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Inflammatory bowel disease, or IBD, is caused by dysregulated inflammation of all or portions of the gastrointestinal tract in a genetically predisposed host.

While the underlying pathophysiology is not well characterized, it is thought that bacteria or viral foreign material may begin the inflammatory process. However, there is no clear data that is suggestive of a specific organism that can cause IBD.

IBD consists of two subtypes: Crohn’s disease and ulcerative colitis.

While the symptoms of both are similar, patients with Crohn’s disease more frequently present with fatigue and abdominal pain, whereas patients with ulcerative colitis more frequently present with bloody stools and diarrhea.

Additionally, as IBD is a systemic inflammatory disease, both Crohn’s disease and ulcerative colitis can result in systemic symptoms that include, but are not limited to, painful joints, swollen joints, insomnia/trouble sleeping, and general achiness, all of which result from dysregulated inflammatory processes.

In Crohn’s disease, tissue inflammation is driven by unrestrainable immune response against luminal bacterial antigens.

This immune response may be driven by gut microbiota or may be due to defects in a patient’s innate immunity, which impact the ability to clear bacterial infections.

The dysregulation of the immune system is driven by hyperactivity of T cells and excessive production of cytokines, namely TNF, IL-12, and IL-23, ultimately promoting a Th1 lymphocytic phenotype.

Humoral immunity also plays a role, as IL-21 converts naïve B-cells to the cytotoxic granzyme-B, resulting in epithelial damage.

This damage results in poor clearing of bacterial and foreign material, which results in a granulomatous inflammation paired with immune response.

Release of neutrophils to this tissue damage is delayed in Crohn’s disease, which delays clearance of bacteria and increases the duration of the inflammatory response.

In ulcerative colitis, a deficient mucosal layer in the colon results in greater permeability and subsequent uptake of luminal antigens. These presenting antigens active the innate immune response through dendritic cells using Toll-like receptors and NOD-like receptors.

Unlike Crohn’s disease, ulcerative colitis is associated with a Th2 response mediated by natural killer T cells producing IL-5 and IL-13. In particular, IL-13 exerts cytotoxic functions against epithelial cells and has a positive feedback effect.

TNF-alpha, in particular, is also elevated in patients with ulcerative colitis.

The immune response is further amplified by recruitment of proinflammatory cytokines via release of chemoattractants such as CXCL8.

Genetics are known to play a significant role in the risk of developing IBD. In first-degree relatives of patients with IBD, there is a fivefold higher relative risk that they too will develop IBD.

In fact, a total of 201 genetic loci are associated with IBD and often have overlapping inflammatory pathways with other diseases.

Research suggests that there is a stronger genetic component in patients with Crohn’s disease compared to patients with ulcerative colitis.

The NOD2/CARD15 gene, which is responsible for host defense against bacterial proteins, was the first gene to be identified as increasing susceptibility to Crohn’s disease.

Fifty percent of patients with CD have at least 1 NOD2 gene mutation and 17% have a double mutation.

Patients with 2 NOD2 gene mutations appear to have younger age of disease onset, more frequent stricture disease, and less frequent colonic involvement, suggesting earlier onset.

Interestingly, NOD2 gene mutations are not associated with ulcerative colitis, which underscores the complex role genetics plays in the development of IBD. Development of IBD is also attenuated by individual-level environmental exposures.

Urban living is a risk factor for development of both Crohn’s disease and ulcerative colitis.

Differences in the natural bacterial composition of rural and urban diets is thought to explain this difference. High fat and high sugar diets may promote the growth of proinflammatory bacteria while concurrently decreasing protective bacteria.

While tobacco smoke is a known risk factor in developing Crohn’s disease, it is also known to be protective in developing ulcerative colitis.

Patients with Crohn’s disease who smoke are more likely to have perianal and structuring disease than those who do not.

It is known that tobacco smoke can result in a local immune response in the respiratory and gastrointestinal tract, and as Crohn’s disease affects the length of the GI tract, this site-specific response may result in disease development.

This may explain why tobacco smoke has such a strong correlation with the development of Crohn’s disease.

How tobacco smoke is protective in ulcerative colitis is less clear but is likely due to the difference in humoral immunity response where the presence of nicotine and carbon monoxide may lead to decreased proinflammatory cytokines.

Nonetheless, it is recommended that patients with IBD avoid or quit smoking to minimize the negative effect smoking may have.

While vaccinations are not associated with development of IBD, the use of certain medications, such as antibiotics, NSAIDs, statins, and contraceptives have been associated with a two-fold increased risk of IBD. This is thought to be due to the medications causing alterations in the gut microbiome.

Diet can also play a key role in the development of IBD, as diet ultimately affects metabolic functions of gut microbiota.

Diets rich in saturated fatty acids and processed meats may increase the risk of IBD, although the specific mechanism is currently unclear.

A high fiber diet may reduce the risk of Crohn’s disease by 40%, but this benefit has not been seen in ulcerative colitis.

Increased fiber intake results an increase in short-chain fatty acids which promote the release of anti-inflammatory IL-18 and IL-10.

While a higher consumption of vegetables does not affect development of Crohn’s disease, it is known to be protective in development of ulcerative colitis.

The increased dietary fiber from vegetables is thought to increase protective bacteria which prevent the development of ulcerative colitis.

In this video we have learned that Crohn’s disease and ulcerative colitis may share similar inflammatory pathways but differ in their genetic and environmental risk factors.

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