Team:NEU CHINA/Description

 Description

PROJECT
    Once IBD has been diagnosed, the symptoms can often be effectively managed. However, Crohn’s disease and ulcerative colitis are chronic illnesses, and changes are likely to occur over time. Symptoms may recur at times and complications may develop (Fig. 4).

     In a given year after IBD diagnosed:
• 48% of people with ulcerative colitis are in remission
• 30% have mild disease activity
• 20% have moderate disease activity
• 1% to 2% have severe disease [18]




Figure 5. The step-up therapy of IBD.
Background
DESCRIPTION & INSPIRATION
    Today Inflammatory Bowel Disease (IBD) has become a global health issue (Fig. 1). Inflammatory bowel disease (IBD) is a complex of several symptoms that involve chronic inflammation of the gastrointestinal tract. The chronic inflammation can cause serious destruction to the digestive tract and lead to abdominal pain, bleeding diarrhea and even colorectal cancer [1]. The unsuppressed inflammation significantly decreases the life quality and serious symptoms even threaten life [2].
Figure 1. IBD is becoming a growing global problem.
Symptoms of IBD
    Once IBD is diagnosed, it will be a painful experience for patients, which seriously affects the quality of life of patients. As the lining of the intestine becomes inflamed and ulcerated, it loses its ability to adequately process food and waste or absorb water, resulting in loose stools (diarrhea), and in severe cases weight loss. Most people with Crohn’s disease or ulcerative colitis experience an urgency to have a bowel movement and have crampy abdominal pain. Inflammation can cause small sores (ulcers) to form in the colon and rectum. These can join together and become large ulcers that bleed, resulting in bloody stools. Blood loss can eventually lead to anemia if unchecked (Fig. 3).

Figure 3. Typical symptoms of GI tract inflammation and IBD associated symptoms.
    IBD is such a life-long disease that is easy to repeat and deteriorate. It seriously affects the physical and mental health of patients and poses a great threat to public health. It is disappointing that, so far, people's efforts and achievements in the diagnosis and treatment of IBD have not been able to meet the public needs; now, more and more people around the world are suffering from IBD, and much more social resources spent on the IBD therapies.
    Fortunately, in these years, since inflammatory bowel diseases were identified, major scientific advances, specifically in the fields of genetics, immunology, and microbiology, have led to greater understanding of the underlying mechanisms involved in IBD, resulting in the development of increasingly effective treatments. The extraordinary creativity of synthetic biology may offer a useful, safe and economically effective IBD therapy. We are confidence in finding the disease curing strategies for these diseases and we are willing to make bold attempts to change the statues.

    These chronic, life-long symptoms can be treated but not cured. IBD can significantly decrease a patient’s quality of life and may have a high financial burden [3]. During our human practices, we heard of those annoying symptoms not only cause the pain on the body of patient, but also on the mental. Most of them fell disappointed with lives along with IBD, even some of them have been diagnosed with deep depression.
   Treatment with medication is the first therapeutic option [19]. The main purpose of medical treatment is to achieve remission, maintain remission and improve quality of life.
    Traditional medicines for IBD mainly follow the Step-up therapy, which starts at a certain level according to the severity of the disease, and gradually escalates the therapy when the lower-level therapy fails [20].  (Fig. 5) After we visited local hospitals and talked with the doctors, combing with the results of the survey we did, we found that this routine step-up treatment is not suitable for the cure of IBD because both Crohn’s disease and ulcerative colitis are chronic illnesses, which means patients need to take a lot of medicine along his whole life. Using the basic drug from the bottom to top will be a heavy economic burden for both family and society. Besides, the microbiology condition in a patient could change rapidly over time after the inflammation elimination with a kind of medicine and anti-inflammation medications may loss effects due to drug resistance [21]. Furthermore, IBD is easy to deteriorate to rectal cancer.

    Fortunately, in these years, since inflammatory bowel diseases were identified, major scientific advances, specifically in the fields of genetics, immunology, and microbiology, have led to greater understanding of the underlying mechanisms involved in IBD, resulting in the development of increasingly effective treatments. The extraordinary creativity of synthetic biology may create “living medicines” to tackle significant health problems through the microbiome. Many companies have been starting on the gut. Which is the biggest home to microbiome in the human body. Zbiotics is the first company to develop a genetic engineered probiotic. We are confidence in finding the disease curing strategies for IBD with genetic engineered probiotics and we are willing to make bold attempts to change the statues.
    So, here comes our original design for IBD therapy (Fig. 6) To reduce changes in the intestinal flora of patients with IBD, this year, we expect to build a kind of engineered bacterium originally presenting in the healthy people’s body to secrete several medicines to remiss the disordered inflammatory in patients’ guts, which can be a kind of microorganism transplantation. Considering the problem of drug resistance and IBD’s recurrence, combining immunotherapy, we chose human endogenous verification factor IL-10 and myrosinase in natural cruciferous plants to help patients relieve the symptoms of IBD at the host level (Fig. 6).
Repeated illness and easy deterioration
    The IBD can be classified into two major categories: ulcerative colitis (UC) and Crohn’s disease (CD). In general, UC disease is similar to Crohn’s disease, both of which have been determined as chronic IBD and cause inflammation in the gastrointestinal tract. They also share the symptoms; include diarrhea, abdominal pain and weight loss. However, rectal bleeding is the common symptom of UC, not in Crohn’s disease. CD is mostly associated with abdominal pain and rectal lesions, while UC patients usually suffer from intermittent pain consistent with bowel movements [3].
   

Incidence and Prevalence
    Studying the epidemiology of IBD may offer a novel perspective to understand possible etiologic factors. Some research indicated that IBD incidence is much higher in Caucasians than other races and developed countries also with more prevalence [8].
    Compare to Western countries, East Asian with much lower incidence and prevalence of UC and CD, although the difference between these two geographic regions will disappear [9, 10]. However, there is a recent trend showing that the IBD prevalence is climbing every year in East Asian. For instance, the estimated IBD patients are up to 11.6 cases per 100,000 person-years and 1.4 cases per 100,000 person-years, respectively [11, 12]; however, this statistical data is underestimated due to the insufficient non-hospital based data. Moreover, the definite UC cases are increasing by 3 times from 1980s to 1990s in China [13] and the total IBD patients are raised 2 times from 1990s to 2001 [14, 15]. Compared to mainland, the incidence of CD tripled over the last 10 years in Hong Kong, while the incidence of UC increased mildly [16, 17].

Figure 4. The graph of the repeating and deterioration of IBD diagnosed in a year.
Description&Inspiration











REFERENCES

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[2]Baumgart, D.C. and W.J. Sandborn, Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet, 2007. 369(9573): p. 1641-57.
[3]Mehdizadeh, S., et al., Diagnostic yield of capsule endoscopy in ulcerative colitis and inflammatory bowel disease of unclassified type (IBDU). Endoscopy, 2008. 40(1): p. 30-5.
[4]Farmer, R.G., W.A. Hawk, and R.B. Turnbull, Jr., Clinical patterns in Crohn's disease: a statistical study of 615 cases. Gastroenterology, 1975. 68(4 Pt 1): p. 627-35.
[5]Ogura, Y., et al., A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature, 2001. 411(6837): p. 603-6.
[6]Shoda, R., et al., Epidemiologic analysis of Crohn disease in Japan: increased dietary intake of n-6 polyunsaturated fatty acids and animal protein relates to the increased incidence of Crohn disease in Japan. Am J Clin Nutr, 1996. 63(5): p. 741-5.
[7]Hovde, O. and B.A. Moum, Epidemiology and clinical course of Crohn's disease: results from observational studies. World J Gastroenterol, 2012. 18(15): p. 1723-31.
[8]Whelan, G., Epidemiology of inflammatory bowel disease. Med Clin North Am, 1990. 74(1): p. 1-12.
[9]Shivananda, S., et al., Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD). Gut, 1996. 39(5): p. 690-7.
[10]Loftus, E.V., Jr., et al., Crohn's disease in Olmsted County, Minnesota, 1940-1993: incidence, prevalence, and survival. Gastroenterology, 1998. 114(6): p. 1161-8.
[11]Ouyang, Q., et al., Management consensus of inflammatory bowel disease for the Asia-Pacific region. J Gastroenterol Hepatol, 2006. 21(12): p. 1772-82.
[12]Park, D.I., et al., Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti-tumor necrosis factor treatment. Part 2: management. Intest Res, 2018. 16(1): p. 17-25.
[13]Jiang, X.L. and H.F. Cui, An analysis of 10218 ulcerative colitis cases in China. World J Gastroenterol, 2002. 8(1): p. 158-61.
[14]Wang, Y., Q. Ouyang, and A.C.I.w. group, Ulcerative colitis in China: retrospective analysis of 3100 hospitalized patients. J Gastroenterol Hepatol, 2007. 22(9): p. 1450-5.
[15]Group, A.C.I.W., Retrospective analysis of 515 cases of Crohn's disease hospitalization in China: nationwide study from 1990 to 2003. J Gastroenterol Hepatol, 2006. 21(6): p. 1009-15.
[16]Leong, R.W., J.Y. Lau, and J.J. Sung, The epidemiology and phenotype of Crohn's disease in the Chinese population. Inflamm Bowel Dis, 2004. 10(5): p. 646-51.
[17]Lok, K.H., et al., Epidemiology and clinical characteristics of ulcerative colitis in Chinese population: experience from a single center in Hong Kong. J Gastroenterol Hepatol, 2008. 23(3): p. 406-10.
[18]Langholz E, Munkholm P, Davidsen M, Binder V. Course of ulcerative colitis: analysis of changes in disease activity over years. Gastroenterology. 1994;107:3-11
[19]Kozuch PL, Hanauer SB. Treatment of inflammatory bowel disease. A review of medical   therapy. World J Gastroenterol . 2008;14(3):354-377.
[20]Podolsky DK. Inflammatory bowel disease. N. Engl. J. Med. 2002; 347: 417–29.
[21]Pamer EG. Resurrecting the intestinal microbiota to combat antibiotic-resistant pathogens. Science. 2016;352(6285):535–538

Langholz E, Gastroenterology. 1994.
List 1. iGEM teams that have worked on the diagnosis and treatment of IBD.
Figure 6. The original diagram of our project, the "gut firemen" bacteria.
Synthetic biology is tool
Figure 2. The causes of IBD.
Causes
    Although causes of IBD are not entirely understood, it is believed with association with genetic, immune response and environmental factors (Fig. 2). The immune system is responsible for host protection via eliminating any pathogens and antigens; however, IBD patients’ immune responses are over-activated and cause the intestinal inflammation. The inappropriate inflammatory responses are genetic associated. These years, environmental factors have been served as the “trigger” that initiates the harmful immune response in the intestines [4-7].
   There are so much essential and pioneering contributions have been made by the previous iGEM teams on the diagnose and treatments for IBD (List 1). Some teams like iGEM16 team ShanghaiTechChina_B, made a big progress in using immunotherapy to cure IBD; iGEM17 team SHSBNU_China constructed the two-component system detector used in detecting inflammation, including the IBD. Thanks to their valuable and detailed works in advance, we could naturally attempt to combine immunotherapy and microbiota transplantation together to create a therapy for IBD. Following this direction and referring to what we had done last year (more details please click here), this year, we upgrade the “gut firemen” with a bigger whole diagram, including a more sensitive but less leakage nitric oxide sensor, an effective and precise tunable regulation system, a significantly improved kill switch and the brand-new models. Besides, to verify the feasibility of our project, we demonstrated relatively enough characterizations about the therapeutic compounds and their secretions. The more details about the “gut firemen”, please click the design page and the results of our characterization please click the demonstrations page. We believe the future of engineered probiotics is exciting and their impacts on human health will be widespread.
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NEU-CHINA
Current treatments need improvements