Team:NEU China A/Introduction

Inflammatory bowel disease is a chronic inflammatory disease that affects the gastrointestinal tract. It has two major clinically defined forms, one is Crohn's disease that can affect any parts of the gastrointestinal tract, and the other is ulcerative colitis that affects the colonic mucosa [1]. Although the pathophysiology of IBD is largely unknown, some factors that have a major role motivating of IBD have been identified, including genetic factors, the host's immune system, and environmental factors [2]. Patients with IBD often have symptoms such as abdominal pain, diarrhea, blood in the stool, and weight loss during disease activity [3], which decrease the life quality of patients dramatically. Unfortunately, IBD is not curable and IBD patients have a higher risk of developing colorectal cancer [1].

2. War inside the intestine

In general, when the immune system overreacts to the flora normally resident in the gut, it causes a series of inflammatory events that may damage and destroy the intestinal wall [4]. Some biomolecules are released by bacteria which induce an inflammatory reaction to intestinal epithelial cells, causing the destroyed tight junction between intestinal epithelial cells and the reduced of mucus layer thickness . When dendritic cells in the lamina propria sense these biomolecules, they release inflammatory signals to recruit immune cells, which exacerbates the inflammatory response. Microorganisms in the intestinal lumen pass through the leaky intestinal epithelial barrier, which further exacerbates the immune response against bacteria and creates a vicious circle. These immunological attacks and inflammatory injuries eventually lead to the death of intestinal epithelial cells [5]. IBD occurs when this condition persists without intervention.

3. A growing global disease

IBD is a global disease that is most common in North America, Western Europe, Northern Europe, Australia, and New Zealand [6, 7], which may be related to the higher level of industrialization in these regions [8]. There are more than 1 million IBD patients in the United States [9], and the medical burden associated with IBD directly exceeds $6 billion per year [10]. In Canada, more than 200,000 people have IBD, and the annual medical burden exceeds CDN$1.2 billion [11]. In Europe, there are more than 2.5 million IBD patients with an annual health care burden of more than €4.6 billion [12]. Due to the growing number of cases, huge medical expenses, the loss of work capacity of the sick and the aging of the sick population, IBD will place a heavy burden on the world in the next decade [7, 13].

4. Rising in the Asia

In the past few decades, IBD has shown a growing trend in low-incidence areas, especially in new industrialized areas such as Asia [14, 15]. This is likely to be related to the Westernization of residents' dietary patterns and the rapid urbanization process [16, 17].

Asia is one of the continents that experiencing fastest urbanization in the world [18], and there is a close relationship between urbanization and IBD [19]. In Asia, the high incidence of IBD is mainly found in some highly urbanized areas, such as Hong Kong, Macau and Guangzhou, while residents and rural residents in some less industrialized areas show lower morbidity [14]. People who flood into cities have access to better health care and sanitation, but the abuse of antibiotics and overly hygienic habits can interfere with normal gut flora [5, 20]. In addition, due to the poor quality of air condition, heavy mental stress, a more sedentary lifestyle and consumption of high-fat foods, people who live in a developed city are more likely to get IBD [5, 20]. At present, the incidence of IBD in Asia is rising rapidly. In Hong Kong, for example, the number of cases increased by 30 times from 1985 to 2014 [21], and the gastroenterology ward was crowded with young IBD patients [20].

Western diets are broadly defined as containing high amounts of saturated fat, red meat, sugar and low amounts of fruit, vegetables, grains, seafood, poultry meat [17]. Studies have confirmed the association between Western diet and the pathogenesis of IBD [22, 23]. In addition, immigration studies showed that people move from developing countries to developed countries and adopt to Western lifestyles are more likely to suffer from IBD.

In the long run, the incidence of IBD in Asia will soon be similar to Europe and America [20]. To make matters worse, compared with European and American countries, the efforts of Asian countries to cope with the medical and economic burden of IBD are seriously inadequate [20]. In addition, many patients who have been sick for a long time are unaware of the fact that they have IBD, which leads to underdiagnosis of IBD [20].

5. Current therapies

The treatment of IBD is very complicated. Traditionally, IBD has been treated with Step up therapy, which starts at a certain level depending on the severity of the disease, and gradually escalates the therapy when the lower-level therapy fails [25]. The order from low to high is as follows: aminosalicylic acid preparation (aspirin) → glucocorticoid → immunosuppressant (azathioprine) →biological agents (anti-TNF) → surgery [26]. This routine step up treatment is not suitable for patients at risk of rapid disease progression and may delay optimal medication time and increase the risk of hospitalization and surgery. The use of top down therapy, that is, the preferential use of anti-TNF monoclonal antibody than the step up strategy can more effectively induce and maintain remission and change the disease process [25].

Surgical treatment is often seen as a last resort, but as the understanding of the disease continues to deepen, it has been found that some patients with early-stage IBD have a better quality of life than patients who administrate biological agents [27]. This provides us with a new top down therapy that prioritizes the use of surgery. But for patients with complex IBD, surgical treatment can easily lead to disability and a significant decline in quality of life.

There are pros and cons of specific drug treatments. Non-specific anti-inflammatory drugs are inexpensive, and immunosuppressive agents are effective, which can reduce the need for surgery and hospitalization in patients with IBD, and reduce the risk of clinical recurrence and glucocorticoid dependence in patients with IBD [28]. However, non-specific anti-inflammatory drugs are prone to tolerance and fail. Biologics are currently the most effective drugs, but they are expensive and difficult for ordinary people to bear. For example, in the United States, 75 kg of IBD patients are treated with a standard dose of infliximab, which costs about $26,700 per year, while a year of azathioprine (a biologic immunosuppressive agents) costs only $750 per year [28]. Therefore, immunosuppressive agents are a reasonable and cost-effective treatment strategy for patients with IBD and still have value in use [28]. In addition, clinical studies have found that anti-TNF biologics combined with steroid immunosuppressive agents have better efficacy than monotherapy. At the same time, the risk of solid tumors and serious infections increases [29]. In short, IBD patients need tailored personalized treatment options.

The recent emergence of Fecal microbiota transplantation (FMT) provides a new option for the treatment for IBD. FMT is referred as transplanting the flora of healthy human feces into the intestine of a patient, rebuilding the normal intestinal flora, and achieving the purpose of treating diseases inside and outside the intestine. However, FMT itself has a difficult choice of donors, long-term safety is not clear, patients with low acceptance and poor efficacy, thus, the efficacy of FMT for IBD is limited [30].

6. Our solution

This year, our team NEU_China_A try to use engineered bacteria to explore an inexpensive, safe and efficient way to deal with the dilemma in the intestinal tract of patients with IBD. See project design for details.

7. IBD related iGEM projects

We list the iGEM teams that have worked on in the diagnosis and treatment of IBD to facilitate future team enquiries.

Reference

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