Eating, for human beings, is a means of obtaining energy, and at the same time, it is also the instinct of every human being to maintain survival. Along with the continuous progress of people's living conditions, the choice of food in people's daily life also tends to be more diversified. It is becoming more and more common to find food from different regions, countries and nationalities on the same table, and the different eating habits of people from different regions have been blended with the increasing globalisation.

However, the difference in speed between the progress of civilisation and the evolution of mankind can sometimes cause problems for a number of people - for example, because of the susceptibility caused by the HLA-DQA1 and HLA-DQB1 genes to celiac disease, one of the most typical gluten intolerance disorders. But wherever this population ingests trace amounts of gluten proteins through food, most of them trigger an immediate pathological reaction, which undoubtedly poses a huge problem for this group of people in terms of study, employment, travelling, etc. due to the highly restrictive nature of their diet. UM-Macau, through our Gluten Enzymatic Intestinal Guardians programme, is addressing this issue for our community and the world this year.

    Celiac disease occurs because the enzymes in the human digestive system are unable to break down gluten completely, leaving a 33-amino acid peptide chain that is rich in proline and glutamine, resulting in a structure that is stable even in the presence of digestive enzymes. In the general population, the 33-mer peptide has no effect; however, in people with HLA-DQA1 and HLA-DQB1 susceptibility genes, the 33-mer peptide will be taken up by intestinal M-cells as an antigen and recognised by basal dendritic cells, over-activating the intestinal immune system and causing destruction of normal tissues, leading to the development of celiac disease. leading to the development of celiac disease.

The typical patient with celiac disease suffers from significant malabsorption, as well as symptoms including diarrhoea, steatorrhea, iron-deficiency anaemia, weight loss and impaired growth. Particularly in children with celiac disease, it is clear that impaired nutrient absorption due to the destruction of the small intestinal epithelial tissue by celiac disease has a more severe impact on physical development - with an over-activated immune system attacking the small intestinal tissues and prolonged periods of high dietary restriction, children and adolescents with celiac disease children and adolescents with celiac disease are at risk of developmental stagnation, weight loss, and impaired growth; at the same time, because of the impact of celiac disease on the brain-gut axis during development, irritability and depression often accompany children with celiac disease, increasing the risk of depression, bipolar disorder, and other psychiatric disorders.

Reasonable interventions for celiac disease are of great importance in improving the quality of life of patients and preventing the development of celiac disease into multiple malignant complications. Until now, the common clinical treatments have been limited to gluten-free diets and oral enzyme therapy, which has been gradually developed since the beginning of this century.
As for now, the only treatment for celiac disease is a lifelong strict gluten-free diet - any gluten-containing foods such as wheat, rye, and barley should not be consumed as even small amounts of gluten can be harmful to celiac disease sufferers. Removal of gluten from the diet of celiac disease patients provides substantial symptomatic relief for most patients, leading to improvements in celiac disease at both the serological and histological levels. At the same time, adherence to a gluten-free diet has been shown to alleviate some of the stunted growth in children and to prevent a number of common complications.

Just as people adopt taking multi-enzyme tablets to alleviate some of the symptoms of indigestion, when people discovered at the beginning of this century that the direct cause of the onset of celiac disease comes from the 33 peptides of gluten that cannot be completely broken down in the human body, how to digest this peptide chain that the human body can not be digested by the use of enzymes has become a new direction of development. However, due to technical problems, human beings have not yet found a 33-peptide digestive enzyme from nature that can tolerate gastric acid and other digestive enzymes, and this therapy has not yet been widely put into practice in the clinic.

For oral therapy, in addition to the difficulty of helping the enzyme to overcome gastric acid, the residence time and effect of the enzyme as a drug in the intestinal tract are completely unpredictable, and its behaviour in the intestinal tract is not a factor that we can control, so even if the enzyme is able to reach the intestinal tract safely, the decomposition of 33-mer peptide is still uncertain in many aspects.
Even though existing gluten-free diets can result in improvement of symptoms in 70% of patients within two weeks, keeping patients on a gluten-free diet for an extended period of time is in itself highly restrictive in terms of the patient's lifestyle. A gluten-free diet would limit the consumption of a significant number of traditional staple foods, including bread and pasta. resulting in a severe reduction in food choices, and maintaining a gluten-free diet may not only cause the further nutrient deficiency, but also become even more difficult for patients when they are socialising, communicating, or travelling; and because the global prevalence of celiac disease is very unevenly distributed, community-based care initiatives for coeliac disease are highly variable. uneven, the difficulty of finding food that fully meets one's requirements on special occasions or in non-coeliac endemic areas can easily lead to a relapse of the condition during unavoidable social life. Because of these difficulties, it has led to maintaining a gluten-free diet itself becoming a challenge for patients to remain compliant with their treatment and creating new inconveniences and disturbances in their lives.

Therefore, to overcome the difficulty of controlling the drug behavior and let the species in gut produce enzyme themselves, UM-Macau proposes our own solution to celiac disease based on synthetic biology - GEIG-Gluten Enzymatic Intestinal Guardians.

Celiac Disease (CD) is the worldwide autoimmune gluten intolerance disease. Current treatments include lifelong gluten-free diets and oral enzyme therapy, but these therapies bring inconvenience to patients’ lives and the latter is still immature.
UM-Macau aims to establish a rapid and targeted delivery and adhesion system that releases prolyl endopeptidases through probiotics under the control of NO sensors, as an alleviator of inflammatory-like environmental factors in CD intestine.
To accurately deliver probiotics to the duodenal region and adhere to epithelial cells for a longer time, UM-Macau uses microbe-based therapeutics (MBTs) film capsule and inserts adhesion protein genes (Mefp-5 & cp19k) integrated by Pasr promoter according to the relative acidic environment.
UM-Macau will conduct a modeling test to predict the colonization on mucus layers and efficiency of bacteria adhesion, set the suicide switch in vitro and population density control system as safety module based on teamperature, quorum sensing and quenching.

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