IBD OverviewInflammatory bowel disease (IBD) is an idiopathic, dysregulated, relapsing, and debilitating immune reaction to the host’s intestinal microflora, triggered by a host of factors, including genetics, environmental and physiologic factors. Previously thought to be triggered by adaptive immune responses, recent research has shed considerable light on the role of the innate immune system in causing an imbalance between the beneficial and commensal microflora residing in the human gut, leading to an aggravated inflammatory response, causing IBD. In other words, the immune system is supposed to protect the host from foreign bodies, pathogens, and consequent infections, but in IBD, the host’s immune system mistakes the body’s own microbes, food and other materials for foreign bodies and attacks the intestine. This leads to a release of white blood cells at these sites, which causes inflammation.

The two most common forms of IBD are Ulcerative Colitis (UC) and Crohn’s Disease (CD).Though both conditions have similarities in terms of manifestations and symptoms, the basic difference between them lies in the location and nature of inflammation caused.

UC is a chronic gastrointestinal disorder that involves the rectum and the colon (the large bowel), mainly in the mucosa and sub mucosa regions of the gut. Unlike CD, this condition is a continuous manifestation restricted to the rectum and the colon, with ulcerations along the mucosa and sub mucosa. It starts with mild symptoms that gradually progress to severe ones, with periods of remission in between. The most common manifestation of UC is progressive loosening of stool with blood, accompanied by abdominal pain and occasional fever. Loss of appetite, fatigue and weight loss are common consequences. However, unlike CD, the periods of remission in patients with UC are longer. Patients with UC are at an increased risk of colon cancer.

CD is referred to as the chronic inflammation of any part of the gastrointestinal (GI) tract, though it most commonly pertains to inflammation of the small bowel, sometimes extending to the top layers of the large bowel. It is a transmural condition, involving all layers of the gastrointestinal wall (mucosa, sub mucosa, muscular is externa and serosa), and is normally discontinuous in pattern, with patches of healthy bowel lying in between patches of damaged and inflamed bowel. Common symptoms include persistent diarrhea with occasional rectal bleeding, irregular and frequent bowel movements, weight loss, malaise, and fatigue. The most common complication specific to CD is blockage of the intestine due to excess inflammation and swelling, leading to abdominal cramps, bloating, and vomiting. Ulceration and fistulas are common in CD, and the ulcers are at a high risk of getting infected.

Both CD and UC can become very severe and may require surgery, but it has been observed that patients with CD are at a greater risk of requiring surgical intervention as a result of complications than those with UC.

Most of the symptoms in both cases are very similar. Extra-intestinal manifestations are also common in cases of IBD. These include oral aphthae (mouth ulcers), erythema nosodum (inflammation of fat cells under skin, noticed especially on the shins, and resolves within a span of 3-6 weeks), arthritis of large joints and episcleritis (inflammation of the episclera of the eyes) among others. It is because of these non-specific symptoms that distinguishing between UC and CD becomes difficult. The medical term to denote this condition is called intermediate colitis (IC). IBD should not be confused with irritable bowel syndrome (IBS), which deals with muscle contractions of the colon, and is not related to the intestine.

Symptoms normally correspond to active, acute infection, which should be diagnosed properly by the consulting physician. Differential diagnosis needs to be done in order to distinguish between ischemic infections, colitis and IBS among others. A variety of laboratory tests, cultures and imaging techniques are combined to appropriately diagnose the condition.

Treatment options for IBD include a mixture of aminosalicyalates, antibiotics, corticosteroids and immunomodulators, along with supportive nutritional therapy to prevent malabsorption and increase the healthy lifespan of the diseased.

Etiology:

Patients with IBD normally have a genetic predisposition, but there is no sole factor that could be named responsible for the condition. It is a combination of genetic, pathogenic (immunologic), physiological (including dietary routine and lifestyle) and environmental factors that govern the incidence of IBD. What actually triggers the condition is yet to be identified.

Among a number of etiologic theories postulated as possible causes of IBD, the most prominent ones are defective microbial clearance by an inefficient or faulty immune system leading to a persistent infection, defective mucosal clearing of commensal antigens leading to intense inflammation, and faulty immunoregulation. However, recent theories involving both animal and human studies, have stressed upon the genetic makeup of IBD to provide a more conclusive viewpoint of the root causes of the condition.

Crohn’s Disease: 

One of the major genes to be studied in relation to the development of CD is the CARD15 (caspase recruitment domain family member 15, previously known as NOD2) gene. This gene is responsible for bacterial cell wall recognition, which in turn encodes for NF (nuclear factor) κB, a mediator of pro-inflammatory cytokines and protective molecules (eg: antimicrobial peptides), which processes the foreign antigen (eg: an invading or commensal gut microbe) and ensure homeostasis. Three single nucleotide polymorphisms (SNP mutations) have been discovered so far, which lead to an increase in the number of commensal bacteria in the intestine, faulty down-regulation of the innate immune system (NFκB activation), and ineffective bacterial clearance, all of which are major documented findings in patients with CD.

Another gene studied in this regard is the IL23R gene, which is responsible for the synthesis of the Interleukin 23 (IL23) receptor protein. This regulatory protein is crucial as it is present on the surface of most immune cells (T-cells, Natural Killer cells, monocytes and dendritic cells), and mediates pro-inflammatory pathways against pathogens. It does so by binding to IL23, a potent pro inflammatory cytokine that leads to an immune reaction against invading pathogens. It is also responsible for the regulation of production of IL-17 via activation of Th17 lymphocytes from the memory cells and contributes to their survival as well. The study of mouse knock-out models with IL23R showed increased and uncontrolled production of pro inflammatory cytokines (high serum levels of IL23, IL17), which was concluded to contribute to colitis and Crohn’s Disease. Hence, a mutation in the protective variant of IL23R, can be said to be a direct contributor to CD. It is interesting to note that this gene was studied mostly in Jewish, German, Belgian, and Scottish populations.

Genes involved in autophagy have also been studied to be direct contributors to susceptibility against CD. Autophagy is the process by which pathogens and foreign antigens are digested intracellularly via lysosomes, and damaged proteins are permanently degraded. If a gene responsible for autophagy is mutated, it can cause an imbalance in the ratio of the harmless resident symbiotic and harmful invading pathogenic flora, and cause problems in the GI tract, predisposing CD. The protein ATG16L1 (located on chromosome 2) is responsible for the synthesis of one such autophagy related genes (ATGs), and a mutation of this protein has been linked to the development of ileal CD.

Several other mutated genes that have been studied to have a direct impact on patients developing CD include TNFSF15 (Tumor Necrosis Factor Super Family 15), CTLA4 (responsible for synthesis and differentiation of regulatory T-cells, controlling the rate and degree of inflammation), IBD5 (Inflammatory bowel disease 5, mutations on which have been directly related to signal transduction across intestinal epithelium and also with the synthesis of pro inflammatory cytokines) among others.

Ulcerative Colitis:

There have been fewer evidences of genetic predisposition in case of UC. Some of the mutated genes thought to be responsible for UC overlap with CD as well. Genes like the DLG5, which is responsible for the maintenance of intestinal epithelial wall integrity, have been found to be contributors towards susceptibility to both CD and UC. Similarly, the MDR1 gene, coding for multidrug resistance and transport of amphipathic substances through membranes, has shown increased susceptibility towards development of ulcerative colitis. Other than these, the gene ECM1 encoding for extracellular matrix protein 1 responsible for maintenance of skin integrity and homeostasis, has also been studied to have susceptibility loci (when mutated or knocked out in animal models) predisposing towards development of UC.

There have been a few studies among Japanese population which shows genetic mutations of some genes of the Human Leukocyte Antigen (HLA), located on chromosome 6, responsible for antigen presentation and processing, increases risk for one type of IBD while decreasing the risk for the other type. Such instances however, have been rare in case of European populations.

Genetic predispositions have been seen to affect children more than adults, in studies conducted across North America and Europe. This might be because children have a developing immune system, which is more prone to damage than that in a fully formed adult.

Risk factors for the development of IBD include:

  • Family history: People with a family history of IBD, especially with a first degree relative being affected by IBD, are at 5 to 20 times the risk of developing it themselves, as compared to normal people. A child has a 5% risk from parents and around a 70% chance from an identical twin. Non-identical twins have a comparatively lesser risk, of 5-10%.
  • Smoking has been studied distinctively to be one of the prime risk factors contributing to the development of IBD. The risks of developing CD increases in smokers, whereas when one quits smoking, one is at a higher risk of developing UC. There have been no reports of the decreasing risks of UC with smoking.
  • Ethnicity: IBD has been found to be prevalent mostly in North American and European countries, and the least in Asian and African countries. Caucasians and Jewish people are highly prone to developing IBD. On a more general note, industrialized and developed countries have been found to have a greater incidence of IBD. It can be said that urbanization and westernization exposes people to its hazardous after effects (industrial smoke, pollution, allergens, etc.) which act as predisposing conditions.
  • Use of certain medications might increase risks of developing IBD. Studies have been carried out that show increased risk of IBD among people who use isotretinoin for acne treatment. Also, the use of pain killers and pain relievers (aspirin, ibuprofen,naproxen, etc.) could contribute to the formation of gastrointestinal ulcers, which complicates IBD. Hence, proper advice from a physician is necessary.
  • Age: IBD affects people mostly between the ages of 15-30 years. 10% of the people are diagnosed with it within a span of 18 years. According to the CDC, the prevalence of UC is higher among men, and CD is slightly higher among females.

Epidemiology:

There has been a considerable rise in the number of cases of IBD in North America and Europe since the second half of the twentieth century. Places with a colder climate and urbanization tend to have a higher incidence of IBD. Annually, around 1.4 million people are diagnosed with IBD, with 70,000 visits to the physician and another 100,000 hospitalizations taking place in the U.S. alone due to IBD and its complications.  Though an exact prevalence cannot be estimated due to the absence of a “gold standard” of diagnosis and misclassifications of the condition, a rough estimate based on numerous studies shows that  around 70 to 150 people per 100,000 are affected by IBD (UC or CD). The prevalence for CD ranges from 319/100,000 in North America, to 322/100,000 in Europe, and that for UC ranges from 249/100,000 in North America, to as much as 505/100,000 in Europe. Internationally, the prevalence for UC ranges from 0.5 to 24.5/100,000, and for CD ranges from 0.1-16/100,000 with the prevalence of IBD in general, being approximately 396/100,000.

The rate of incidence of CD is highest in North America, followed by Europe, and then in Asia and the Middle-East. The rate of incidence of UC is highest in Europe, followed closely by North America, then the Middle-east and Asia.

Pathophysiology:

IBD is defined traditionally as the “dysregulated response of the mucosal immune system towards intraluminal antigens of bacterial origins in genetically predisposed people.” There have been studies speculating this theory and concluding that more than the pathogenetic aspect, the pathophysiology of IBD is more dependent on a faulty innate immune system that is unable to regulate immune responses as it is expected to, which leads to excess inflammation and forms the very basis of IBD.

The innate immune system forms the first line of defense against foreign pathogens, fighting against them depending on their chemical nature and not specificity. The cells of the innate immune system include mediators like cytokines, adhesion molecules, chemokines and lymphocytes, which are responsible for recruiting inflammatory cells to the site, regulating effector cell responses and presenting the antigens to the adaptive immune system through antigen presentation, for further processing and eventual destruction. In this case, it is assumed that the failure of the regulatory cytokines released by the innate immune system, like IL10 interferon γ (IFNγ) and transforming growth factor β (TGFβ), contribute mainly to the development of severe inflammation. Studies have shown that the T lymphocytes in the effector pathways (mostly Thelper cells) do not undergo apoptosis after activation, as anti-IL12 and anti-TNF antibodies are not secreted (IL12 and Tumor Necrosis Factor being two of the most potent pro-inflammatory cytokines) which again contributes to inflammation. The research pertaining to mutations of the NOD2 (CARD15) gene, which is another trigger for regulating the innate immune system after attachment to pathogenic cell wall antigen, is another theory which enhances our understanding of the failure of the innate immune system in IBD patients.

The intestinal epithelium is another important part of the innate immune system, with the mucosal glands providing immunity against pathogens, maintaining mucosal homeostasis as well as forming the protective covering of the intestines. Genetic predispositions might affect the integrity of this barrier, which makes the intestine free to be invaded by commensal pathogens from other sites (e.g.: fecal pathogens) and lead to a faulty activation of the mucosal immune system. This is because the epithelial cells have antigen presenting cells embedded all over, which get activated on exposure to fecal bacteria, cause faulty antigen presentation and lead to inflammation.

As far as the effector immune responses are considered, the helper T lymphocytes fail to undergo apoptosis after their synthesis by the cytokines. The Th1 cytokines (IL12, IFNγ, TNF) contribute to the development of Crohn’s disease, whereas the development of ulcerative colitis has been attributed to predominantly Th2 cytokines (IL4 and IL5). However, this theory has also been challenged by recent studies, which have shown anti-TNF therapies that have been successful in inducing remission of UC. Also, an increase in the IL13 population has also been seen in some cases of UC. In fact, suppressing the IL13 receptors has been taken up as a therapeutic target to treat the inflammation caused in UC. On the other hand, it has been seen that anti-TNF antibodies and IL-10 (an anti-inflammatory cytokine) could not cause remission of CD, which indicates involvement of mixed cytokine profiles in IBD. Generally speaking, in an acute infection stage, the conditions can be said to be polarized towards Th1 or Th2 populations with fresh lymphocytes being recruited by the mucosal barriers in order to restore homeostasis, but when progressing to a chronic stage, both UC and CD can be said to exhibit mixed profiles of effector T-cells, as there is a considerable increase in the number of homeostatic pathways.

Ulcerative colitis starts in the rectum and extends proximally till the colon (might involve the entire large intestine at times). The rectum is always a part of UC and in 25% of the cases, the condition remains localized within the rectum itself, a condition known as ulcerative proctitis. Around 10-12% of the cases involve the entire large intestine, a condition known as pancolitis (a more severe form). Other cases see an involvement of the distal terminal ileum, a condition known as backwash ileitis. It is a continuous condition spread evenly over the mucosa and sub mucosal linings, without affecting the muscularis mucosae (separating the lamina propria mucosa and sub mucosa), with no ‘skip-areas’ unless previously treated for rectal therapy. The periods of acute inflammation are followed by comparatively longer remission periods than CD.

The early stage infection involves formation of erythematous and hemorrhagic areas over the membrane with inflammatory mucosal islands in between, known as ‘pseudopolyps’. Large mucosal ulcers with purulent exudates often harbor bacteria which cause worsening of the condition. In extreme cases, the colon loses its muscularity and dilates indefinitely, to resemble the structure of a lead-pipe. This condition is called toxic or fulminant colitis, which might also lead to perforation of the colon in some cases. People with UC are at an increased risk of developing colon cancer.

Crohn’s disease is a chronic transmural, inflammatory condition, affecting all the layers of the bowel, and capable of affecting any part of the GI tract, starting from the mouth to the anus. CD mostly affects the distal ileum and the colon, with three distinct patterns of infection (namely inflammation, strictures and fistulas). Depending on the location of inflammation, the different types of CD are named as, ileocolitis (involving the ileum and colon, 35-45% cases), ileitis (ileum only, 35% cases), granulomatous colitis (only colon, 32%), jejunoileitis (small bowel, 28%), with a mere 5% of the cases spreading to the duodenum.

The condition begins with cryptic inflammation, and spreads transmurally, affecting the lymph nodes and vessels (lymphedema) and causing thickening of the bowel wall and mesentery. Hypertrophy of muscularis mucosae and formation of strictures (narrowing of the intestinal lumen) is common. Mucosal lesions with intervals of ‘skip areas’ in between two consecutive lesions; give the structure a ‘cobblestone’ appearance. Fistulas (formation of abnormal connections between the intestine and other adjacent organs like loops of the bowel, abdomen and bladder in severe cases) form another common feature of CD. Surgical intervention in complications is more common in CD (around 75% cases needing surgery) as compared to UC (25%). People with colonic involvement have an increased risk of developing colorectal cancer. Formation of abscesses and non-necrotizing tumors is observed on a number of occasions in CD patients. Kidney stones and gall stones are formed as a result of malabsorption of fats and bile salts and vitamin deficiency, all caused as a result of a diseased intestine.