Causes of IBD

What is the immune system?

The immune system is your body’s defence system against foreign organisms that can cause illness (i.e., pathogens,e.g., bacteria, viruses, fungi). It is a complex system of interrelated biological mechanisms working in concert to keep you healthy. The immune system includes:

• White blood cells (e.g., lymphocytes, neutrophils)
• Antibodies (e.g., Immunoglobulin [IgG])
• Spleen
• Lymphatic system
• Bone marrow
• Thymus

Autoimmunity

If the immune system is activated in response to non-threatening stimuli this can result in the body attacking its own healthy tissues (i.e., autoimmunity). The digestive tract is one such area where this can occur –individuals with IBD are ‘stuck’ in a sustained immunological reaction that causes chronic inflammation in the digestive tract. The autoimmunity in IBD is suggested to be a result of a non-specific immune response, followed by ongoing activation of the specific (i.e., adaptive) immune system. See below for a description of these immune responses.

The immune response can be broken down into non-specific (or innate) resistance, and specific (or adaptive) resistance. Non-specific resistance is a generalised, fast immune response to a pathogen. This system is mobilised quickly because it is not specific to a certain pathogen, as is the case in the specific (adaptive) immune system.Non-specific immune resistance can be broken down into two lines of defence, including:

• Skin and mucous membranes: act as a physicalor mechanical barrier to attack, preventing pathogens from entering the body. Acids, enzymes, mucous membranes, and movement (e.g., contractions of the bowel) work together to prevent pathogens from settling into the body.
• If pathogens manage to penetrate the first line of defence (i.e., skin, mucous membranes), they are faced with the second line of defence. This involves inflammation, where blood flow is increased to the site of infection, and potentially a fever. Phagocytes (e.g., neutrophils, macrophages) and killer cells, attack the invader at the site of infection. Proteins of the complement system support these defence cells by ‘marking’ pathogens for scavenger cells, drawing immune cells from the blood, dissolving the cell walls of bacteria, and fighting viruses directly and indirectly.

Specific (or adaptive) resistance sets in if the non-specific resistance fails to destroy the pathogen. Unlike non-specific resistance, this response uses cells (e.g., T and B lymphocytes) and antibodies specific to a given threat. Specific resistance takes longer to kick in but has some advantages. Firstly, it targets pathogens more accurately and efficiently than non-specific resistance. Secondly, it can ‘remember’ a particular pathogen, responding more quickly and effectively to pathogen that have previously been encountered.

While the exact cause of IBD remains unknown, the predominant view is that genetics appear to some part. Evidence for this comes from studies examining genes associated with susceptibility to IBD, twin studies, ethnic studies and familial aggregation studies.A brief summary of the genetic contribution in IBD is shown below.

Family studies

• Up to 20% of those with IBD have a family history of the condition
• A family history of the condition is associated with a 10-fold increase in the likelihood of developing IBD
• There is a greater likelihood of developing IBD if you are a first degree relative of someone with IBD compared with second- and third-degree relatives

Ethnic studies

• Ethnic research in the United States found higher rates of IBD (43.6 per 100,000) whites compared to African Americans(29.8 per 100,000), Hispanics (4.1 per 100,000) and Asians (5.6 per 100,000)
• Jews in the United States are 2 – 4 more likely to have IBD than non-Jewish whites
• There is a higher risk of IBD in Ashkenazi Jews across different time periods around the world
• The risk of IBD a first-degree relative developing the condition is higher in Jewish populations compared to non-Jews

Twin studies

Determining the potential genetic component of a disease can be complicated by the fact that related individuals may be exposed to significantly different environments. Twin studies somewhat fix this issue, as monozygotic (identical twins) are both genetically identical, of the same sex, and are assumed to share a similar environment (i.e., born at the same time, usually sharing the same culture and geographical location). If monozygotic twins share a particular trait (e.g., Crohn’s disease) more often than dizygotic twins (sharing, on average, 50% of their DNA), this suggests that there is a genetic influence in that trait. Research has found that:

• Monozygotic (identical) twins are more likely to both have IBD compared to dizygotic (fraternal) twins.
• Monozygotic twins are more likely to share Crohn’s disease (42 – 58%) than ulcerative colitis(6 – 17%), suggesting that the contribution of genes is greater in Crohn’s disease than ulcerative colitis

Gene susceptibility studies

Genome-wide association studies allow us to examine genetic variation across the genome (i.e., the complete set of an organism’sgenetic instructions, or DNA)to identify potential associations between a given trait (e.g., Ulcerative colitis) andgenetic variation (single-nucleotide polymorphisms [SNPs). Researchers can compare SNPs across those that have IBD and those that do not to find the SNPs that are associated with the illness. The SNPs that are associated with IBD suggest potential areas of the genome that can be investigated for genes related to the illness and the potential. Research thus far has identifiedgenetic variations implicated in immune response regulation (e.g., IL23R, NOD2).

Susceptibility Genesin IBD:

In Crohn’s disease

• CD susceptibility is associated with several specific chromosomes including 16q2 (named IBD1), 12q (IBD2), 6p (IBD3), and 10
• Nucleotide-binding oligomerization domain-containing protein 2 (NOD2; recently renamed to CARD15) genewas identified and shown to be associated with an increased susceptibility to CD. The

In ulcerative colitis

• Ulcerative colitis has been linked to the DR2 allele

Our current understanding of IBD is that it is caused by a complex combination of genetic and environmental factors. Environmental factors associated with IBD include smoking, early childhood exposure to microorganisms, and certain medications.

Smoking

Smoking appears to have a contradictory effect on IBD, depending on which type of IBD a person is diagnosed with. Individuals that smoke are at a greater risk of developing Crohn’s disease but at a lower risk of developing ulcerative colitis. Smoking in Crohn’s disease is associated with a worsening of symptoms and poorer patient outcomes. Conversely, smoking appears to be a protective factor for the development of ulcerative colitis and appears to reduce the severity of disease. Despite the benefits for ulcerative colitis, smoking is not an appropriate treatment for ulcerative colitis. Smoking is known to cause at least 13 different cancers and carries the risk of cardiovascular disease.Given the significant adverse impact of smoking on health (including mortality) it is not recommended, for information about quitting smoking head to http://www.quit.org.au/

Hygiene hypothesis

The hygiene hypothesis is a proposed explanation for the cause of IBD. This idea proposes that early childhood exposure to different microorganisms is a protective factor against IBD. That is, abnormal immune responses (i.e., autoimmunity), as seen in IBD, are the result of reduced exposure to microorganisms in early childhood. This reduced exposure causes a change the way in which the body deals with microorganisms in later life. This theory may explain why individuals in developing countries are less likely to develop IBD. The role of microorganism exposure in early childhood is yet to be properly understood.

Gut microbiota

The digestive tract contains its’ own microbiome, an environment of many different microorganisms. This environment serves as an important barrier to keeping pathogens (i.e., disease-causing bodies) at bay. It is theorised that changes in the composition of the microbiome are related to the development of IBD, however this area is poorly understood.

Medications

Several medications have been identified as potential risk factors for developing IBD. These include: Non-steroidal anti-inflammatory drugs (NSAIDs; e.g., aspirin, ibuprofen), oral contraceptives, and antibiotics.