Etiology of Ulcerative Colitis

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.

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, 2, 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, 7, 8, 9]. Further details are presented in Tables 1–5 [4, 7, 9].

Gene	Locus	SNP	Protein name	Function
ECM1	1q21	rs3737240	Extracellular matrix protein 1	Involved in cell proliferation
HNF4A	20q13	rs6017342	Hepatocyte nuclear factor 4α	Regulates cellular differentiation along crypt-villus axis
CDH1	16q22	rs12597188	E-cadherin	Involved in epithelial adherens junction
LAMB1	7q31	rs886774	Laminin β1	Protein involved in cell adhesion and differentiation
GNA12	7p22	rs798502	guanine nucleotide-binding protein alpha 12	Protein is involved as modulators or transducers in various transmembrane signaling systems

Table 1.

Genes associated with UC that affect the epithelial barrier.

Gene	Locus	SNP	Protein name	Function
IL8RA / IL8RB	2q35	rs11676348	Interleukin 8 receptor alpha/ Interleukin 8 receptor beta	Activation of neutrophils
IL2 / IL21	4q27	rs17388568	Interleukin 2/ Interleukin 21	T-cell proliferation and other activities crucial to regulation of the immune response /Immunoregulatory activity. May promote the transition between innate and adaptive immunity
IFNG / IL26	12q14	rs7134599	Interferon gamma protein/ Interleukin 26	Cytokine is critical for innate and adaptive immunity/mucosal immunity, proinflammatory function
IL7R	5p13	rs3194051	Interleukin-7 receptor protein	Normal development of T cells
TNFRSF9	1p36	rs35675666	Tumor Necrosis Factor Receptor Superfamily Member 9	Co-stimulatory immune checkpoint molecule
TNFRSF14	1p36	rs10797432	Tumor necrosis factor receptor superfamily member 14	May mediate the signal transduction pathways that activate the immune response
IRF5	7q32	rs4728142	Interferon regulatory factor 5 protein	Transcription factor that plays a critical role in innate immunity
LSP1	11p15	rs907611	Lymphocyte-specific protein 1	Mediate neutrophil activation and chemotaxis
FCGR2A	1q23	rs1801274	Low-affinity immunoglobulin gamma Fc region receptor II-a protein	By binding to IgG it initiates cellular responses against pathogens and soluble antigens. Promotes phagocytosis of opsonized antigens.

Table 2.

Genes associated with UC—Immune-mediated.

Gene	Locus	SNP	Protein name	Function
OTUD3 / PLA2G2E	1p36	rs138347004	OTU Domain-Containing Protein 3 /Phosphatidylcholine 2-Acylhydrolase 2E	Protein turnover/role in inflammation and the immune response
PIM3	22q13	rs5771069	Serine/threonine-protein kinase pim-3	Prevent apoptosis, promote cell survival and protein translation
DAP	5p15	rs2930047	Death-associated protein 1	Negative regulator of autophagy. Involved in mediating interferon-gamma-induced cell death
CAPN10	2q37	rs4676410	Calcium-Activated Neutral Proteinase 10	Calcium-regulated non-lysosomal thiol-protease, which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction
JAK2	9p24	rs10758669	Tyrosine-Protein Kinase JAK2	Involved in cell growth, development, differentiation, or histone modifications. Mediates essential signaling events in both innate and adaptive immunity.

Table 3.

Other genes associated with UC.

Gene	Locus	SNP	Protein name	Function
IL10	1q32	rs3024505	Interleukin 10	Downregulates the expression of Th1 cytokines, MHC class II antigens, and co-stimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production. IL-10 can block NF-κB activity and is involved in the regulation of the JAK-STAT signaling pathway
CARD9	9q34	rs10781499	Caspase recruitment domain-containing protein 9	Regulatory role in cell apoptosis
MST1	3p21	rs3197999	Macrophage-stimulating protein	Stimulates macrophages
ICOSLG	21q22	rs2838519	ICOS ligand	Co-stimulatory signal for T-cell proliferation and cytokine secretion; induces also B-cell proliferation and differentiation into plasma cells
IL1R2	2q11	rs2310173	Interleukin 1 receptor, type II	Binds interleukin alpha (IL1A), interleukin beta (IL1B), and interleukin 1 receptor, type I(IL1R1/IL1RA), and acts as a decoy receptor that inhibits the activity of its ligands
YDJC	22q11	rs181359	YdjC chitooligosaccharide deacetylase homolog	Predicted to enable deacetylase activity and magnesium ion binding activity. Predicted to be involved in carbohydrate metabolic process
PRDM1	6q21	rs6911490	PR domain zinc finger protein 1	Transcription factor regulating downstream cytokines. It is activated by TLRs and IRF-4 and is crucial in T cell, B cell, and myeloid lineage cell differentiations
TNFSF15	9q32	rs4246905	TNF superfamily member 15	It can activate both the NF-κB and MAPK signaling pathways and acts as an autocrine factor to induce apoptosis in endothelial cells
SMAD3	15q22	rs17293632	Mothers against decapentaplegic homolog 3	Up-regulation of genes and TGF-β-induced repression of target genes
PTPN2	18p11	rs1893217	Tyrosine-protein phosphatase non-receptor type 2	Involved in cell growth, differentiation, mitotic cycle, and oncogenic transformation
TNFRSF6B	20q13	rs6062504	Tumor necrosis factor receptor superfamily member 6B	Regulatory role in suppressing FasL- and LIGHT-mediated cell death and T cell activation
HLA:DRB1*03	6p21	rs9268853	Major histocompatibility complex, class II, DR beta 1	Displays foreign peptides to the immune system to trigger the body’s immune response

Table 4.

Genes associated with IBD—Immune-mediated.

Gene	Locus	SNP	Protein name	Function
ORMDL3	17q12	rs2872507	ORMDL sphingolipid biosynthesis regulator 3	Negative regulation of B cell apoptotic process
RTEL1/SLC2A4RG	20q13	rs2297441	Regulator of telomere elongation helicase 1/ SLC2A4 regulator	ATP-dependent DNA helicase is implicated in telomere-length regulation, DNA repair, and the maintenance of genomic stability. / transcription factor involved in SLC2A4 and HD gene transactivation
PTGER4	5p13	rs6451493	Prostaglandin E2 receptor 4	May play an important role in intestinal epithelial transport
KIF21B	1q32	rs7554511	Kinesin Family Member 21B	Plus-end-directed microtubule-dependent motor protein, which displays processive activity. Involved in delivery of gamma-aminobutyric acid (GABA(A)) receptor to the cell surface
NKX 2-3	10q24	rs6584283	Homeobox protein Nkx-2.3	Transcription factor
CREM	10p11	rs12261843	cAMP responsive element modulator	Bound to the -180 site of the IL-2 promoter to repress its transcription
CDKAL1	6p22	rs6908425	Cdk5 regulatory associated protein 1-like 1	Associated with adaptive immunity
STAT3	17q21	rs12942547	Signal transducer and activator of transcription 3	Essential for the differentiation of the TH17 helper T cells
ZNF365	10q21	rs10761659	Protein ZNF365	Contributes to genomic stability by preventing telomere dysfunction
PSMG1	21q22	rs9977672	Proteasome assembly chaperone 1	Enables proteasome binding
IL23R	1p31	rs11209026	Interleukin-23 receptor	Associates constitutively with Janus kinase 2 (JAK2) and also binds to transcription activator STAT3 in a ligand-dependent manner
IL12B	5q33	rs6871626	Subunit beta of interleukin 12	Sustain a sufficient number of memory/effector Th1 cells to mediate long-term protection against an intracellular pathogen
AK2	1p35	rs804427	Adenylate Kinase 2	Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP
FUT2	19q13	rs516246	Galactoside 2-alpha-L-fucosyltransferase 2	regulates several processes such as cell-cell interaction including host-microbe interaction, cell surface expression, and cell proliferation
TYK2	19p13	rs11879191	Non-receptor tyrosine-protein kinase TYK2	Tyk2 is activated by IL-10, and its deficiency affects the ability to generate and respond to IL-10. Involved in the regulation of the JAK–STAT pathway

Table 5.

Other genes associated with IBD.

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. 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, 14, 15, 16, 17, 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 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.

Genetic predisposing factors for UC
HLA
ADCY7
67% of susceptibility loci are shared between UC and CD
Low disease hereditability in UC

Table 6.

Genetic predisposing factors for UC.

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, 29, 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, 32, 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, 36, 37, 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, 40, 41, 42, 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, 53, 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 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].

Environmental factors in UC
Smoking
Appendectomy
Breastfeeding
Antibiotic usage in childhood
NSAIDs
Air pollution
Hypoxia

Table 7.

Summary of environmental factors in UC.

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, 64, 65, 66, 67, 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, 77, 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 pro-inflammatory 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, 90, 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).

Increased risk	Decreased risk
Soft drinks	Fruits
Sucrose	Vegetables
Red meat	n-3 PUFAs
n-6 PUFAs	Normal levels of vitamin D
Food additives	Low FODMAP
Zinc deficiency	Diet guidance
Luminal iron exposure	IgG-guided exclusion diet

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, 94, 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, 99, 100, 101]. There are four controlled positive faecal microbial transplantation clinical studies that confirm the therapeutic effect for ulcerative colitis patients [102, 103, 104, 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, 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).

Decreased diversity of UC gut microbiome, virome, and mycobiome over time

dysbiosis: either a result or a cause of gut inflammation in ulcerative colitis

Imbalance: ↓ protective microbes (Firmicutes and Bacteroides) /; ↑ inflammatory microbes (Enterobacteriaceae and Fusobacteriaceae)

Dysbiosis in the earliest years of life → alteration of gut immunity →; ↑ susceptibility to IBD

Table 9.

Overview of microbiota changes in UC.

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, 115, 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, 120, 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 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, 127, 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, 131, 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).

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

HLA allelic connections may influence antigen presentation

Complex UC immunity: a nonclassical Th2 response Th9 response Th17 response interleukin (IL)-23 inflammatory pathway

Table 10.

Overview of the immune responses in UC.

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, 134, 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, 142, 143].

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

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

Major mediators of inflammation: colonic mesenchyme

Table 11.

New advances in UC.

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.

Acknowledgments

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.