Inflammatory Biomarkers in Paediatric Inflammatory Bowel Diseases: History
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Naser A. Alsharairi

Inflammatory bowel disease (IBD) is a distinct chronic, idiopathic, and relapsing disorder classified into two major conditions, including Crohn’s disease (CD) and ulcerative colitis (UC), which cause inflammation in the gastrointestinal tract (GIT). Short-chain fatty acids (SCFAs) produced by anaerobic bacterial fermentation of indigestible dietary fibre in the gut have potential value for their underlying epigenetic role in the treatment of obesity and asthma-related inflammation through mediating the relationships between VLCKD and the infant gut microbiota. 

  • children
  • gut microbiota
  • inflammatory bowel disease

1. Introduction

IBD is a distinct chronic, idiopathic, and relapsing disorder classified into two major conditions, including Crohn’s disease (CD) and ulcerative colitis (UC), which cause inflammation in the gastrointestinal tract (GIT). CD affects all parts of the GIT, but is localised most often to the colon and distal ileum, whereas UC affects the colon only [1]. IBD affects not only adults, but also children of all age groups, with higher rates of CD than UC and/or IBD-unclassified (IBDU) reported in most Western countries. In contrast, data from developing countries suggests higher rates of UC than CD [2]. When IBD is detected in children, overlapping histological, radiologic, and clinical features may pose a challenge differentiating between CD and UC [3]. A diagnosis of IBDU occurs when children have features on histological and clinical evaluations that are inconsistent with either CD or UC children [4]. However, it has been shown that IBDU children share similarities of molecular analysis of gene expression and serological features only with UC children two years after the diagnosis of IBDU [5]. Globally, the incidence of IBD in children under 19 years of age at diagnosis increased between 1985 and 2018 as follows: 0.1 to 13.9/100,000 for CD; 0.1 to 10.6/100,000 for UC; and 0.1 to 3.6/100,000 for IBDU [6]. Due to this increase, researchers have been exploring treatment options to manage paediatric IBD. The currently preferred treatments are largely focused on a group of biological agents that have been approved for use in the treatment of CD and UC/IBDU. The anti-tumour necrosis factor (TNF) agents, adalimumab (commercialised as Humira®) and infliximab (commercialised as Remicade®), have been shown to be effective in reducing moderate-to-severe complications of CD in children, and might be clinically beneficial against UC in children [7]. Vedolizumab (commercialized as Entyvio®), a humanised α4β7-integrin antagonist, was also demonstrated by a few retrospective studies to be effective in maintaining remission in children with CD and UC/IBD-U [8]. Recently, etrolizumab, a humanised anti-β7 antibody, has been demonstrated to have treatment efficacy in children diagnosed with moderate-to-severe CD and UC [9].
Although the aetiology of paediatric IBD is not well known, it is thought that key contributing factors, including genetics (e.g., loss of function variants in specific genes) [10] and the environment (e.g., dietary patterns, exposure to antibiotics, air pollution, appendectomy, enteric infections) [11], may lead to the development of disease, which exacerbates inflammatory immune responses. There is also growing interest in gut microbiota as another potential factor contributing to IBD pathogenesis. The colonization of the gut with diverse microbes is thought to occur during delivery and immediately after birth, and is influenced by multiple factors, including maternal gut microbiota, nutrition, antibiotic exposure, mode of feeding/delivery, and body mass index (BMI) [12]. Immune system development in early life may interact with gut microbiota composition, and the depletion of beneficial microbes may increase the risk of inflammatory diseases [12]. The gut microbiota has maintained a symbiotic relationship with its host through a range of functions, such as facilitating immune system development, protection from pathogenic bacteria, strengthening the integrity of the digestive tract, and production of beneficial metabolites such as SCFAs [13]. Butyrate, propionate, and acetate are the main fermentation-derived SCFA metabolites from indigestible complex carbohydrate (CHO) produced by gut microbes belonging to the phylum, Firmicutes, through a range of cross-feeding mechanisms/microbial metabolic pathways [14]. The metabolic cross-feeding of lactate, an intermediary metabolite formed by Bifidobacterium and lactic acid bacteria (LAB), can enhance the production of butyrate [15]. Although the gut microbiota composition of children with IBD differed from that of healthy children in several studies, it is consistently characterised by reduced abundances of SCFA-producing bacteria considered as ‘healthy microbiota’. The gut microbiota of children with CD and/or UC showed decreased genera belonging to the phyla, Actinobacteria (Bifidobacterium), Firmicutes (Lactobacillus, Blautia, Ruminococcus, Faecalibacterium prausnitzii, Roseburia), and Bacteroidetes (Bacteroides). However, the genera, Escherichia, Actinobacillus, Granulicatella, Enterococcus, and Streptococcus, were observed to have increased [16][17].

2. Epigenetics of Paediatric IBD

Epigenetics has revealed a potential mechanism that may explain how environmental triggers and genetic susceptibility interact in IBD [18]. Evidence from many studies suggests that epigenetic modification, in particular DNA methylation, which exists at cytosines in the cytosine–guanine (CpG) dinucleotide context, plays a key role in paediatric IBD phenotypes, as it is considered a key regulatory mechanism of gene expression in response to environmental cues, without modifying the primary nucleotide sequence [19][20]. However, the little evidence that exists examining histone methylation suggests that this modification takes place in the intestine of paediatric IBD. In CD children, genes exhibiting decreased histone H3-lysine 4 trimethylation (H3K4me3) signatures are found to be associated with the severity of inflammation in IECs [21]. Ileal IECs play a significant role in integrating commensal microbiota-derived cues to regulate immune homeostasis and gene expression. Genes characterized by increased H3K4me3 levels (e.g., DUOX2, NOS2) in IECs from CD children in response to commensal microbiota are enriched in several pathways, including the regulation of reactive oxygen species (ROS), G alpha signalling, digestive system development, and nitric oxide (NO) biosynthesis, suggesting that commensal microbiota may modify histone alterations that reflect intestinal inflammation in CD [21]. Large-scale, genome-wide studies have revealed significant mucosal DNA methylation changes in IBD-associated genes in children. For example, a systematic meta-analysis of 84 genetic studies identified specific genetic variants (rs11209026, rs7517847, rs12521868, rs26313667, rs1800629, rs2241880, rs2066847, rs2066844, and rs2066844) in differential DNA methylated genes (NOD2, IL23R, ATG16L1, IBD5, and TNF-α) known to cause CD and UC [19]. A study that assessed DNA methylation profiles of the colonic mucosa found that 182 CD and 3365 UC susceptible genes (including STAT3, SLPI, ITGB2, SAA1, IFITM1, and S100A9) were associated with differentially methylated regions (DMRs) [22]. Another study detected a number of UC-associated changes in DNA methylation at nine CpG sites located in the TRIM39-RPP21 gene [23]. In respect to the correlation between the colonic mucosal DNA methylation of paediatric IBD and microbiome changes, a study showed that SLC9A3, a gene with decreasing methylation UC-specific DMR, was associated with a reduced abundance of Bacteroides [24].

3. Role of Inflammatory Biomarkers in Paediatric IBD

Loss-of-function mutations in G-protein coupled receptors (GPCRs) may result in reduced ligand-binding affinity to many chemokines/cytokines, local mediators, and neurotransmitters during childhood development [25], which may lead to an increased risk of IBD. Naïve CD4+ T cells differ according to cytokine-producing T-helper (Th) subsets, including Th1 (interferon-gamma, IFN-γ, TNF-α), Th2 (IL-4, IL-5, IL-6, IL-13), and Th17 (IL-17) cells, which are implicated in the dysregulation of colonic mucosa in IBD patients [26][27]. Paediatric CD patients were shown to have a mixed Th1/Th2/Th17 cytokine profile, with increased serum levels of IL-1β, IFN-γ, IL-6, TNF-α, C-X-C motif chemokine ligand 10 (CXCL10), and IL-17A observed in both the ileum and colon [28][29]. Increased serum IL-4 and IL-6 levels were detected in the intestinal mucosa of paediatric UC patients, in which the GATA binding protein 3 (GATA3) and signal transducer and activator of transcription-4 (STAT4) signalling molecules were involved [30]. Compared with paediatric CD patients, significantly more mRNAs related to IL5, IL-13, IL-23, and IL17A cytokines were observed in the rectal mucosa of UC patients [31]. Serum levels of IL-6 were found to be higher in the ileum of paediatric CD patients than those of healthy children, whereas the serum levels of IL-22 and IL-17A were higher in UC patients than in CD patients [32]. Although Foxp3+Treg cells are found in higher density in the inflamed mucosa of paediatric IBD patients, they maintain immune homeostasis [32][33]. A higher density of Foxp3+ cells in the ileum of untreated paediatric CD patients compared with adult patients may be attributed to the disparate pattern of CD phenotypic expression [34]. In a previous in vitro experiment, serum levels of IL-17 and TNF-α were increased in the peripheral blood of paediatric patients with CD and UC. Patients displayed a decreased expression of Foxp3+, CD4+, and CD25+, and an increased percentage of Th17 cells. Myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCS) expressing CD200, a type I transmembrane glycoprotein, were found to be elevated, and significantly associated with Th17, but negatively associated with regulatory T cells (Tregs). On the contrary, the expression of the CD200 receptor, CD200R1, on mDCs was found to be reduced and negatively associated with Th17 [35]. The mRNA expression of pro-inflammatory cytokines IL-6 and IL-23 expressed at high levels in the colonic mucosa of paediatric patients with CD and UC is found to be associated with a higher frequency of CD4+ IL-17a+ and a lower frequency of CD4+Foxp3+Tregs [36]. An experimental study demonstrated that treatment with infliximab, a chimeric monoclonal antibody, does not inhibit the production of TNF-α, but also hampers expansion of FOXP3+ Tregs in the colonic mucosa of paediatric CD patients [37]. Another recent experimental study reported that paediatric patients with active CD and UC, though having a high expression of CTLA-4 in FOXP3+ Tregs in peripheral blood during pharmacological (aminosalicylates or azathioprine) therapy, showed a significant decrease of CD4+Foxp3+Tregs levels after therapy compared to the same patients and healthy children at disease onset [38].
In a human IBD model, which is characterised by increased histone deacetylases (HDACs), nuclear factor-κB (NF-κB), nuclear factor kappa-B kinase β (IKKβ), TNF-α, NOD2, and toll-like receptor (TLR) upregulation have been reported to occur in the inflamed IECs, resulting in high pro-inflammatory cytokine expression levels [39]. HDAC1 has been shown to be implicated in several diseases, in which it takes off the acetyl group from lysine residues of histone/non-histone proteins via acetyltransferases (HATs), which results in DNA inaccessibility, gene transcription repression, and chromatin compression [40]. The acetylation of histone H3 lysine 27, which is identified in regions with several risk loci for IBD [41], has been found to be downregulated in the inflamed mucosa of UC patients, resulting in high IL-6 mRNA levels [42]. HDAC1 induces an inflammatory response in the colon epithelium of UC patients by activating NF-κB, and reducing histone H3 acetylation and tight-junction protein, zonula occludens 1 (ZO-1), expression [43]. Loss-of-function NOD2 gene mutations enhance NF-κB activation, which, in turn, bind to the promoters of pro-inflammatory cytokines in paediatric CD patients [44]. This suggests that cytokines with pro-inflammatory effects could play a key role in the pathogenesis of paediatric IBD.

This entry is adapted from the peer-reviewed paper 10.3390/nu14194113

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