Open access peer-reviewed chapter

Etiology of Ulcerative Colitis

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Carmen-Monica Preda and Doina Istrătescu

Submitted: 02 January 2022 Reviewed: 28 July 2022 Published: 01 September 2022

DOI: 10.5772/intechopen.106842

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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.


  • 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, 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 15 [4, 7, 9].

GeneLocusSNPProtein nameFunction
ECM11q21rs3737240Extracellular matrix protein 1Involved in cell proliferation
HNF4A20q13rs6017342Hepatocyte nuclear factor 4αRegulates cellular differentiation along crypt-villus axis
CDH116q22rs12597188E-cadherinInvolved in epithelial adherens junction
LAMB17q31rs886774Laminin β1Protein involved in cell adhesion and differentiation
GNA127p22rs798502guanine nucleotide-binding protein alpha 12Protein is involved as modulators or transducers in various transmembrane signaling systems

Table 1.

Genes associated with UC that affect the epithelial barrier.

GeneLocusSNPProtein nameFunction
IL8RA / IL8RB2q35rs11676348Interleukin 8 receptor alpha/ Interleukin 8 receptor betaActivation of neutrophils
IL2 / IL214q27rs17388568Interleukin 2/ Interleukin 21T-cell proliferation and other activities crucial to regulation of the immune response /Immunoregulatory activity. May promote the transition between innate and adaptive immunity
IFNG / IL2612q14rs7134599Interferon gamma protein/ Interleukin 26Cytokine is critical for innate and adaptive immunity/mucosal immunity, proinflammatory function
IL7R5p13rs3194051Interleukin-7 receptor proteinNormal development of T cells
TNFRSF91p36rs35675666Tumor Necrosis Factor Receptor Superfamily Member 9Co-stimulatory immune checkpoint molecule
TNFRSF141p36rs10797432Tumor necrosis factor receptor superfamily member 14May mediate the signal transduction pathways that activate the immune response
IRF57q32rs4728142Interferon regulatory factor 5 proteinTranscription factor that plays a critical role in innate immunity
LSP111p15rs907611Lymphocyte-specific protein 1Mediate neutrophil activation and chemotaxis
FCGR2A1q23rs1801274Low-affinity immunoglobulin gamma Fc region receptor II-a proteinBy 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.

GeneLocusSNPProtein nameFunction
OTUD3 / PLA2G2E1p36rs138347004OTU Domain-Containing Protein 3 /Phosphatidylcholine 2-Acylhydrolase 2EProtein turnover/role in inflammation and the immune response
PIM322q13rs5771069Serine/threonine-protein kinase pim-3Prevent apoptosis, promote cell survival and protein translation
DAP5p15rs2930047Death-associated protein 1Negative regulator of autophagy. Involved in mediating interferon-gamma-induced cell death
CAPN102q37rs4676410Calcium-Activated Neutral Proteinase 10Calcium-regulated non-lysosomal thiol-protease, which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction
JAK29p24rs10758669Tyrosine-Protein Kinase JAK2Involved 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.

GeneLocusSNPProtein nameFunction
IL101q32rs3024505Interleukin 10Downregulates 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
CARD99q34rs10781499Caspase recruitment domain-containing protein 9Regulatory role in cell apoptosis
MST13p21rs3197999Macrophage-stimulating proteinStimulates macrophages
ICOSLG21q22rs2838519ICOS ligandCo-stimulatory signal for T-cell proliferation and cytokine secretion; induces also B-cell proliferation and differentiation into plasma cells
IL1R22q11rs2310173Interleukin 1 receptor, type IIBinds 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
YDJC22q11rs181359YdjC chitooligosaccharide deacetylase homologPredicted to enable deacetylase activity and magnesium ion binding activity. Predicted to be involved in carbohydrate metabolic process
PRDM16q21rs6911490PR domain zinc finger protein 1Transcription 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
TNFSF159q32rs4246905TNF superfamily member 15It can activate both the NF-κB and MAPK signaling pathways and acts as an autocrine factor to induce apoptosis in endothelial cells
SMAD315q22rs17293632Mothers against decapentaplegic homolog 3Up-regulation of genes and TGF-β-induced repression of target genes
PTPN218p11rs1893217Tyrosine-protein phosphatase non-receptor type 2Involved in cell growth, differentiation, mitotic cycle, and oncogenic transformation
TNFRSF6B20q13rs6062504Tumor necrosis factor receptor superfamily member 6BRegulatory role in suppressing FasL- and LIGHT-mediated cell death and T cell activation
HLA:DRB1*036p21rs9268853Major histocompatibility complex, class II, DR beta 1Displays foreign peptides to the immune system to trigger the body’s immune response

Table 4.

Genes associated with IBD—Immune-mediated.

GeneLocusSNPProtein nameFunction
ORMDL317q12rs2872507ORMDL sphingolipid biosynthesis regulator 3Negative regulation of B cell apoptotic process
RTEL1/SLC2A4RG20q13rs2297441Regulator of telomere elongation helicase 1/ SLC2A4 regulatorATP-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
PTGER45p13rs6451493Prostaglandin E2 receptor 4May play an important role in intestinal epithelial transport
KIF21B1q32rs7554511Kinesin Family Member 21BPlus-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 2-310q24rs6584283Homeobox protein Nkx-2.3Transcription factor
CREM10p11rs12261843cAMP responsive element modulatorBound to the -180 site of the IL-2 promoter to repress its transcription
CDKAL16p22rs6908425Cdk5 regulatory associated protein 1-like 1Associated with adaptive immunity
STAT317q21rs12942547Signal transducer and activator of transcription 3Essential for the differentiation of the TH17 helper T cells
ZNF36510q21rs10761659Protein ZNF365Contributes to genomic stability by preventing telomere dysfunction
PSMG121q22rs9977672Proteasome assembly chaperone 1Enables proteasome binding
IL23R1p31rs11209026Interleukin-23 receptorAssociates constitutively with Janus kinase 2 (JAK2) and also binds to transcription activator STAT3 in a ligand-dependent manner
IL12B5q33rs6871626Subunit beta of interleukin 12Sustain a sufficient number of memory/effector Th1 cells to mediate long-term protection against an intracellular pathogen
AK21p35rs804427Adenylate Kinase 2Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP
FUT219q13rs516246Galactoside 2-alpha-L-fucosyltransferase 2regulates several processes such as cell-cell interaction including host-microbe interaction, cell surface expression, and cell proliferation
TYK219p13rs11879191Non-receptor tyrosine-protein kinase TYK2Tyk2 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
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
Antibiotic usage in childhood
Air pollution

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 riskDecreased risk
Soft drinksFruits
Red meatn-3 PUFAs
n-6 PUFAsNormal levels of vitamin D
Food additivesLow FODMAP
Zinc deficiencyDiet guidance
Luminal iron exposureIgG-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.



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.


  1. 1. Abraham BP, Kane S. Fecal markers: Calprotectin and lactoferrin. Gastroenterology Clinical North America. 2012;41:483-495
  2. 2. Ng SC, Bernstein CN, Vatn MH, et al. Geographical variability and environmental risk factors in inflammatory bowel disease. Gut. 2013;62:630-649
  3. 3. Porter RJ, Kalla R, Ho GT. Ulcerative colitis: Recent advances in the understanding of disease pathogenesis. F1000Res. 2020;9:294
  4. 4. Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422):119-124
  5. 5. Dobre M, Mănuc TE, Milanesi E, et al. Mucosal CCR1 gene expression as a marker of molecular activity in Crohn’s disease: Preliminary data. Romanian Journal of Morphology and Embryology. 2017;58(4):1263-1268
  6. 6. de Lange KM, Barrett JC. Understanding inflammatory bowel disease via immunogenetics. Journal of Autoimmunity. 2015;64:91-100
  7. 7. Kaur A, Goggolidou P. Ulcerative colitis: Understanding its cellular pathology could provide insights into novel therapies. Journal of Inflammation. 2020;17:15
  8. 8. Cho JH. The genetics and immunopathogenesis of inflammatory bowel disease. Nature Reviews. Immunology. 2008;8(6):458-466
  9. 9. Anderson CA, Boucher G, Lees CW, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nature Genetics. 2011;43(3):246-252
  10. 10. Goyette P, Boucher G, Mallon D, et al. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nature Genetics. 2015;47(2):172-179
  11. 11. Ţieranu CG, Dobre M, Mănuc TE, et al. Gene expression profile of endoscopically active and inactive ulcerative colitis: Preliminary data. Romanian Journal of Morphology and Embryology. 2017;58(4):1301-1307
  12. 12. Luo Y, de Lange KM, Jostins L, et al. Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7. Nature Genetics. 2017;49(2):186-192
  13. 13. Spehlmann ME, Begun AZ, Saroglou E, et al. Risk factors in German twins with inflammatory bowel disease: Results of a questionnaire-based survey. Journal of Crohn’s & Colitis. 2012;6(1):29-42
  14. 14. Halfvarson J, Bodin L, Tysk C, Lindberg E, Järnerot G. Inflammatory bowel disease in a Swedish twin cohort: A long-term follow-up of concordance and clinical characteristics. Gastroenterology. 2003;124(7):1767-1773
  15. 15. Ng SC, Woodrow S, Patel N, Subhani J, Harbord M. Role of genetic and environmental factors in British twins with inflammatory bowel disease. Inflammatory Bowel Diseases. 2012;18(4):725-736
  16. 16. van Dongen J, Slagboom PE, Draisma HH, Martin NG, Boomsma DI. The continuing value of twin studies in the omics era. Nature Reviews. Genetics. 2012;13(9):640-653
  17. 17. Yoshitake S, Kimura A, Okada M, Yao T, Sasazuki T. HLA class II alleles in Japanese patients with inflammatory bowel disease. Tissue Antigens. 1999;53(4 Pt 1):350-358
  18. 18. Inoue N, Tamura K, Kinouchi Y, et al. Lack of common NOD2 variants in Japanese patients with Crohn’sdisease. Gastroenterology. 2002;123(1):86-91
  19. 19. Yang H, McElree C, Roth MP, Shanahan F, Targan SR, Rotter JI. Familial empirical risks for inflammatory bowel disease: Differences between Jews and non-Jews. Gut. 1993;34(4):517-524
  20. 20. Hedin C. Molecular genetics of inflammatory bowel disease. D’Amato M, Rioux JD, editors. Springer; 2013
  21. 21. Manuc M, Ionescu EM, Milanesi E, et al. Molecular signature of persistent histological inflammation in ulcerative colitis with mucosal healing. Journal of Gastrointestinal and Liver Diseases. 2020;29(2):159-166
  22. 22. Lee HS, Cleynen I. Molecular profiling of inflammatory bowel disease: Is it ready for use in clinical decision-making? Cell. 2019;8(6):535
  23. 23. Ventham NT, Kennedy NA, Nimmo ER, Satsangi J. Beyond gene discovery in inflammatory bowel disease: The emerging role of epigenetics. Gastroenterology. 2013;145(2):293-308
  24. 24. Kalla R, Ventham NT, Kennedy NA. MicroRNAs: New players in inflammatory bowel disease. Gut. 2015;64(6):1008
  25. 25. Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: A systematic review of population-based studies. Lancet. 2017;390(10114):2769-2778
  26. 26. Kirsner JB. Historical aspects of inflammatory bowel disease. Journal of Clinical Gastroenterology. 1998;10(3):286-297
  27. 27. Kaplan GG, Ng SC. Understanding and preventing the global increase of inflammatory bowel disease. Gastroenterology. 2017;152(2):313-321
  28. 28. Wang YF, Ou-Yang Q , Xia B, et al. Multicenter case-control study of the risk factors for ulcerative colitis in China. World Journal of Gastroenterology. 2013;19(11):1827-1833
  29. 29. Benchimol EI, Kaplan GG, Otley AR, et al. Rural and urban residence during early life is associated with risk of inflammatory bowel disease: A population-based inception and birth cohort study. The American Journal of Gastroenterology. 2017;112(9):1412-1422
  30. 30. Amarapurkar AD, Amarapurkar DN, Rathi P, et al. Risk factors for inflammatory bowel disease: A prospective multi-center study. Indian Journal of Gastroenterology. 2018;37(3):189-195
  31. 31. Parigi SM, Eldh M, Larssen P, Gabrielsson S, Villablanca EJ. Breast milk and solid food shaping intestinal immunity. Frontiers in Immunology. 2015;6:415
  32. 32. Renz H, Brandtzaeg P, Hornef M. The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Natural Review in Immunology. 2011;12:9
  33. 33. Rogier EW, Frantz AL, Bruno ME, et al. Lessons from mother: Long-term impact of antibodies in breast milk on the gut microbiota and intestinal immune system of breastfed offspring. Gut Microbes. 2014;5(5):663-668
  34. 34. Xu L, Lochhead P, Ko Y, Claggett B, Leong RW, Ananthakrishnan AN. Systematic review with meta-analysis: Breastfeeding and the risk of Crohn’s disease and ulcerative colitis. Aliment Pharmacology Therapy. 2017;46(9):780-789
  35. 35. Hegar B, Wibowo Y, Basrowi RW, et al. The role of two human milk oligosaccharides, 2’-Fucosyllactose and Lacto-N-Neotetraose, in infant nutrition. Pediatric Gastroenterology Hepatology Nutrition. 2019;22:330-340
  36. 36. Harmsen HJ, Wildeboer-Veloo AC, Raangs GC, et al. Analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods. Journal of Pediatric Gastroenterology and Nutrition. 2000;30:61-67
  37. 37. Boudry G, Charton E, Le Huerou-Luron I, et al. The relationship between breast milk components and the infant gut microbiota. Frontiers in Nutrition. 2021;8:629740
  38. 38. Zuurveld M, van Witzenburg NP, Garssen J, et al. Immunomodulation by human milk oligosaccharides: The potential role in prevention of allergic diseases. Frontiers in Immunology. 2020;11:801
  39. 39. Bernstein CN, Rawsthorne P, Cheang M, Blanchard JF. A population-based case control study of potential risk factors for IBD. The American Journal of Gastroenterology. 2006;101(5):993-1002
  40. 40. Timm S, Svanes C, Janson C, et al. Place of upbringing in early childhood as related to inflammatory bowel diseases in adulthood: A population-based cohort study in Northern Europe. European Journal of Epidemiology. 2014;29(6):429-437
  41. 41. Bager P, Simonsen J, Nielsen NM, Frisch M. Cesarean section and offspring’s risk of inflammatory bowel disease: A national cohort study. Inflammatory Bowel Diseases. 2012;18(5):857-862
  42. 42. Castiglione F, Diaferia M, Morace F, et al. Risk factors for inflammatory bowel diseases according to the “hygiene hypothesis”: A case-control, multi-centre, prospective study in Southern Italy. Journal of Crohn’s & Colitis. 2012;6(3):324-329
  43. 43. Ng SC, Tang W, Leong RW, et al. Environmental risk factors in inflammatory bowel disease: A population-based case-control study in Asia-Pacific. Gut. 2015;64(7):1063-1071
  44. 44. Ungaro R, Bernstein CN, Gearry R, et al. Antibiotics associated with increased risk of new-onset Crohn’s disease but not ulcerative colitis: A meta-analysis. The American Journal of Gastroenterology. 2014;109(11):1728-1738
  45. 45. Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease. The American Journal of Gastroenterology. 2010;105(12):2687-2692
  46. 46. Meyer AM, Ramzan NN, Heigh RI, Leighton JA. Relapse of inflammatory bowel disease associated with use of nonsteroidal anti-inflammatory drugs. Digestive Diseases and Sciences. 2006;51(1):168-172
  47. 47. Bernstein CN, Eliakim A, Fedail S, et al. Review Team: World Gastroenterology Organisation Global Guidelines Inflammatory Bowel Disease: Update August 2015. Journal of Clinical Gastroenterology. 2016;50(10):803-818
  48. 48. Wang P, Hu J, Ghadermarzi S, et al. Smoking and inflammatory bowel disease: A comparison of China, India, and the USA. Digestive Diseases and Sciences. 2018;63(10):2703-2713
  49. 49. Andersson RE, Olaison G, Tysk C, Ekbom A. Appendectomy and protection against ulcerative colitis. The New England Journal of Medicine. 2001;344(11):808-814
  50. 50. Andersson RE, Olaison G, Tysk C, Ekbom A. Appendectomy is followed by increased risk of Crohn’s disease. Gastroenterology. 2003;124(1):40-46
  51. 51. Kikut J, Skonieczna-Żydecka K, Sochaczewska D, Kordek A, Szczuko M. Differences in dietary patterns of adolescent patients with IBD. Nutrients. 2021;13(9):3119
  52. 52. Bernstein CN. Psychological stress and depression: Risk factors for IBD? Digestive Diseases. 2016;34(1-2):58-63
  53. 53. Graff LA, Walker JR, Bernstein CN. Depression and anxiety in inflammatory bowel disease: A review of comorbidity and management. Inflammatory Bowel Diseases. 2009;15:1105-1118
  54. 54. Guthrie E, Jackson J, Shaffer J, et al. Psychological disorder and severity of inflammatory bowel disease predict health-related quality of life in ulcerative colitis and Crohn’s disease. The American Journal of Gastroenterology. 2002;97:1994-1999
  55. 55. Ananthakrishnan AN, Higuchi LM, Huang ES, et al. Aspirin, nonsteroidal anti-inflammatory drug use, and risk for Crohn disease and ulcerative colitis: A cohort study. Annals of Internal Medicine. 2012;156(5):350-359
  56. 56. Kish L, Hotte N, Kaplan GG, et al. Environmental particulate matter induces murine intestinal inflammatory responses and alters the gut microbiome. PLoS One. 2013;8(4):e62220
  57. 57. Kaplan GG, Hubbard J, Korzenik J, et al. The inflammatory bowel diseases and ambient air pollution: A novel association. The American Journal of Gastroenterology. 2010;105(11):2412-2419
  58. 58. Opstelten JL, Beelen RMJ, Leenders M, et al. Exposure to ambient air pollution and the risk of inflammatory bowel disease: A European Nested Case-Control Study. Digestive Diseases and Sciences. 2016;61(10):2963-2971
  59. 59. Eltzschig HK, Carmeliet P. Hypoxia and inflammation. The New England Journal of Medicine. 2011;364(7):656-665
  60. 60. Hartmann G, Tschöp M, Fischer R, et al. High altitude increases circulating interleukin-6, interleukin-1 receptor antagonist and C-reactive protein. Cytokine. 2000;12(3):246-252
  61. 61. Vermeulen N, Vermeire S, Arijs I, et al. Seroreactivity against glycolytic enzymes in inflammatory bowel disease. Inflammation Bowel Diseases. 2011;17(2):557-564
  62. 62. Dulai PS, Buckey JC Jr, Raffals LE, et al. Hyperbaric oxygen therapy is well tolerated and effective for ulcerative colitis patients hospitalized for moderate-severe flares: A phase 2A pilot multi-center, randomized, double-blind, sham-controlled trial. The American Journal of Gastroenterology. 2018;113(10):1516-1523
  63. 63. Hou JK, Abraham B, El-Serag H. Dietary intake and risk of developing inflammatory bowel disease: A systematic review of the literature. The American Journal of Gastroenterology. 2011;106(4):563-573
  64. 64. Nie JY, Zhao Q. Beverage consumption and risk of ulcerative colitis: Systematic review and meta-analysis of epidemiological studies. Medicine (Baltimore). 2017;96(49):e9070
  65. 65. Wang F, Feng J, Gao Q , et al. Carbohydrate and protein intake and risk of ulcerative colitis: Systematic review and dose-response meta-analysis of epidemiological studies. Clinical Nutrition. 2017;36(5):1259-1265
  66. 66. Li F, Liu X, Wang W, Zhang D. Consumption of vegetables and fruit and the risk of inflammatory bowel disease: A meta-analysis. European Journal of Gastroenterology and Hepatology. 2015;27(6):623-630
  67. 67. Preda CM, Manuc T, Istratescu D, et al. Environmental factors in Romanian and Belgian patients with inflammatory bowel disease: A Retrospective Comparative Study. Maedica (Bucur). 2019;14(3):233-239
  68. 68. Preda CM, Manuc T, Chifulescu A, et al. Diet as an environmental trigger in inflammatory bowel disease: A retrospective comparative study in two European cohorts. Revista Espanola de Enfermedades Digestivas. 2020;112(6):440-447
  69. 69. Ge J, Han TJ, Liu J, et al. Meat intake and risk of inflammatory bowel disease: A meta-analysis. The Turkish Journal of Gastroenterology. 2015;26(6):492-497
  70. 70. John S, Luben R, Shrestha SS, Welch A, Khaw KT, Hart AR. Dietary n-3 polyunsaturated fatty acids and the aetiology of ulcerative colitis: A UK prospective cohort study. European Journal of Gastroenterology and Hepatology. 2010;22(5):602-606
  71. 71. de Silva PS, Olsen A, Christensen J. An association between dietary arachidonic acid, measured in adipose tissue, and ulcerative colitis. Gastroenterology. 2010;139(6):1912-1917
  72. 72. Khalili H, Chan SSM, Lochhead P, Ananthakrishnan AN, Hart AR, Chan AT. The role of diet in the aetiopathogenesis of inflammatory bowel disease. Natural Review in Gastroenterology and Hepatology. 2018;15(9):525-535
  73. 73. Brown K, DeCoffe D, Molcan E, Gibson DL. Diet-induced dysbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients. 2012;4(8):1095-1119
  74. 74. De Filippo C, Cavalieri D, Di Paola M, et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proceedings of the National Academy Science U S A. 2010;107(33):14691-14696
  75. 75. Sun M, Wu W, Liu Z, Cong Y. Microbiota metabolite short chain fatty acids, GPCR, and inflammatory bowel diseases. Journal of Gastroenterology. 2017;52(1):1-8
  76. 76. Agus A, Denizot J, Thévenot J, et al. Western diet induces a shift in microbiota composition enhancing susceptibility to Adherent-Invasive E. coli infection and intestinal inflammation. Scientific Reports. 2016;6:19032
  77. 77. Machiels K, Joossens M, Sabino J, et al. A decrease of the butyrate-producing species Roseburiahominis and Faecalibacteriumprausnitzii defines dysbiosis in patients with ulcerative colitis. Gut. 2014;63(8):1275-1283
  78. 78. Koleva P, Ketabi A, Valcheva R, Gänzle MG, Dieleman LA. Chemically defined diet alters the protective properties of fructo-oligosaccharides and isomalto-oligosaccharides in HLA-B27 transgenic rats. PLoS One. 2014;9(11):e111717
  79. 79. Ananthakrishnan AN, Khalili H, Konijeti GG, et al. Long-term intake of dietary fat and risk of ulcerative colitis and Crohn’s disease. Gut. 2014;63(5):776-784
  80. 80. Chan SS, Luben R, Olsen A, et al. Association between high dietary intake of the n-3 polyunsaturated fatty acid docosahexaenoic acid and reduced risk of Crohn’s disease. Aliment Pharmacological Therapy. 2014;39(8):834-842
  81. 81. Chapkin RS, Davidson LA, Ly L, Weeks BR, Lupton JR, McMurray DN. Immunomodulatory effects of (n-3) fatty acids: Putative link to inflammation and colon cancer. The Journal of Nutrition. 2007;137(Suppl. 1):200S-204S
  82. 82. Werner T, Wagner SJ, Martínez I, et al. Depletion of luminal iron alters the gut microbiota and prevents Crohn’s disease-like ileitis. Gut. 2011;60(3):325-333
  83. 83. Sturniolo GC, Di Leo V, Ferronato A, D’Odorico A, D’Incà R. Zinc supplementation tightens “leaky gut” in Crohn’s disease. Inflammatory Bowel Diseases. 2001;7(2):94-98
  84. 84. Reich KM, Fedorak RN, Madsen K, Kroeker KI. Vitamin D improves inflammatory bowel disease outcomes: Basic science and clinical review. World Journal of Gastroenterology. 2014;20(17):4934-4947
  85. 85. Ruemmele FM. Role of diet in inflammatory bowel disease. Ann NutrMetab. 2016;68(Suppl. 1):33-41
  86. 86. Fahoum L, Moscovici A, David S, et al. Digestive fate of dietary carrageenan: evidence of interference with digestive proteolysis and disruption of gut epithelial function. Molecular Nutritional Food Research. 2017;61(3). DOI: 10.1002/mnfr.201600545
  87. 87. Chassaing B, Van de Wiele T, De Bodt J, Marzorati M, Gewirtz AT. Dietary emulsifiers directly alter human microbiota composition and gene expression ex vivo potentiating intestinal inflammation. Gut. 2017;66(8):1414-1427
  88. 88. Chassaing B, Koren O, Goodrich JK, et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature. 2015;519(7541):92-96
  89. 89. Kyaw MH, Moshkovska T, Mayberry J. A prospective, randomized, controlled, exploratory study of comprehensive dietary advice in ulcerative colitis: Impact on disease activity and quality of life. European Journal of Gastroenterology and Hepatology. 2014;26(8):910-917
  90. 90. Pedersen N, Ankersen DV, Felding M, et al. Low-FODMAP diet reduces irritable bowel symptoms in patients with inflammatory bowel disease. World Journal of Gastroenterology. 2017;23(18):3356-3366
  91. 91. Jian L, Anqi H, Gang L, et al. Food exclusion based on IgG antibodies alleviates symptoms in ulcerative colitis: A Prospective Study. Inflammatory Bowel Diseases. 2018;24(9):1918-1925
  92. 92. Lathrop SK, Bloom SM, Rao SM, et al. Peripheral education of the immune system by colonic commensal microbiota. Nature. 2011;478(7368):250-254
  93. 93. Morgan XC, Tickle TL, Sokol H, et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biology. 2012;13(9):R79
  94. 94. Nagalingam NA, Lynch SV. Role of the microbiota in inflammatory bowel diseases. Inflammatory Bowel Diseases. 2012;18(5):968-984
  95. 95. Spor A, Koren O, Ley R. Unravelling the effects of the environment and host genotype on the gut microbiome. Nature Reviews. Microbiology. 2011;9(4):279-290
  96. 96. Duvallet C, Gibbons SM, Gurry T, Irizarry RA, Alm EJ. Meta-analysis of gut microbiome studies identifies disease-specific and shared responses. Nature Communications. 2017;8(1):1784
  97. 97. Gevers D, Kugathasan S, Denson LA, et al. The treatment-naive microbiome in new-onset Crohn’sdisease. Cell Host & Microbe. 2014;15(3):382-392
  98. 98. Norman JM, Handley SA, Baldridge MT, et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell. 2015;160(3):447-460
  99. 99. Zuo T, Lu XJ, Zhang Y, et al. Gut mucosal virome alterations in ulcerative colitis. Gut. 2019;68(7):1169-1179
  100. 100. Qiu X, Ma J, Jiao C, et al. Alterations in the mucosa-associated fungal microbiota in patients with ulcerative colitis. Oncotarget. 2017;8(64):107577-107588
  101. 101. Ott SJ, Kühbacher T, Musfeldt M, et al. Fungi and inflammatory bowel diseases: Alterations of composition and diversity. Scandinavian Journal of Gastroenterology. 2008;43(7):831-841
  102. 102. Moayyedi P, Surette MG, Kim PT, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology. 2015;149(1):102-109
  103. 103. Rossen NG, Fuentes S, van der Spek MJ, et al. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology. 2015;149(1):110-118
  104. 104. Costello SP, Hughes PA, Waters O, et al. Effect of fecal microbiota transplantation on 8-week remission in patients with ulcerative colitis: A Randomized Clinical Trial. Journal of the American Medical Association. 2019;321(2):156-164
  105. 105. Paramsothy S, Kamm MA, Kaakoush NO, et al. Multidonor intensive faecalmicrobiota transplantation for active ulcerative colitis: A randomised placebo-controlled trial. Lancet. 2017;389(10075):1218-1228
  106. 106. Paramsothy S, Nielsen S, Kamm MA, et al. Specific bacteria and metabolites associated with response to fecal microbiota transplantation in patients with ulcerative colitis. Gastroenterology. 2019;156(5):1440-1454
  107. 107. Glotzer DJ, Glick ME, Goldman H. Proctitis and colitis following diversion of the fecal stream. Gastroenterology. 1981;80(3):438-441
  108. 108. Penders J, Thijs C, Vink C, et al. Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics. 2006;118(2):511-521
  109. 109. Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proceedings of the National Academy Science U S A. 2011;108(Suppl. 1):4554-4561
  110. 110. Friedrich M, Pohin M, Powrie F. Cytokine networks in the pathophysiology of inflammatory bowel disease. Immunity. 2019;50(4):992-1006
  111. 111. Na YR, Stakenborg M, Seok SH, Matteoli G. Macrophages in intestinal inflammation and resolution: A potential therapeutic target in IBD. Natural Reviews in Gastroenterology and Hepatology. 2019;16(9):531-543
  112. 112. Graham DB, Luo C, O’Connell DJ, et al. Antigen discovery and specification of immunodominance hierarchies for MHCII-restricted epitopes. Nature Medicine. 2018;24(11):1762-1772
  113. 113. Zhou L, Chong MM, Littman DR. Plasticity of CD4+ T cell lineage differentiation. Immunity. 2009;30(5):646-655
  114. 114. Reboldi A, Cyster JG. Peyer’s patches: Organizing B-cell responses at the intestinal frontier. Immunological Reviews. 2016;271(1):230-245
  115. 115. Neurath MF. Cytokines in inflammatory bowel disease. Nature Reviews. Immunology. 2014;14(5):329-342
  116. 116. Van Klinken BJ, Van der Wal JW, Einerhand AW, Büller HA, Dekker J. Sulphation and secretion of the predominant secretory human colonic mucin MUC2 in ulcerative colitis. Gut. 1999;44(3):387-393
  117. 117. Teng MW, Bowman EP, McElwee JJ, et al. IL-12 and IL-23 cytokines: From discovery to targeted therapies for immune-mediated inflammatory diseases. Nature Medicine. 2015;21(7):719-729
  118. 118. Kobayashi T, Okamoto S, Hisamatsu T, et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease. Gut. 2008;57(12):1682-1689
  119. 119. Nalleweg N, Chiriac MT, Podstawa E, et al. IL-9 and its receptor are predominantly involved in the pathogenesis of UC. Gut. 2015;64(5):743-755
  120. 120. Lee JC, Lyons PA, McKinney EF, et al. Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis. The Journal of Clinical Investigation. 2011;121(10):4170-4179
  121. 121. Hepworth MR, Monticelli LA, Fung TC, et al. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature. 2013;498(7452):113-117
  122. 122. Pantazi E, Powell N. Group 3 ILCs: Peacekeepers or troublemakers? What’s your gut telling you?! Frontiers in Immunology. 2019;10:676
  123. 123. UK IBD Genetics Consortium, Barrett JC, Lee JC, et al. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nature Genetics. 2009;41(12):1330-1334
  124. 124. Rimoldi M, Chieppa M, Salucci V, et al. Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nature Immunology. 2005;6(5):507-514
  125. 125. Ueno A, Ghosh A, Hung D, Li J, Jijon H. Th17 plasticity and its changes associated with inflammatory bowel disease. World Journal of Gastroenterology. 2015;21(43):12283-12295
  126. 126. Park S, Abdi T, Gentry M, Laine L. Histological disease activity as a predictor of clinical relapse among patients with ulcerative colitis: Systematic review and meta-analysis. The American Journal of Gastroenterology. 2016;111(12):1692-1701
  127. 127. Dinallo V, Marafini I, Di Fusco D, et al. Neutrophil extracellular traps sustain inflammatory signals in ulcerative colitis. Journal of Crohn’s & Colitis. 2019;13(6):772-784
  128. 128. Strober W, Fuss IJ. Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology. 2011;140(6):1756-1767
  129. 129. de Souza HS, Fiocchi C. Immunopathogenesis of IBD: Current state of the art. Natural Review in Gastroenterology and Hepatology. 2016;13(1):13-27
  130. 130. Mann ER, Li X. Intestinal antigen-presenting cells in mucosal immune homeostasis: Crosstalk between dendritic cells, macrophages and B-cells. World Journal of Gastroenterology. 2014;20(29):9653-9664
  131. 131. Kmieć Z, Cyman M, Ślebioda TJ. Cells of the innate and adaptive immunity and their interactions in inflammatory bowel disease. Advanced Medical Science. 2017;62(1):1-16
  132. 132. Satsangi J, Landers CJ, Welsh KI, Koss K, Targan S, Jewell DP. The presence of anti-neutrophil antibodies reflects clinical and genetic heterogeneity within inflammatory bowel disease. Inflammatory Bowel Diseases. 1998;4(1):18-26
  133. 133. West AP, Shadel GS. Mitochondrial DNA in innate immune responses and inflammatory pathology. Natural Review in Immunology. 2017;17(6):363-375
  134. 134. Ho GT, Aird RE, Liu B, et al. MDR1 deficiency impairs mitochondrial homeostasis and promotes intestinal inflammation. Mucosal Immunology. 2018;11(1):120-130
  135. 135. Boyapati RK, Dorward DA, Tamborska A, et al. Mitochondrial DNA is a pro-inflammatory damage-associated molecular pattern released during active IBD. Inflammatory Bowel Diseases. 2018;24(10):2113-2122
  136. 136. Bär F, Bochmann W, Widok A, et al. Mitochondrial gene polymorphisms that protect mice from colitis. Gastroenterology. 2013;145(5):1055-1063
  137. 137. Boyapati RK, Tamborska A, Dorward DA, Ho GT. Advances in the understanding of mitochondrial DNA as a pathogenic factor in inflammatory diseases. F1000Res. 2017;6:169
  138. 138. Piccinini AM, Midwood KS. DAMPening inflammation by modulating TLR signalling. Mediators of Inflammation. 2010;2010:672395
  139. 139. Lamkanfi M, Dixit VM. Mechanisms and functions of inflammasomes. Cell. 2014;157(5):1013-1022
  140. 140. Kalla R, Ventham NT, Kennedy NA, Quintana JF, Nimmo ER, Buck AH, et al. MicroRNAs: New players in IBD. Gut. 2015;64(3):504-517
  141. 141. Parikh K, Antanaviciute A, Fawkner-Corbett D, et al. Colonic epithelial cell diversity in health and inflammatory bowel disease. Nature. 2019;567(7746):49-55
  142. 142. Kinchen J, Chen HH, Parikh K, et al. Structural remodeling of the human colonic mesenchyme in inflammatory bowel disease. Cell. 2018;175(2):370-386
  143. 143. West NR, Hegazy AN, Owens BMJ, et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nature Medicine. 2017;23(5):579-589

Written By

Carmen-Monica Preda and Doina Istrătescu

Submitted: 02 January 2022 Reviewed: 28 July 2022 Published: 01 September 2022