Factors Affecting Disease Activity in Children and Adults with Inflammatory Bowel Disease: An Exploration of Pro-Inflammatory and Anti-Inflammatory Elements

For children and adults with inflammatory bowel disease (IBD), the overarching aim of clinical management is the induction and maintenance of remission, with mucosal healing as a key target outcome [1,2,3]. While each individual with IBD experiences a unique disease path, the illness burden may be driven by disease phenotype, complications, surgery, degree of inflammation, and psychosocial impact [4]. The most frequently used measure of IBD status is that of disease activity, indicating the degree of inflammation and symptom burden experienced by individuals. There are many ways to measure disease activity, such as clinical indices, serum and stool markers, and endoscopic assessment [4]. There are also many factors that can affect disease activity; these may include the anti-inflammatory components of conventional treatments, dietary regimens, complementary/alternative medicines, and pro-inflammatory elements such as psychosocial manifestations and environmental factors. There are, therefore, substantial options for research studies that investigate single interventions or outcomes, as well as multivariate components within the topic of IBD. The aim of this Special Issue was to gather evidence on wide-ranging factors that influence disease activity among children and adults with IBD.

Cytokines and other inflammatory mediators play key roles in the pathogenesis of IBD [5]. Following secretion by activated dendritic cells and macrophages, the role of cytokines is to regulate the inflammatory response, with pro-inflammatory or immune-modulatory consequences [5,6]. The focus on cytokines has increased since the advent of new treatments for IBD that modify the immune system by inhibiting the activity of specific cytokines [7]. Interleukin (IL)-33 is a cytokine from the IL-1 group that initiates an inflammatory response to infectious or immunological challenges [8] with signalling via the ST2 receptor [6]. The role of the IL-33/ST2 axis has been studied in a number of immune-mediated conditions. In the setting of IBD, it has been shown to be both protective and pathogenic [6]. Different levels of expression are noted for those with Crohn’s disease (CD) or ulcerative colitis (UC) compared to healthy controls [9]. As research into the IL-33/ST2 axis evolves rapidly, it is important to update and summarise findings to enable clinicians and researchers to obtain a broad overview of the latest findings. In this Special Issue, Giordano et al. [10] provided a comprehensive update on the multi-faceted role of the IL-33/ST2 pathway in IBD, and gave their perspective of the future directions for research in this field. The summary highlights that expression of this cytokine in response to tissue injury may compromise the gut epithelial barrier integrity and permeability.

The role IL-33 plays in the inflammatory process differs between those with CD and UC. In particular, this review highlights that there is an intricate interplay between this cytokine and other factors that drive intestinal fibrosis in those with CD [6]. The association between IL-33 and colorectal cancer is also discussed, although findings have shown it both to promote and inhibit tumour growth. Giordano et al. [10] suggest further work is focused on the role of micro ribonucleic acids (miRNAs) in IL-33 modulation, and the interaction between miRNAs and the gut microbiota.

Cytokines and chemokines are produced and released by innate immune cells (IIC) in response to infection and inflammation, with IIC including various circulating and tissue cell types, in addition to tissue-resident mast cells and macrophages [11]. The innate immune system is a rapid and essential defence mechanism to respond to and eliminate pathogenic organisms, and comprises IIC, receptors to detect structural motifs of microorganisms, and anatomical barriers such as the mucous layer and intestinal epithelium [12]. Dysregulation of the innate immune system is noted in individuals with IBD, with persistent immune activation leading to prolonged inflammation [12,13]. Biomarkers may be tested to indicate an acute phase reaction, including serum white cells, C-reactive protein, erythrocyte sedimentation rate, amyloid A protein, and procalcitonin [14]. Tobi et al. [15], in this Special Issue, suggest the use of new innate immune system biomarkers: the FERAD ratio (derived from serum ferritin/faecal p87), and the more commonly available absolute neutrophil/lymphocyte ratio (NLR). In this study, the FERAD ratio as shown not to differ between study participants with CD or UC, but was substantially lower in those with IBD than in healthy controls. The colonic regional expression of p87 differed according to the location where biopsies were taken from. Participants with CD had higher levels in the cecum than the rectum, and levels of p87 immunohistochemistry in the transverse colon were lower in those with UC compared to CD. Tobi et al. [15] propose that, with further work, these biomarkers may be ideal to guide treatment and facilitate early detection of colitis-associated colorectal cancers.

In recent years, studies have shown that adipose tissue, while classically involved in energy storage and homeostasis, also has additional regulatory functions, and plays a critical role in inflammatory processes [16,17]. Adipose-derived mediators include members of the aforementioned IL-1 group of cytokines. Adipokines are also produced predominantly by adipocytes: these include leptin, adiponectin, resistin, and visfatin [16]. A previous systematic review looking at the association between adipokines and IBD reported inconclusive findings in regard to levels among people with IBD compared to healthy controls, but did note some association between adipokines and disease severity [17]. In another work, adipokine levels did not differ between people with IBD and healthy controls, and were not associated with disease activity indices [18]. With data linking adipokines and IBD pathogenesis being inconclusive, experimental animal studies have allowed for more in-depth investigation into this topic. Garella et al. [19] report, in this Special Issue, the results of an electrophysiological evaluation of the role of adipokines in causing functional gastrointestinal alterations in murine tissue. It was shown that resistin did not appreciably modify the smooth muscle cell (SMC) excitability, but did increase SMC capacitance, which is consistent with pro-relaxing effects. The research presented by Garella et al. [19] adds to the evidence base that there are various proteins/receptors that respond to resistin, and that may be targeted with pharmacological treatments.

Looking more directly at patients with IBD for those with CD, UC, and IBD-unclassified, the symptom burden can be substantial, with individuals experiencing up to 16 different symptoms per week [20]. One of the most burdensome symptoms is lack of energy or fatigue [20]. Among children and adults with IBD, fatigue has been associated with reduced health-related quality of life during periods of active disease, as well as during remission [21,22]. Furthermore, fatigue adversely impacts on work productivity, physical activity, and leads to high healthcare utilisation [23]. Mediating factors associated with worse fatigue among adults with IBD include pain interference, disease activity, sleep disturbance, anxiety and depression, with physical activity and satisfaction within social roles having an inverse relationship [24]. Among children with IBD, mediating factors are active disease, anxiety and depression, and disturbed family relationships, with fatigue shown to reduce physical activity [25]. With studies having isolated the main causes of fatigue, it leads the way to developing interventions that may improve this debilitating symptom.

In this Special Issue, Martinato et al. [26] carried out a systematic review to identify studies that reported on such interventions, specifically those that can be implemented by nursing personnel. The authors found few studies that satisfied their inclusion criteria, but the two that were included in their synthesis were psychology based and focused on Solution-Focused-Therapy (SFT), and Problem-Solving-Therapy (PST). While both nurse-implemented interventions led to decreased fatigue among those randomised to the intervention, other outcomes were not significantly associated, such as quality of life and anxiety and depression. Martinato et al. [26] discuss other interventions that have been developed, and their efficacy as described in other reviews, but highlight that there are very few interventions designed to be specifically nurse-led. Their findings indicate that further work is warranted to develop programmes that target fatigue among this population that can be implemented by nursing staff.

The epidemiology of IBD is a complex and changing picture, with increasing rates among adults in newly-industrialised countries [27,28], stabilising rates for adults in industrialised counties [27,28], and increasing rates among children around the world [29,30]. Rates of IBD have previously been reported as being higher in Western European countries than Eastern European countries [31]; however, following plateauing rates in the Western countries and rising incidence in Eastern countries this disparity is levelling out [32,33]. In addition, a North/South gradient has been reported in large-scale studies [34,35,36], with possible associations with vitamin D levels leading to lower rates in those living closer to the equator. Migration has been explored as a factor for explaining epidemiological variation [37], as well as environmental components such as diet, the intestinal microbiome, and ultra-processed foods [38,39]. The differences in epidemiology of IBD between regions should be a research priority. In this Special Issue, Bhayani et al. [40] explore causative factors for the rising incidence of IBD, CD, and UC in the Asian subcontinent as compared to Western countries, focusing on age of onset, sex, genetics, the microbiome, and the hygiene hypothesis. Differences in age of onset and sex disparities are highlighted, with similarities in findings of microbiome studies, and challenges in defining causative factors relating to genetics and the hygiene hypothesis. While the review reports no North/South gradient evident in the Asian subcontinent, this is not the case in East Asia [41]. This emphasises the importance of studies such as the review by Bhayani et al. [40] that has focused on a specific region and explored how the IBD epidemiology differs from other regions within Asia as well as Western countries and global patterns.

This collection of articles has provided a multi-faceted overview of some current work focusing on the complexities of IBD at both the cellular level, as well as looking at outcomes directly affecting people with IBD and regional populations. The ongoing programme of work into the inflammatory process, both at the level of the innate and adaptive immune systems, should assist in identifying further targets for new treatments [5,42]. This process should herald the dawn of a new era towards personalised medicine [12]. Developing the potential of new biomarkers that may identify those with IBD at greater risk of colorectal cancer is vital for people with IBD as they have a twofold risk compared to healthy controls, and it is the cause of up to 15% of all deaths in patients with IBD [43]. The development of interventions that can be implemented by healthcare professionals to address symptoms with high frequency and distress, such as fatigue, should be prioritised. While there remains no cure for IBD, ensuring that outcomes such as work productivity, school attendance, and health related quality of life are optimised is important for adults and children alike, and may reduce overall health system costs [23]. With the ever-evolving nature of IBD around the world there is ongoing value in epidemiological studies that explore why populations are similar or differ, leading to new foci on causative factors. The role of research in the field of IBD is instrumental in moving treatment options forward, improving patient outcomes, and looking at the impact of this condition on a global scale.