The exposome-diet-epigenome axis in inflammatory bowel diseases—a narrative review

Introduction

Inflammatory bowel disease (IBD) is a progressive immune-mediated chronic gastrointestinal (GI) disease, including Crohn’s disease (CD) and ulcerative colitis (UC), and is exemplified by a persistent relapsing-remitting inflammation profile (1). IBD is a complex condition involving multiple factors, including genetics, environment, and gut microbiota (2,3). The most common theory is that it is caused by a faulty immune response in the gut, which leads to an impaired intestinal barrier. Factors related to lifestyles, such as diet, physical activity, medication use, sleep, anxiety, and pollution, are essential in evaluating the risk of developing IBD (4). The incidence of IBD is increasing worldwide, especially in recently industrialized areas worldwide, such as South America, Africa, and Asia (1,5). More than 3 million people have been diagnosed with IBD. Medical care costs are high to the public health care systems, and several patients become less productive due to sickness, leading to disability and premature retirement (6,7).

The Montreal Classification for CD is a worldwide system used to characterize CD patients (8). According to this classification, CD is classified into three main categories: age at diagnosis, location of disease, and disease behavior. The age-at-diagnosis category divides patients into pediatric (<17 years old) and adult (≥17 years old) groups (8). The location of the disease is classified according to the inflamed area in the GI tract and includes three subcategories: L1 (terminal ileum), L2 (colon), L3 (ileocolon), and L4 (upper GI). Disease behavior is classified into three subcategories: B1 (non-penetrating and non-stricturing disease), B2 (stricturing), and B3 (penetrating). Furthermore, the Montreal Classification also includes additional categories to classify disease behavior based on the presence or absence of perianal disease, which would be indicated by a ‘p’ appended to behavior categories (B1p, B2p, and B3p). This classification system is useful in predicting disease outcomes and guiding treatment decisions in patients with CD (8).

Environmental factors are important in the genesis of IBD manifestations. A few decades ago, with the increase in IBD incidence and research advances about the metabolomic, new pathways were explored to better understand how environmental factors are associated with the disease (9). Epigenetic regulation is an important explanation for the influence of environmental factors on the development of IBD (10). The epigenome, which refers to the chemical modifications of DNA, can directly influence different processes, such as transcription, replication, recombination, repair, histone methylation, and modification (11).

The crucial role of epigenetics and the more accepted concept of the “epigenome” has motivated many researchers to investigate different approaches. The epigenome plays a fundamental role in controlling gene expression and regulating critical biological processes such as embryonic development, cellular differentiation, and response to environmental stimuli (4,9-12). Diet is one of the most critical environmental factors in the development of IBD (9). Nutrients can, directly and indirectly, affect the epigenome, and diet can alter the microbiome, leading to epigenetic modifications (10). Although we do not know the exact cause of remission for IBD, exploring the contribution of epigenetics, especially diet, may help develop future therapeutic approaches to improve the outcome of the disease (9,10,13). In this review, we discuss the role of diet in modulating the microbiome and influencing epigenetic changes through the exposome-diet-epigenome axis. We could hence favor a future therapeutic approach to improve the outcome of the disease. We present this article in accordance with the Narrative Review reporting checklist (available at https://dmr.amegroups.com/article/view/10.21037/dmr-22-85/rc)

Methods

To interpret the evidence on the association of environmental factors and endogenous factors in individuals with IBD and create a connection between these factors, we performed a thorough literature review. We selected articles published from 1942 to 2023 by searching the MEDLINE database at the NIH National Library of Medicine PubMed (Table 1). In this database, we selected articles indexed in English. Editorial comments, technical reports, abstracts published in scientific events, and case studies were excluded.

Genome in IBDs

IBD is a complex and multifactorial disorder influenced by various factors, including genetics and the environment (14). The genome is a significant risk factor for disease development (11-14). IBD among relatives and twins reiterates its importance (11,12). Both main IBD have a genetic component, but the heritability factor is relatively higher in CD than in UC (9).

Since the 1980s, IBD has been considered a polygenic disease, and several epidemiological studies have found multiple susceptibility loci associated with the occurrence of the disease (13,14). Genome-Wide Association Studies (GWAS) have successfully identified about 240 loci contributing to IBD susceptibility (15). Several loci showed specific mutations resulting in loss-of-function immune pathway variants that generally respond to the host microbiome for intestinal homeostasis (16-18). For example, the Nucleotide-binding oligomerization domain-containing protein 2 (NOD2, also known as CARD15) was the first gene identified through genome studies for CD susceptibility (19,20). NOD2 discovery suggested that pattern recognition receptors and innate immunity have an important role in physio pathogenesis (13). Another important cellular-stress mechanism with polymorphisms related to IBD is autophagy. GWAS analysis also found the gene ATG16L1 (autophagy-related 16-like 1) and IRGM (immunity-related GTPase family protein) linked to IBD (15,17). The role of the inflammatory signaling pathways, such as IL 23-driven T helper cell responses, also has been described in IBD (12,13,16,21). IL10 locus is associated with UC and CD with potential therapeutic functionality (22). Two meta-analyses have revealed 47 UC susceptibility loci, and 71 were shown for CD (22,23). The analysis emphasized the role of impaired barrier function in UC etiology (23). Indeed, some genetic variants that control epithelial barrier functions have been reported to be associated with IBD, such as TTC7A, which maintains apicobasal epithelial polarity, and EPCAM and SPINT2 epithelial adhesion genes (18).

Other autoimmune and immune-mediated diseases such as rheumatoid arthritis, psoriasis, multiple sclerosis, type 1 diabetes, and celiac disease commonly share some genetic locus (21,22). For example, ankylosing spondylitis and IBD are associated with IL23R and TNFSF15 (22). Celiac disease shares four risk loci with CD (PTPN2, IL18RAP, TAGAP, and PUS10) (24). González-Serna and coauthors showed four new loci share between systemic sclerosis and CD (IL12RB2, IRF1/SLC22A5, STAT3, and an intergenic locus at 6p21.31) (25).

Despite the success in identifying several loci and replicable genome studies associations, all these genetic factors explain a modest fraction of phenotypic variance of 08% for UC and 13% for CD, demonstrating the complexity of IBD disorders (26). According to Fofanova et al. [2016], the phenotypic concordance in twin studies is between 27–56% for CD and less than 20% for UC (9). That is, the genetic predisposition alone is inefficient in determining the development or not of IBD (9). Furthermore, the increase in the incidence of chronic-immune diseases, besides IBD, demonstrates that other environmental factors influence disease pathogenesis in addition to genetic factors (25,27).

Environmental factors “exposome”

Chronic immune-mediated diseases such as IBD are emerging whiting industrialization (14,28). Increasing evidence suggests that environmental factors have an important role in IBD incidence and outcome (4). IBD is considered a disease of the industrialized world (29,30). Several studies have shown epidemiological evidence of the association of environmental factors, such as urbanization, westernized diet, air pollution, food chemical additives, smoking, psychological factors, sleep disturbances, exercise, antibiotics, oral contraceptive pills, and microplastic exposure to IBD (31-33).

However, the mechanism behind these remains unknown. These factors can be analyzed in IBD by exerting an effect on the gut microbiome. Improved sanitation and personal hygiene in developed countries have reduced infectious diseases. However, some studies have shown that better health conditions are associated with an increased risk of IBD. Research compiled by Vedamurthy and Ananthakrishnan [2019] suggests that living in a large family, crowded rural homes, having a pet at home, consuming unpasteurized milk, being in contact with Helicobacter pylori, and parasitic worm colonization are negatively associated with the prevalence of IBD (32). A hygienic environment has reduced the number and diversity of microbiota, resulting in changes in the microbiome profile. Fewer episodes of infections throughout life can result in an abnormal immune response (34).

Other external environmental factors influencing IBD consist of the maternal lifestyle and in-utero events, mode of child delivery (vaginal vs. cesarean), breastfeeding, food choices, smoking, drugs, vaccination, alcoholism, physical activity, stress, appendicectomy, vitamin D deficiency, and others factors not yet discovered until now (4,35-37). Curiously, the smoking habit has the opposite effect in UC than in CD (38-41). Smoking increases smokers’ risk of developing CD, and disease outcome is impaired (33). In contrast, smoking protects against UC and favors better disease development (38-40). In this context, several potential active mediators in smoke may be responsible for these clinical effects, including nicotine and carbon monoxide, which could modulate the autoantibodies production, inflammatory profile, and leukocyte migration. However, the precise mechanism remains unknown (38,41).

Epigenetics can be mitotically heritable changes in gene function that cannot be explained by altered DNA sequences (12). It can influence the transcriptional expression contributing to IBD by working through DNA methylation, histone alterations, or silencing by non-coding RNAs (ncRNAs) (4,42,43). How these environmental factors induce changes in the exposome of individuals needs to be better studied. Through epigenetics studies, it is possible to evaluate their influence in terms of duration, frequency, and time they occur and how they modulate IBD.

Diet in IBDs

The higher incidence rates of IBD in Westernized societies point to the potential role of diet concerning dietary patterns and specific nutrients in developing and managing the disease (44). Western diet, characterized by a high intake of saturated fat, refined sugar, and salt and low consumption of fiber, fruits, and vegetables, is associated with gut dysbiosis, resulting in differences in microbial composition and reduced microbial diversity (35).

Furthermore, our research group showed in a review that high saturated fat, sucrose, monosaccharide consumption, and long-term fast food dietary consumption are associated with CD (44). At the same time, breastfeeding and fiber might play a protective role. Regarding UC, the dietary risk factors are overconsumption of animal fat and cholesterol, sucrose, and linoleic acid. In contrast, breastfeeding and high consumption of n-3 polyunsaturated fatty acids (PUFAs) are associated with a diminished risk of UC (44). The specific components, related to a higher IBD risk, and the Westernized diet, characterized by ultra-processed food consumption, can worsen experimental gut inflammation by exploiting the gut microbiota or engaging innate immune receptors and related cellular stress signaling (45). Through genetic colocalization and Mendelian randomization techniques, researchers have identified the causal relationship between n-6 PUFAs, and the derived metabolites as a causality factor for CD (46,47). Another study has shown the protective effects of n-3 PUFAs on IBD, commonly found in foods such as fish oil, flaxseed, and other sources (46). The recommended dietary intake ratio of omega-3:omega-6 depends on the disease under consideration (48). According to Cholewski et al. [2018], the ideal consumption would be to follow the proportion of the Japanese population from 1:2 to 1:4 (48). However, some researchers suggest consumption from 1:5 to 1:10 of n-3:n-6 would already be adequate for the general population (48).

In addition to ingesting this essential nutrient, such as the PUFA ratio, evaluating the patient’s entire dietary context is necessary. Researchers have evaluated specific diets for IBD treatment. Some nutritional strategies, such as exclusive enteral nutrition (EEN) (49) and Crohn’s Disease Exclusion Diet (CDED) (50,51), have been found effective in inducing remission, at least in CD. According to the ESPEN guideline (52), an EEN is recommended as the first-line therapy to induce remission in children and adolescents with mild active CD. This nutrition therapy is based on administering a liquid nutrition formula (polymeric diet with moderate fat content) via a feeding tube, which completely excludes food intake for several weeks (49). CDED has the advantage of allowing real food and recommends a better-acceptable alternative to the exclusive use of enteral formula. However, other dietary strategies, such as the specific carbohydrate diet (SCD), modulating early life microbiome through dietary intervention in pregnancy (MELODY), anti-inflammatory diet for IBD (IBD-AID), and low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet, have shown effects in improving symptoms (49-54).

These aspects highlight the importance of intervention studies in IBD patients to evaluate clinical outcomes and quality of life.

Gut microbiome

The microbiome plays a crucial role as an environmental factor that can modulate the exposome, leading to epigenetic modifications in the host. The microbiome study is part of an important axis that directs the occurrence of IBD: the exposome-microbiome-epigenome axis (4).

Bacterial load is the best-studied component of intestinal microorganisms. Bacterial microbiota can reach 10¹¹–10¹² organisms in the GI tract per gram of luminal content in the colon (55). This colonization by microorganisms in the gut starts during the intrauterine period and may play a role in IBD within a predisposing environment (54,56,57). Influenced by the delivery, lack of breastfeeding, and early environmental exposures, gut microbiota paves the way for early-life health or IBD (56-58). According to Ramos and Papadakis [2019], the interplay between genetic predisposition and environmental influence on the microbiome may lead to inappropriate immune activation by weakening the gut barrier (33).

The gut microbiome interacts with the host symbiotically and plays important roles: digestion of substrates and nutrient production; production of vitamins and short-chain fatty acids (SCFAs); protection of mucosal homeostasis repressing the growth of harmful microorganisms; and development and regulation of the immune system (59,60).

Influenced by the microbiome and diet, SCFAs are gut microbiota-derived metabolites produced by anaerobic fermentation of indigestible fibers mainly found in fruits, vegetables, and abundance in flaxseed, chia seed, barley, oats, and other foods (2,4,60-62). The three main SCFAs are acetate, butyrate, and propionate, which exert anti-inflammatory effects and promote the integrity of epithelial barrier function (2,4,10,60-62). These metabolites play a key role in the microbiome-host interface and maintain intestinal homeostasis by supporting epithelial cell function, stimulating mucus quality and synthesis, and strengthening intestinal barrier integrity (61). For example, Akkermansia muciniphila, a human intestinal mucin-degrading bacterium, has been identified as a critical propionate-producing (63). The microorganisms: Faecalibacterium prausnitzii, Eubacterium rectale, Eubacterium hallii, Ruminococcus bromii, Roseburia spp., Lactobacillus spp., and Bifidobacterium spp., are responsible for the most significant fraction of butyrate production (64-66). Fermentation of resistant starch is thought to contribute significantly to butyrate production in the colon, so reducing these organisms would significantly reduce their production.

Furthermore, the host-associated microbiome prevents the growth of harmful microorganisms by the support the innate immune defense against pathogenic bacteria through the stimulation of antimicrobial molecules (61). Alterations in the gut microbiota are known as dysbiosis. Dysbiosis states of the microbiome might be an environmental stimulus in altering the host-mucosal defenses and triggering immune responses favoring the disease onset (66). For example, the gut of an infant with dysbiosis promotes a strong lymphocyte T helper cell (Th1) bias, which induces the immune system to become pro-inflammatory and produce the cytokines interleukin-12 (IL-12) and interferon (IFN)-γ secretion (57,67). This inflammatory condition alters the immune system, which can lead to long-term consequences such as IBD, allergies, irritable bowel syndrome (IBS), and autoimmune diseases.

Bacterial dysbiosis modifies various chemicals triggering host reactions that may affect several physiological functions such as immunity, neurobiology, metabolism, and intestinal absorption (66,68). Three main bacterial phyla are in the human gut: Firmicutes, Bacteroidetes, and Actinobacteria (66). Proteobacteria and Verrucomicrobia are also in the human gut microbiome but in lesser quantities (67,69). IBD is characterized by decreased diversity, reduced proportions of Firmicutes, and increased proportions of Proteobacteria and Actinobacteria (70). Pro-inflammatory bacterial species actions are enriched in IBD patients (Escherichia, Fusobacterium); oppositely, anti-inflammatory species (Faecalibacterium, Roseburia) are significantly reduced in IBD. Moreover, the literature has shown a lower abundance of Clostridium coccoides, Clostridium leptum, Faecalibacterium prausnitzii, and Bifidobacterium in IBD (64,71).

The Proteobacteria phylum increases in IBD patients, including Enterobacteriaceae and Gammaproteobacteria (71). Proteobacteria are anaerobic bacteria whose expansion is facultative, usually associated with dysbiosis (72). Lactobacillus, Bifidobacterium, and Faecalibacterium are gut microbiota species that may have a protective role in IBD (70).

Accordingly, there has been a surge of interest in microbiome-based drug development as a therapeutic for IBD. Yet there is still no consensus on whether dysbiosis is a cause or consequence in the context of IBD. That relationship and the therapeutic approach benefits of its treatment require further studies (34).

Diet can modulate microbiota

Depletion of commensal microbes and consequent dysbiosis can impair mucosal healing and enhanced recruitment of proinflammatory leukocytes to the lamina propria and induce chronic inflammation and colitis in genetically predisposed individuals (60). High-fat diet (HFD) modulates the gut microbiome negatively, which can impact the mucosal integrity and immune system, altering the humoral response, mediated by B lymphocytes and antibodies produced by them, and cellular response, mediated by T lymphocytes and cytokines (73). In this case, the passage of luminal materials may be related to excessive immune activation and the release of cytokines, such as IL-4, IL-6, IL-12, IL-13, TNF, IL-1B, IFN-γ, and inhibition of cytokines, such as IL-10, IL-17, and IL-22. As a result, increased tight junction permeability may lead to the additional passage of macromolecules from the intestinal lumen and increased immune activation, exacerbating the symptoms of IBD (73). Several studies of IBD-associated microbiome have proven that dietary components can alter the intestinal microbiota and may influence epigenetic changes. Thus, diet plays a crucial role in modulating the microbiome and epithelial barrier (65). Dietary fat has sparked the interest of researchers in gut barrier regulation in IBD, particularly in Western countries. Mediterranean, Indian, Japanese, and Southeast Asian diets, rich in unsaturated fatty acids and fiber, are associated with anti-inflammatory properties (74). In contrast, a Western-style diet, rich in saturated fatty acids and sugars and poor in fiber, is associated with adverse health impacts on intestinal microbiota and might also have a role in the pathogenesis of IBD (72,73,75). Numerous studies have shown that an HFD induces gut permeability alterations due to gut microbiota changes. The results of these studies reveal that HFD expands microbes involved in reducing barrier integrity, such as Oscillibacter spp. and Desulfovibrio spp. While reducing microbes that promote the intestinal barrier, such as Bifidobacterium spp., Lactobacillus spp., Clostridiales spp., Bacteriodetes spp., and Akkermansia muciniphila (76). The exact mechanisms these specific microbial species modulate intestinal permeability are still widely debated; some have been investigated and described in a recently published comprehensive review (72).

Western-style diets are also high in simple carbohydrates such as sugar. High intakes of fermentable carbohydrates (FODMAPs) such as sucrose, fructose, glucose, lactose, or polyols (mannitol, sorbitol, xylitol, and maltitol) have been shown to exceed the absorption capacity of the intestine, increasing intestinal dysbiosis and permeability (69). They may contribute to the onset or maintenance of IBD (69). Moreover, carbohydrate malabsorption, which occurs with ingesting FODMAPs mainly, results in bacterial overgrowth. Excessive carbohydrate fermentation by bacteria in the intestinal lumen produces methane gas or hydrogen, causes abdominal distension, and contributes to IBD pathogenesis (69). The low FODMAP diet was initially used for IBS patients by acting in the reduction of de symptoms (77). In this context, that diet has been tested in IBD patients to reduce abdominal pain, bloating, flatulence, and diarrhea in both CD and UC patients in remission (77).

The high exclusion of fibers for a prolonged time can lead to harmful changes in the intestinal microbiota (69). Recent randomized controlled trials have demonstrated reduced levels of Bifidobacterium due to a low FODMAP diet (78). However, it is necessary to evaluate each patient individually. For example, reduced and controlled consumption of foods with FODMAPs for a determined period has been encouraged for IBD patients with a phenotype similar to IBS, with pain and abdominal distension (77,78).

The low FODMAP dietary strategy must be well calculated since the probability of inadequate fiber intake is very high, besides the low intake of micronutrients and bioactive compounds. This scenario can lead to constipation, dysbiosis, and nutritional deficiency. Fermented fiber within the colon produces organic acids and gases, promotes bacterial diversity, preserves mucosal barriers, and prompts the production of a large amount of SCFA (acetate, propionate, and butyrate). Non-digestible carbohydrates derived from dietary fibers and endogenous products, such as mucin, are substrates for bacterial fermentation (77).

Although acetate production pathways are widely distributed among bacterial groups, the production of propionate, butyrate, and lactate appears more highly substrate-specific (61). IBD patients show a decrease in butyrate-producing bacterial species and reduced expression of butyrate transporters. SCFA positively modulates intestinal homeostasis and reduces inflammation, which is why low fiber intake is also associated with an increased incidence of IBD (69).

Other diet protocols, like a gluten-free diet, have seemed to be used by IBD patients to treat symptoms (78,79). However, changes in the intestinal microbiota caused by the lack of grain-based foods, such as lower concentrations of Bifidobacterium spp. and Lactobacillus spp., can lead to a reduction in SCFA production, whose role is essential for several functions in the body, such as participation in our metabolism, production of anti-inflammatory mediators, and intestinal health (79).

Another food component with an important impact on the microbiota is food additives. There is scientific evidence of the adverse effects of food additives in ultra-processed foods on the microbiota (65). For example, non-nutritive sweeteners (NNSs) like saccharin, aspartame, acesulfame-K, and sucralose have been shown to significantly impact bacterial growth both in vitro and in vivo. They may alter gut microbiota composition (80). Dietary emulsifiers alter human microbiota composition and ex vivo gene expression, enhancing intestinal inflammation (81). Thus, maltodextrins commonly used in producing candies, sports energy products, and soft drinks alter the intestinal microbiota and epithelial cells, reducing mucus production and exacerbating intestinal inflammation (82,83). Like NNSs, other additives typically used to prepare ultra-processed foods can alter the gut microbiota. Xenobiotics like an organochlorine pesticide, glyphosate, and perfluorooctanesulfonic acid can negatively modulate the composition and functions of the microbiome and epithelial barrier and may even influence epigenetic changes in the gut (84,85).

Other types of diet used by IBD patients (additionally information in Table 2) that seem to alter the microbiota include the lactose-free diet, SCD, Mediterranean diet, the IBD-AID, the gluten-free diet, as well as the consumption of prebiotic foods (such as fruits and vegetables) and probiotic foods (such as yogurt, pickles, fermented foods like bread, kombucha, kefir, and also in capsules with lyophilized bacteria). However, there is no clear recommendation for using a specific diet for all patients with IBD (52). Thus, more studies must evaluate how foods modulate the microbiota, leading to a favorable outcome or not for IBD patients. In this context, plus diet, some researchers presented other environmental factors that can contribute to IBD and microbiota modulation (Table 2).

Epigenome in IBDs

All these topics mentioned up to now are responsible for shaping the epigenome. Epigenetic programming begins at fertilization and continues throughout life (114). Food intake during pregnancy has been shown to affect epigenetic reprogramming steps during the early development of offspring, with effects lasting up to 2 generations (115). Indeed, as we have seen, research advances reinforce the idea that epimutations (disease-associated epigenetic changes) are induced by multiple environmental factors (116). Some factors relevant to IBD are smoking habits and diet, which play a vital role in the disease, both by direct action and for the modulation of the intestinal microbiome, and also have epigenetic activity (4).

In addition, there is evidence that various environmental factors contribute to age-acquired epigenetic changes (116). Studies of identical twins show that by age 65, almost 70% of the immune epigenome is environmental (117). Hence epigenetic factors could mediate gene-environment interactions involved in resistant output and disease susceptibility, which makes epigenetics a key mechanism in IBD pathogenesis and other chronic and immune-mediated diseases (115).

The epigenome can be considered stable because epigenetic marks are replicated during mitosis. However, random and environmental factors can cause dynamic changes to the epigenome over time (118). A study of epigenetics examines how environment and behavior influence gene activity, resulting in phenotypic differences (118). In 1942, Waddington introduced the epigenetic concept (119). Epigenetic mechanisms include DNA methylation, histone modification, ncRNAs, and nucleosome positioning (12). Among these mechanisms, ncRNAs are among the most extensively studied in IBD research (12). Natural epigenetic modifications play a vital role in organism function, but if they occur incorrectly, they can cause serious health consequences (116).

DNA modifications: DNA methylation and histone modifications

Epigenetic changes modify gene expression without affecting the DNA sequence (120). Chromatin, a complex of DNA and histone proteins, plays an epigenetic role in transcriptional regulation (121). Several protein complexes that can remodel the chromatin architecture are involved in regulating chromatin by modifying histones or DNA (121). Post-transcriptional modifications to histones allow heterochromatin to be tightly packed or more accessible (122). Nucleic acids form chromatin: genomic DNA, different RNA types, and histone proteins, such as H2A, H2B, H3, H4, and H1, besides other molecules (123).

DNA methylation is stably transferred through repetitive cell divisions, leading to the capacity to permanently transmit epigenetic information during an individual’s lifetime (121,124,125). It also involves adding a methyl group onto the cytosine’s 5’ position to form 5-methylcytosine, one of the most studied epigenetic mechanisms (125). This occurs at a CpG site, where a cytosine nucleotide precedes a guanine nucleotide and is catalyzed by DNA methyltransferases (126). The CpG island is defined as DNA regions that are ≥200 bp long and show a CG:GC ratio ≥0.6. DNA methylation typically prevents transcription factors from producing gene promoters, resulting in gene silencing (4,126). Interestingly, dietary substrates and nutrients drive DNA methylation by providing cofactors (4,126). Vitamins B12 and folate, for instance, act as cofactors, contributing to DNA methylation (37,114). Compared to healthy subjects, IBD patients acquire DNA methylation changes at the cell, tissue, and mostly immune level (37). Moreover, the profile differs between UC and CD patients (4).

In primary human epithelial cells obtained from mucosal biopsies of pediatric IBD patients, genome study analysis revealed differences in DNA methylation and transcriptional changes compared with control samples (126). Pediatric IBD epithelium showed significant overlap with those undergoing methylation changes during fetal intestine development, including key genes in intestinal epithelium related to immunity (114). Ventham et al. [2016] found 439 differentially methylated positions and five differentially methylated regions, mainly vacuole-membrane protein 1 (VMP1) (118). The major differentially methylated position was RPS6KA2, a ribosomal kinase in the serine/threonine kinase family that regulates cell growth and proliferation (118). In peripheral blood mononuclear cells, the promoter region of TRIM39-RPP2 was also significantly hypomethylated in colonic mucosa from pediatric UC patients (127). On the other hand, TRAF6 hypermethylation was observed. Methylation patterns observed in blood samples from the CD change the patterns during disease development/progression or in acute inflammation (128). In addition, the increased risk of colorectal cancer in IBD patients was associated with global hypermethylation, probably driven by inflammation (129).

The importance of correlating blood methylation findings with microbiome assessment results is worth mentioning due to the dysbiosis in patients with IBD. A large multi-omic study evaluated the microbiome of patients with CD and UC for one year and found several species of bacteria not yet cataloged, in addition to a reduction in enzymes, specific fatty acids, and some vitamins such as B5 and B3 (130). More studies like this are needed better understand the role of epigenome associated with the patient’s microbiome.

Proteins called histones are comparatively large and basic proteins that play an important role in the nucleosome of every cell (122,123). Nucleosomes constitute the functional and structural units of chromatin. Due to the nucleosome’s structural characteristics, histone proteins can undergo post-translational modifications at their N-terminal tails, such as acetylation, methylation, phosphorylation, ubiquitination, propionylation, butyrylation, crotonylation, and sumoylation, among others (123,126). Over 400 chromatin-modifying enzymes are regulated by the modifications. Post-translational modifications on histones or DNA are catalyzed by epigenetic “writers”, such as DNA and histone methyltransferases and histone acetyltransferases. In contrast, dynamic modifications are removed by “erasers”, such as demethylases, histone deacetylases (HDACs), and ten-eleven translocation (TET) proteins (121). Experimental colitis in mice with dextran sulfate sodium (DSS) that have HDAC 1 and 2 depletion specific in intestinal epithelial increases the severity of colitis (122). Butyrate can reduce gut inflammation by acting as an HDAC inhibitor and by suppressing nuclear factor kappa B (NF-kB) activation (122). Additionally, Lactobacillus and Bifidobacterium can also affect DNA methylation by regulating methyl-donor availability through their folate production (122). Patients with IBD have lower levels of the catalytic histone methyltransferase subunit of polycomb repressive complex 2 (PRC2) and the enhancer of zeste homolog 2 (EZH2) (122). However, after DSS treatments, mice intestines were protected from inflammation by overexpressing EZH2, indicating the significance of polycomb complexes in intestinal regeneration following epithelial damage (122).

IBD has numerous complex causes, including environmental triggers and genetic predisposition. DNA modifications mentioned above demonstrate the critical role of studying these alterations in IBD models (in vivo) and patient samples. Interactions between the microbiota and the host most likely cause IBD (123). It is essential to comprehend the extent to which these defective responses are supported by epigenetic pathways. In mice and children with newly-diagnosed IBD, changes in the histone H3K4me3 level in intestinal cells revealed an epigenetic profile of their disease (123). The presence of commensal gut bacteria could prop these changes (131). This study demonstrates how epigenetic analyses can complement other methods for identifying epithelial abnormalities, despite the small number of patient samples. It also sheds new light on pathways by which microbiota might be predisposed to intestinal inflammation (123,131).

ncRNAs and miRNAs

ncRNAs are RNAs that are not translated into proteins but are correlated with cellular processes such as translation, RNA splicing, and gene and chromosome structure modulation (12). These molecules include small interfering RNA (siRNA), microRNA (miRNA), long non-coding RNA (lncRNA), and others. The most studied class of small ncRNA is the miRNAs (132). MiRNAs are a class of regulatory RNAs that suppress gene expression. They are single-stranded, noncoding RNA molecules that range in size from 19 to 24 nucleotides and are evolutionarily conserved (133).

Over 60% of human protein-coding genes are regulated by miRNAs (134). MiRNAs and ncRNAs are assumed to play a significant role in regulating metabolic pathways that influence disease progression in IBD (133). This may be seen at both transcriptional and post-transcriptional levels. Fisher and Lin [2016] compiled extensive literature showing miRNAs dysregulated in peripheral blood and mucosal tissue of IBD patients with activity disease (133). MiRNAs are all involved with disease onset and progression, regulating, for example, the Th17 and IL23 pathways and autophagy (12).

McKenna et al. [2010] showed in an animal model study that intestinal miRNAs regulate gut homeostasis (135). Dicer, a miRNA-processing enzyme, plays a vital role in the differentiation and function of the intestinal epithelium. In addition, Dicer-deficient mice have disorganized intestinal epithelial crypts with rapid jejunal epithelial migration, increased goblet cells, accelerated apoptosis, increased inflammation, and reduced epithelial barrier function with neutrophil and lymphocyte migration (135).

Another miRNA directly enrolled in IBD is miR-21. Recent studies have frequently shown the presence of this upregulated miRNA in both UC and CD (133). In peripheral blood and mucosal tissue samples from CD patients, miR-21 was overexpressed (136). Another study showed that mice with a genetic deletion of miR-21 were resistant to DSS induced colitis (137). However, the mechanisms of action of this miRNA in the IBD are still unknown (137).

Fisher and Lin [2016] state that miR-21 has at least three distinct routes that might have harmful consequences in IBD (133): (I) miR-21 may enhance permeability in response to epithelial injury; (II) miR-21 may defend against free radical-induced apoptosis; and (III) miR-21 has been linked to irreversible fibrosis in IBD; specific disease models have indicated that fibrosis is dependent on elevated levels of TNF and subsequent elevation of this miRNA.

Another miRNA involved in essential changes in intestinal epithelial cells (IECs) is miR-200b. This miRNA was significantly decreased in inflamed mucosa of IBD when compared with their adjacent normal tissue, especially for UC (138). Chen et al. [2013] identified that the downregulation of miR-200b expression was correlated with upregulation genes that act on the process of epithelial-mesenchymal transition (EMT), promoting a loss of IECs (138). There is increasing evidence that one of the primary factors in the etiology of IBD is the loss of IECs. Inhibiting EMT and encouraging IEC proliferation, miR-200b is crucial for preserving intestinal epithelium’s integrity (138).

The immune system’s control is another instance of how miRNAs have an epigenetic effect. The interferon gamma locus must be epigenetically silenced for Th2 cells to differentiate (138). Additionally, Th1 and Th17 cell-mediated immune responses are regulated by clusters of up-regulating miRNAs by CD-associated variants of the NOD2 gene expressed by dendritic cells (115).

Another critical and complicating factor in the epigenetic regulation of miRNAs is their involvement in many physiological processes, such as differentiation, proliferation, apoptosis, and the development of other diseases. Some miRNAs and their regulation have been reported in other pathological disorders, including muscular dystrophy, diabetes, and various cancers (132). For example, miR-27a expression was increased in the peripheral blood of CD and UC (139) and breast cancer cell lines and colon cancer cells (139).

Del Follo-Martinez et al. [2013] evaluated the action of a combination of resveratrol and quercetin, derived from apples, grapes, and onions, on colon cancer cells (139). They observed a reduction in the miR-27a levels, which leads to ZBTB10 gene expression and apoptosis induction in HT-29 colon cancer cells. Certain natural compounds, such as phenolic and terpenoid compounds (e.g., curcumin, boswellic acid), can modulate inflammatory pathways by regulating miRNAs involved in processes such as proliferation, differentiation, cell death, angiogenesis, and metastasis formation (140). In this context, these compounds may also be beneficial for treating IBD (140).

On the other hand, the major obstacle in using miRNAs for diagnosis and the therapeutic target is their low specificity, considering that the same miRNA can be modulated in several diseases (132). Moreover, identifying the targets of these miRNAs will provide additional insight into the pathogenesis of IBD (133).

Increasing our understanding of interactions’ pathways among genetic, environmental, and microbial factors can answer why only some people with a specific genetic risk develop IBD (29).

Conclusions

This review focused on some essential aspects of IBD pathogenesis. While looking at this multifactorial disease in context, we noticed the role of “omics” changes in IBD. Genomics could not explain the illness by itself. This allowed the investigation of other pathways, such as the epigenome, microbiome, diet, and exposome, to achieve the best outcome for IBD patients. Different elements of the exposome, such as the maternal lifestyle, microbiota, diet, smoking, physical activity, infection, vitamin D, antibiotics, anti-inflammatory drugs, and different drugs, may induce epigenetic changes related to IBD. Psychological stress/anxiety/depression, oral contraception, geographical location, and other factors potentially predicted the disease. The environmental factors, such as the exposome, still need to be clarified as to how their duration, timing, and frequency may be able to modulate IBD outcomes (13,18,141). Finally, the exposome may become a tool to predict flares and contribute to developing electronic technologies based on artificial intelligence, algorithms, and machine learning. These mathematical tools will make possible to record patients’ exposure to environmental factors continuously and to better understand these complex immune-mediated diseases. In conclusion, the hypothesis of an exposome-diet-epigenome axis (Figure 1) combines the main findings described so far that can influence and lead to IBD outcomes, from diagnosis to degree of severity.

Figure 1 The hypothesis of an exposome-epigenome axis in IBD. Environmental “exposome” factors influencing the occurrence of intestinal inflammation and outcomes in IBD. The blue area shows the factors that may predispose to a better disease outcome, and the red area illustrates the elements of a prone state to IBD that may contribute to the severity of the disease and its complications. Smoking and appendicectomy are considered a risk factor for Crohn’s disease, not for ulcerative colitis. IBD, inflammatory bowel disease.

Acknowledgments

We thank Dr. Tristan Torriani [Assistant Professor of School of Applied Sciences from the University of Campinas (Unicamp), Limeira, São Paulo, Brazil] for revising the English version of our manuscript.

Funding: This work was supported by the National Council for Scientific and Technological Development (CNPq) (grant number #302557/2021-0 for R.F.L., grant number #140520/2019-8 for K.M.S.), the São Paulo Research Foundation (FAPESP) (grant number #2018/17832-2 for P.L.R.M.), and the Unicamp Development Foundation (Grant number #519.292 for B.A.G.R.).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Digestive Medicine Research for the series “Evidence of Epigenetics in Inflammatory Bowel Diseases”. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://dmr.amegroups.com/article/view/10.21037/dmr-22-85/rc

Peer Review File: Available at https://dmr.amegroups.com/article/view/10.21037/dmr-22-85/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dmr.amegroups.com/article/view/10.21037/dmr-22-85/coif). The series “Evidence of Epigenetics in Inflammatory Bowel Diseases” was commissioned by the editorial office without any funding or sponsorship. R.F.L. serves as an unpaid editorial board member of Digestive Medicine Research from October 2021 to September 2023. R.F.L. served as the unpaid Guest Editor of the series. B.A.G.R. receives a postdoctoral scholarship from the Unicamp Development Foundation (grant number #519.292). K.M.S. receives a doctoral scholarship from the National Council for Scientific and Technological Development (CNPq) (grant number #140520/2019-8). P.L.R.M. receives a postdoctoral scholarship from the São Paulo Research Foundation (FAPESP) (grant number #2018/17832-2). R.F.L. receives support from the National Council for Scientific and Technological Development (CNPq) (grant number #302557/2021-0). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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