World IBD Day: An Insight Into Crohn's Disease

Today is World IBD (Inflammatory Bowel Disease) Day – a day to raise awareness about the disease, to urge professionals to take action and to show support to the millions of people around the globe that live with IBD [1]. IBD is an umbrella term to describe conditions that promote chronic inflammation in the gut and is mainly used to describe two conditions: ulcerative colitis and Crohn's disease [2]. It is not clear as to what causes IBD, and a combination of genetic and immunological defects seem to play a role in the development of the disease. However, in recent times we have gained a better understanding of what those defects are, with innovative research allowing more successful therapeutics to be made. Albeit both IBD conditions share similar symptoms, such as abdominal pain and diarrhoea, they differ in their pathogenesis. Ulcerative colitis only affects the colon whilst Crohn's disease can affect any part of the alimentary canal [2].

Crohn's disease is a Type IV autoimmune disorder resulting from failures in the innate and adaptive immune system. Crohn's disease is estimated to affect about one in every 650 people in the United Kingdom and can affect anyone at any age [3]. It had been thought that Crohn's disease typically affects those in urban areas in developed countries, but data has suggested that in fact the prevalence is increasing in developing nations too [3]. It is therefore a disease that has global significance and is clearly impacting the lives of many. There are currently no treatments that are available for Crohn's disease, however biologics have gained recent interest in correcting immunological defects in Crohn's disease patients.

Pathology of Crohn’s Disease

In a healthy gut we have commensal microorganisms which aid in our daily functionality – from digestion to maintaining a healthy gut environment, which constitutes our microbiota. There are regulatory actions (e.g. Treg cells, antimicrobial peptides from Paneth cells and physiological adaptations) that prevent an immune response from being generated towards these commensal microorganisms. Therefore, in the gut there is an active down regulation of an immune response.  This is important for many reasons, but most evidently because a response against food we eat is not wanted! However, when foriegn substances (i.e. pathogenic bacteria) invade the gut there are specific mechanisms which aid in mounting an appropriate immune response. NOD1 and 2 (Nucleotide-binding oligomerization domain-containing proteins) are examples of pattern recognition receptors on the epithelial cells of the gut. These proteins recognise foreign peptidoglycans, polymers which are secreted by microbial organisms. Genetic studies in Crohn’s patients have suggested that loss of function mutations in NOD2 results in decreased expression of the NFkB pathway (Fig. 1).

Figure 1 – Activation of NFkB pathway. Bacteria or peptidoglycans entering the cytosol are activated by NOD1 and NOD2. This activates the NFkB pathway causing the transcription and translation of proinflammatory molecules. Diagram constructed by author, using Biorender, adapted from [4, 5]

The NFkB pathway is important as it plays a role in regulation of inflammation in the gut. NOD2 has been shown to regulate the expression of antimicrobial peptides and maintain the barrier integrity of the epithelial cells [4]. In Crohn’s Disease patients the impairment of NOD2 results in reduced expression of the NFkB pathway and less pro-inflammatory molecules being translated. This breaks down the integrity of the epithelial barriers; resulting in commensal microorganisms being taken up by professional antigen presenting cells (APCs, i.e. dendritic cells), activating naïve T and B cells thereby mounting an inappropriate immune response. To respond to the bombardment of commensal microorganisms crossing the epithelia, an inflated inflammatory response is generated in which a specific subclass of T cells, the T helper 17 cell (Th17), are thought to be important. Th17s have an antagonistic relationship with Treg cells by producing proinflammatory cytokines (i.e. IL-17) which induces the epithelia to attract neutrophils, which aid in mediating inflammation. In the absence of equilibrium, excessive IL-17 secretion can result in excessive inflammation in the gut which causes granulomatous lesions in the gastrointestinal tract (Fig. 2). Therefore, the immunological deficits result in an inflamed GIT with narrowing and abnormal connections of the bowel-fistula, giving rise to the varying digestive related symptoms.

Figure 2 – Histological Photographs of Mucosal Surfaces in Chron’s Disease Patients. (A) Fissuring of the colon in Crohn's disease. (B) Inflammation of the colon, resulting in a granuloma, in Crohn’s disease. Diagram adapted from Ref [6].

Treatments

 To date, there are no specific treatments for Crohn's disease, so treatment courses often involve using medications (such as steroids and immunosuppressants) to alleviate symptoms by reducing inflammation [7]. In addition, dietary control and surgery can be used as alternative means or in conjecture with medication. Biologics have recently become popular as a way to reduce inflammation in the long-term (Table 1). They work by targeting specific proteins (i.e. cytokines) that are implicated in inflammation. Whilst Biologics are an emerging field of therapeutics, long-term studies are needed to establish their efficacy.

Table 1 - Examples of Current Biologics used in the treatment of Crohn's Disease. Biologics target specific cytokines produced in the body. Information compiled from Ref [7].

What can we do?

1. Talk about it and raise awareness

A diagnosis of Crohn’s Disease can be life-changing, with up to 80% of patients with Crohn’s Disease eventually needing surgery in their lives [1]. However, with good healthcare, the condition can be managed. Because of this, IBDs can be considered as ‘invisible disabilities’, and it can be difficult for a healthy individual to understand what those with the condition are going through. Therefore, it is incredibly important that as a community we start to change attitudes towards IBDs and support those with the condition. Whether that is by doing some reading into IBDs or perhaps talking to someone who has Crohn’s disease - it can help start to break the stigma associated with IBDs. By increasing awareness of IBDs to decision-makers, vital research can be conducted and creates hope that one day there might be a cure developed!

2. Make your STEM (and other!) events, fieldwork and workplace inclusive of people with IBDs

Some simple steps can help make your event, fieldwork trip or workplace inclusive of people with IBDs:

• Build plenty of breaks into the schedule

• Ensure that you can cater to diverse dietary needs

• Choose a venue that has accessible toilets, including with a shelf fitted

• Make sure all the toilets are well signposted 

• Add ‘Grace’s Sign’ to the accessible toilet door to remind everyone that not all disabilities are visible!

3. Use your STEM skills to make a difference!

One young person, Grace Warnock from Scotland, used inclusive design to tackle the issue of stigma and people’s lack of awareness around invisible disabilities.  At the age of 10, Grace created ‘Grace’s Sign’ - a sign for accessible toilets, to remind people that not every disability is visible [8]. Having been diagnosed with Crohn’s Disease, Grace experienced first hand that people were sometimes judgemental when she needed to use an accessible toilet. By using her design skills, and creating a campaign, Grace has raised awareness and inspired others to take action, with ‘Grace’s Sign’ now in buildings across the UK, including airports, football stadiums and the Scottish Parliament! Grace has shown how one young person can make a real difference!

Albeit, there are no current treatments that can cure IBDs, our understanding of the pathogenesis of IBDs is getting better as more research has been conducted. It is crucial that we all try to raise awareness about it in hope that one day, not only the stigma around it will be reduced, but also that we could spur in action a chain of events that may result in more funding into, and more research into the treatments for IBDs. Like Grace, each and every one of us can make a huge difference - we only need to take that step!

Definitions

Biologics - Medicines, used to treat long-term medical conditions, that are made from proteins and other substances produced by the human body.

Commensal Microorganisms - Microbial agents that normally do no harm and may, in fact, be beneficial to the host. 

Cytokine - Small proteins that are important in cellular signalling. 

Inflammation - A complex biological response of body tissues to harmful stimuli. 

Naïve B cell - B cell that has not been exposed to an antigen.

Naïve T cell - T cell that remains uncommitted to their helper fate until they are exposed to the relevant cytokine signal. 

Type IV autoimmune disorder -  T-cell-mediated response to endogenous antigens.

References

[1] European Federation of Crohn's & Ulcerative Colitis Associations, 2020. [Online]. Available: https://worldibdday.org. 

[2] NHS, “Inflammatory bowel disease,” 15 April 2020. [Online]. Available: https://www.nhs.uk/conditions/inflammatory-bowel-disease/. [Accessed 9 May 2020].

[3] Crohn's and Colitis UK, “Crohn’s Disease,” October 2016. [Online]. Available: https://www.crohnsandcolitis.org.uk/about-crohns-and-colitis/publications/crohns-disease. [Accessed 9 May 2020].

[4] D. J. Philpott, M. T. Sorbara, S. J. Robertson, K. Croitoru and S. E. Girardin, “NOD proteins: regulators of inflammation in health and disease,” Nature Reviews Immunology, vol. 14, p. 9–23, 2014.

[5] C. A. Janeway, P. Travers, M. Walport and M. J. Shlomchik, Immunobiology, New York: Garland Science, 2001.

[6] B. S. Morson, “Histopathology of Crohn's disease.,” Proceedings of the Royal Society of Medicine, vol. 61, no. 1, p. 79–81. , 1968.

[7] J. D. Betteridge, “Crohn's Disease: Current and Future Biologic Therapies,” The Journal of Lancaster General Hospital , vol. 12, no. 3, 2017.

[8] Points of Light UK, “Grace’s Sign,” May 2018. [Online]. Available: https://www.pointsoflight.gov.uk/graces-sign/. [Accessed 16 May 2020].