Roundtable Review

Do Your Guts Hate You?
Posted 10 June '14

Inflammatory Bowel Disease (IBD) covers a group of disorders characterised by inflammation of the gastrointestinal tract, in particular the small and large intestines.  The two most common forms of IBD are ulcerative colitis and Crohn’s disease. In the UK, over 250 000 people live with a form of IBD and approximately 10 000 new cases are diagnosed each year [1].

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Radiology picture of a patient with Crohn’s disease. Source: Radiology picture of the day. Credit: Dr Marina-Portia Anthony. Available under Creative Commons license Attribution-NonCommercial 2.5 Generic.

Ulcerative colitis usually affects the top layer of cells in the large intestine and is characterised by sores and ulcers on the surface of the lining, which can bleed and secrete pus. These sores can weaken the wall of the intestine, leading to the development of a hole and consequently leakage of digestive products into the abdominal cavity and bloodstream, resulting in infection.

Crohn’s disease can affect the entire wall of the intestine and disease areas are found throughout the gastrointestinal tract; the majority of inflammatory patches, however, are found in the ileum. This inflammation can cause swelling and the formation of scar tissue, which thickens the wall of the intestine and may lead to a stricture or narrowing of the tract. Deep ulcers can also form tunnels known as fistulas, and often require surgery. [2]

The cause of IBD is unknown but is characterised by an abnormal immune system.  The role of the immune system is to protect the body from infection caused by harmful pathogens, returning to a state of homeostasis post-infection [3].  Unfortunately in IBD, it doesn’t ‘shut off’ and starts to overreact to normal gut bacteria, ultimately resulting in the inflammation which is characteristic of IBD [4].

In both ulcerative colitis and Crohn’s disease, patients may experience periods of disease activity and remission. The symptoms of IBD are often exacerbated when an individual is under stress or when they eat certain foods, but the disease flare is unique for each individual and can happen spontaneously.

Links between IBD activity and the interleukin-23 (IL-23) pathways have recently been identified. These pathways promote upregulation of various proteins, some of which stimulate cells of the immune system called CD4+ T cells to differentiate into specialised immune cells, which help in fighting infection. These specialised cells are called Th17 cells.  These cells then produce a proinflammatory signal called an IL-17 cytokine, which helps to enhance the inflammatory response [3].

A genome-wide association study published in Nature in 2009 [5] identified five new regions on chromosomes associated with early-onset IBD susceptibility– 16p11 near the IL-27 gene, 22q12, 10q22, 2q37 and 19q13.11. The region code represents the chromosome number and location: humans have 23 chromosomes, each consisting of a ‘short arm’ called ‘p’ and a ‘long arm’ called ‘q’ – the chromosome number being given before the letter.  Each chromosome arm is then split up into bands, which are assigned a number – giving the location on the chromosome (the number after the letter).

Scientists have questioned for years whether IBD is a genetic disease, and the current consensus is that IBD susceptibility is inherited – which this genomic evidence supports – but environmental factors influence disease etiology. Siblings of affected individuals have shown to be at an increased risk of developing IBD which is further evidence for a genetic component to the disease [6].

A 2010 study found that miRNAs (a molecule which controls the expression of genes and production of proteins) are expressed differently in patients with IBD [7]. It is believed that by identifying the miRNA pattern of IBD, the cause of IBD could be understood. Researchers are also looking at the possibility of using miRNAs as biomarkers for diagnosis and assessment of activity in a clinical setting. This would prove a breakthrough in IBD diagnosis as current methods include endoscopic and histological procedures to assess the state of the gastrointestinal tract, supported by radiographic investigations such as x-rays and barium sulphate enemas.  Endoscopic investigations are inconvenient as large volumes of laxatives and other solutions have to be consumed, often requiring a same-day admission to hospital [8].  The use of biomarkers would shorten the diagnostic journey for patients and could potentially reduce the time taken to commence treatment.

Numerous treatment options are on the market for IBD, many of which are also used to treat other autoimmune disorders, such as Juvenile Idiopathic Arthritis (JIA). Treatment regimes are unique for individual patients and depend on the severity of the diagnosed ulcerative colitis or Crohn’s disease, and tolerance to medication.

After initial diagnosis by a clinician, treatment often commences with strong anti-inflammatory drugs, such as synthetic steroids. Treatment with oral steroids is not ideal due to adverse effects, which include fluid retention and the development of osteoporosis over time.  After two weeks of taking synthetic steroids, the body stops making natural steroids and so withdrawal from the drug has to be done gradually over a period of weeks to months. Pharmacists transfer treatment over to drugs called 5-aminosalicylic acids as soon as possible once disease activity has been suppressed.  The aminosalicylates are drugs derived from salicin, a natural anti-inflammatory agent produced from willow bark.

Depending upon the severity of IBD, immunosuppressant drugs may be required.  Methotrexate (MTX) is often prescribed as a first line of immunosuppression treatment, however due to its chemotherapy-like side effects such as nausea, fatigue and low white blood cell counts, a specially tailored regime may be necessary for the drug to work effectively [9].

The forefront of anti-inflammatory treatment is biologics. These are large protein molecules that are a type of synthetic antibody used to bind to inflammatory mediators and stop them from attacking the body. Tumour Necrosis Factor (TNF) (an inflammatory mediator produced by the body) inhibitors are increasingly being used to treat IBD, one of which is called Infliximab.  Infliximab is a monoclonal antibody against TNF-α and has been shown to reduce disease activity and improve quality of life for patients [10]. A review published in the American Journal of Gastroenterology comparing the efficacy of Infliximab and a second biologic, Natalizumab, reported that both therapeutics induced remission of Crohn’s disease and reduced the likelihood of relapse. Natalizumab is an anti-integrin α4 drug. The α4 integrin is a protein found in the scaffolding of cells and it is involved in attracting immune cells to an area of infection or inflammation. By blocking the integrin, immune cells are not attracted to the site of inflammation, and so theoretically the intensity of IBD could be reduced. [11]

IBD sufferers live a life with an ‘invisible disease,’ but different treatment approaches and an emphasis on preclinical and clinical re-modelling, with the key aim of providing a better treatment regime for patients using available resources [12], could provide new hope. IBD can be debilitating to the patient and their family – both physically and psychologically – as many sufferers do not wish to talk about their illness due to embarrassing nature of the disease.

With increased awareness of IBD, and celebrities such as TOWIE star Sam Faiers announcing their battle with Crohn’s disease [13], we can hope that IBD awareness is raised as a topic for discussion.  A cure would be the ultimate goal, but adequate pain relief and remission are what sufferers need today. These new treatment approaches go some way to helping them lead healthy and productive lives.

References:

[1] Chan, D. et al. Inflammatory bowel disease and exercise: results of a Crohn’s and Colitis UK survey. Gastroenterology. (2014) 5: 44-48.

[2] Podolsky, D.K. Inflammatory Bowel Disease. N Engla J Med. (1991). 325: 928-937.

[3] Maloy, K.J. et al. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. (2011). 474: 298-306.

[4] Giusti, S. et al. Inflammatory Bowel Diseases. CT Colonography atlas – medical radiology. (2013). 75-83.

[5] Imielinski, M. et al. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat Genet. (2009). 41: 1335-1340.

[6] Montgomery, S.M. et al. Siblings and the risk of inflammatory bowel disease. Scand J Gastroenterol (2002).37: 1301-1308.

[7] Iborra, M. et al. MicroRNAs in autoimmunity and inflammatory bowel disease: crucial regulators in immune response. Autoimmunity Reviews. (2012). 11: 305-314.

[8] Roda, G. et al. New proteomic approaches for biomarker discovery in Inflammatory Bowel Disease. Basic Science Review. (2010). 16. 1239-46.

[9] Saibeni, S. et al. The use of methotrexate for treatment of inflammatory bowel disease in clinical practice. Digestive and liver disease. (2012). 44: 123-127.

[10] Guo, Y. et al. Clinical use and mechanisms of infliximab treatment on inflammatory bowel disease: a recent update. Biomed Research International. (2013). 9.

[11] Ford, A.C. et al. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. (2011). 106: 644-659.

[12] Plevy, S.E. et al. Future therapeutic approaches for inflammatory bowel disease. Gastroenterology. (2011). 140: 1838-1846.

[13] Saunders, L. 2014. TOWIE star Sam Faiers diagnosed with Crohn’s Disease
after suffering a mystery illness for the past six weeks. Daily Mail. Available from: http://www.dailymail.co.uk/tvshowbiz/article-2564027/TOWIE-star-Sam-Faiers-diagnosed-Crohns-disease-suffering-six-week-mystery-illness.html

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