outcome was bleeding, and the secondary outcomes were changes in platelet count, hemoglobin (Hgb) level, and hematocrit (HCT) level. Complete blood counts were determined for each group at baseline (day 0: before treatment; DSS1, PO1, and IP1 subgroups) and at 1 day after the last dose (day 5; DSS2, PO2, and IP2 subgroups). On day 5, all surviving mice were sacrificed, and an autopsy was performed. The Plt aggregation was measured using a multiplate Plt function analyzer with adenosine diphosphate and thrombin receptor-activating peptide.

Platelet aggregation was measured at baseline, after 2 h, and 24 h of ticagrelor and eptifibatide therapy. An autopsy showed signs of colitis and there was no evidence of recent bleeding in the liver, spleen, central nervous system, or serous cavities of any of the antiplatelet treatment groups. Histological findings of colonic mucosa in all three experimental groups after autopsy were that DSS2, PO2, and IP2 showed mild inflammation and ulceration.

Maximum weight loss was below 15% in all three experimental groups. Hematochezia was observed in all three experimental groups as blood around the anus and present in the sawdust or as hemoccult positive. Blood was seen from the fourth day of the experiment in all three experimental groups.

The DAI score was not significantly different between the three experimental groups (Kruskal-Wallis test; *p* = 0.925).

Significantly lower levels of Hgb and HCT were found in all three experimental groups (PO1, DSS1, PO1, and IP1 vs. control; Kruskal-Wallis test: *p* = 0.007 and *p* = 0.002, respectively) (**Figures 1** and **2**). However, the Plt count was not significantly different between any of the DSS groups and the control group (Kruskal-Wallis test: *p* = 0.640) (**Figure 3**). There were no significant differences in the drug-related changes in the Hgb, HCT, and Plt levels of the three DSS groups according to the two drugs administered (baseline vs. end of treatment; Kruskal-Wallis test: HGB, *p* = 0.369; HCT, *p* = 0.104; and Plt, *p* = 0.307) (**Figures 4**–**6**).

The authors concluded that administering eptifibatide and ticagrelor to DSS colitis mice did not cause serious adverse events. There was no significant decrease in Plt

#### **Figure 1.**

*Hemoglobin (Hgb) values before initiation of antiplatelet drug administration. Data are presented as mean ± SD. Groups DSS1, IP1, and PO1 represent DSS colitis mice before administration of drugs; K represents the experimental control group. DSS, dextran sulfate sodium; IP, eptifibatide treatment; PO, ticagrelor treatment.*

*Platelets in Ulcerative Colitis: From Pathophysiology to Therapy DOI: http://dx.doi.org/10.5772/intechopen.102041*

#### **Figure 2.**

*Hematocrit (HCT) values before initiation of antiplatelet drug administration. Data are presented as mean ± SD. Groups DSS1, IP1, and PO1 represent DSS colitis mice before administration of drugs; K represents the experimental control group. DSS, dextran sulfate sodium; IP, eptifibatide treatment; PO, ticagrelor treatment (Kruskal-Wallis test: p = 0.002).*

#### **Figure 3.**

*Platelet (PLT) count for all groups. Data are presented as mean ± SD. Groups DSS1, IP1, and PO1 represent DSS colitis mice before administration of drugs; K represents the experimental control group. Groups DSS2, IP2, and PO2 represent DSS colitis mice after administration of drugs. DSS, dextran sulfate sodium; IP, eptifibatide treatment; PO, ticagrelor treatment (Kruskal-Wallis test: p = 0.640).*

count or Hgb and HCT levels, and autopsy found no bleeding into the liver, spleen, serous cavities or intracranially. These observations support the potential use of antiplatelet therapy for treating UC in humans as an addition to the standard therapy. Ticagrelor could be used in the moderate form of UC and eptifibatide in the severe form, together with standard therapy.

#### **5.2 Evaluation of anti-inflammatory effect of anti-platelet agent-clopidogrel in experimentally induced inflammatory bowel disease**

The goal of this research was to evaluate the anti-inflammatory effect of clopidogrel on an animal model for Crohn's disease (TNBS model) and ulcerative colitis (oxazolone induced) in rats. Rats were weighing 150–200 g and were housed in standard conditions, on a standard diet and water ad libitum. Ulcerative colitis was induced by intrarectal administration of oxazolone on first day. Rats were divided into four groups, each consisting of six animals: **Control** group (healthy rats),

*Ulcerative Colitis - Etiology, Diagnosis, Diet, Special Populations, and the Role of Interventional…*

#### **Figure 4.**

*Percent change in values of hemoglobin (Hgb) relative to basal values. Groups DSS2, IP2, and PO2 represent DSS colitis mice after administration of drugs. DSS, dextran sulfate sodium; IP, eptifibatide treatment; PO, ticagrelor treatment (Kruskal-Wallis test: HGB, p = 0.369).*

#### **Figure 5.**

*Percent change in values of hematocrit (HCT) relative to basal values. Groups DSS2, IP2, and PO2 represent DSS colitis mice after administration of drugs. DSS, dextran sulfate sodium; IP, eptifibatide treatment; PO, ticagrelor treatment (Kruskal-Wallis test: HCT, p = 0.104).*

**Oxazolone** group (induced UC without treatment), **Standard** group (oxazolone + sulfasalazine for the next 21 days), and **Test** group (oxazolone + clopidogrel per os for the next 21 days). At regular time intervals percentage change in body weight, colon mucosal damage index (CMDI), DAI, and myeloperoxidase (MPO) activity were measured. The CMDI, DAI, and MPO were used to assess inflammatory changes in colonic mucosa. It was shown that the test group resolved symptoms and significantly reduced MPO activity, DAI, and CMDI, better than other groups [49].

#### **5.3 Acetylsalicylic acid reduces the severity of dextran sodium sulfate-induced colitis and increases the formation of anti-inflammatory lipid mediators**

The goal of this study was to evaluate the effect of acetylsalicylic acid (ASA) on DSS colitis in mice. Female C57BL/6 mice, average body weight 19–21 g, were divided into three groups: **Control group**, **another group** receiving 3% DSS and no treatment *Platelets in Ulcerative Colitis: From Pathophysiology to Therapy DOI: http://dx.doi.org/10.5772/intechopen.102041*

#### **Figure 6.**

*Percent change in values of platelets (PLT) relative to basal values. Groups DSS2, IP2, and PO2 represent DSS colitis mice after administration of drugs. DSS, dextran sulfate sodium; IP, eptifibatide treatment; PO, ticagrelor treatment (Kruskal-Wallis test: PLT, p = 0.307).*

and **ASA** group, receiving 3% DSS and daily intraperitoneal ASA for 5 days. Bodyweight, occult blood in stool samples, histological evaluation of the distal colon, and magnetic resonance imaging (MRI) were measured to evaluate colitis severity. The authors concluded that DSS colitis can be alleviated by ASA [50].

#### **5.4 CD40-CD40 ligand mediates the recruitment of leukocytes and platelets in the inflamed murine colon**

The aim of this study was to evaluate the role of the CD40-CD40L signaling pathway in intestinal inflammation in DSS colitis in mice and the anti-inflammatory effect of Trapidil (triazolopyrimidine) on intestinal inflammation. Trapidil is an antagonist of platelet-derived growth factor and it was developed to inhibit the response of monocytes to CD40L. They found a 10-fold increase in CD40 expression in endothelial cells in the colon (an important result of CD40-CD40L signaling pathway), increased recruitment of Plt and leukocytes in colonic venules due to CD40-CD40L pathway and significant inhibition of CD40-CD40L signaling pathway with Trapidil [51].

#### **5.5 The role of P-selectin in experimental colitis as determined by antibody immunoblockade and genetically deficient mice**

The objective of this study was to evaluate the role of Psel on leukocyte recruitment and the effect of its blockade with an anti-P-sel antibody. They induced DSS colitis in wild type and P-selectin−/− C57BL/6 J mice. Disease activity index, plasma IL-6, length of colon and rectum, histological damage of the colon, and MPO activity of the distal colon were evaluated. Leukocyte-endothelial interaction in colonic venules was assessed using intravital microscopy. Vascular cell adhesion protein 1 (VCAM-1) and intercellular adhesion molecule 1 expression on endothelial cells and expression of very large antigen-4 integrin on circulating leukocytes were obtained. They found that Psel has an important role in intestinal inflammation in DSS colitis. Its blockade or genetic deficiency offers protection against DSS colitis. They also found that treatment of DSS colitis with Psel antibody was very potent in reducing

DAI, MPO activity, and leukocyte adhesion. The VCAM-1 over-expression in the colon and extracolonic organs and increased level of IL-6 in circulation were observed in P-selectin−/− mice, but not in mice treated with anti-P-sel antibodies. The conclusion was that Psel is a key molecule for the development of DSS colitis and that Psel antibodies administration or genetic deficiency offers protection against DSS colitis by diminishing leukocyte recruitment in the colon [52].

#### **5.6 Daily aspirin use does not impact clinical outcomes in patients with inflammatory bowel disease**

It was a retrospective analysis of 174 patients with pre-existing inflammatory bowel disease, who were taking aspirin, due to cardiac comorbidity, for at least 18 months and did not differ in age, gender, disease duration, smoking status, medication usage, or baseline C-reactive protein. They were looking for the connection between aspirin and inflammatory bowel disease (IBD) related hospitalization/ surgery/corticosteroid required during the period of follow-up. Their results indicate that aspirin use did not have a clinical impact on IBD patients [53].

#### **6. The role of antiplatelet drugs in the treatment of UC**

A retrospective analysis of 36 patients with pre-existing IBD (test group), who started on combination therapy of aspirin and clopidogrel for at least 6 months, due to PCI for coronary artery disease. There was a control group with IBD matched for gender and age, not taking antiplatelet therapy. They found no change in frequency of IBD exacerbations between groups, after the initiation of the aspirin and clopidogrel in the test group [54].

#### **6.1 Antibacterial activity of ticagrelor in conventional antiplatelet dosages against antibiotic-resistant Gram-positive bacteria**

After analysis of the PLATO study, the question was raised whether ticagrelor has antibacterial activity in standard anti Plt dosages against Gram-positive bacteria because patients treated with ticagrelor had a lower risk of infection-related death than patients treated with clopidogrel. Authors proved that in vitro ticagrelor has bactericidal activity against all Gram-positive strains tested, including drug-resistant strains glycopeptide intermediate *Staphylococcus aureus*, methicillin-resistant *Staphylococcus epidermidis*, methicillin-resistant *S. aureus*, and vancomycin-resistant *Enterococcus faecalis*. These bactericidal concentrations are not reached in the systemic circulation but might be reached at the infection site probably by drug accumulation [55].

#### **6.2 Repurposing a platelet aggregation inhibitor ticagrelor as an antimicrobial against Clostridioides difficile**

The author tested the antimicrobial activity of ticagrelor against different types of *Clostridium difficile* (C. diff) in vitro. They found that ticagrelor has minimal inhibitory concentration (MIC) 20–40 μg/ml for all types of C. diff. Ticagrelor had a more rapid killing profile compared to metronidazole and vancomycin, and also inhibited biofilm formation, which is very important for the pathogenicity of C. diff infection.

Ticagrelor effectively reduced spore germination of C. diff, caused membrane disruption in C. diff and had an additive effect on metronidazole and vancomycin [56].

#### **7. Conclusion**

The exact pathophysiology of ulcerative colitis is unknown. Except immune cells, it is important to take platelet function into the consideration so we could improve the response rate to the standard therapy in ulcerative colitis patients. Antiplatelet therapy is still not a part of the therapeutic armamentarium for this disease. We have increasing evidence that raises the possibility of using antiplatelet therapy in humans with ulcerative colitis. Antiplatelet therapy in UC is safe and it seems that ticagrelor could be the drug of the first choice.

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Acronyms and abbreviations**



#### **Author details**

Stanko Petrovic\*, Slobodan Obradovic, Marijana Petrovic and Nemanja Rancic Military Medical Academy, Belgrade, Serbia

\*Address all correspondence to: stanko53p@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Platelets in Ulcerative Colitis: From Pathophysiology to Therapy DOI: http://dx.doi.org/10.5772/intechopen.102041*

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