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As we developed a brand-new way to alleviate IBD utilizing muscone molecular switch to induce lactic acid secretion, our contribution for future iGEM teams can be discussed in 2 sections: Parts and Treatment for IBD.

Parts


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fig 1 Overall Design

Muscone molecular switch in Saccharomyces cerevisiae: Great treatment experience without pain or regular medication

We selected the muscone gas molecule as the upstream control signal for the therapeutic system. We utilized the muscone receptor MOR215-1 from mouse olfactory epithelial cells and introduced it into a plasmid system expressed in Saccharomyces cerevisiae. Subsequently, we chose the mating pathway in Saccharomyces cerevisiae as the signal transduction pathway for the muscone signal within the yeast. Based on the corresponding literature, we optimized and replaced five amino acids at the C-terminus of the Gα protein in the original mating pathway, enabling the muscone receptor to be integrated into the mating pathway of Saccharomyces cerevisiae. Ultimately, this allows for the expression of downstream genes through the pFUS1 promoter. This composite part can be utilized in future iGEM design for brand-new smell-induced treatment.

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fig 2 Muscone Molecular Switch in Saccharomyces Cerevisiae

Tetrathionate Sensing Colonization System: High efficiency in treatment

We selected the signaling pathway of the sensor, designed by a previous team, that can detect tetrathionate (a marker of IBD) and we connected the ALS3 adhesion protein downstream. When the system detects the marker of IBD, Saccharomyces cerevisiae can adhere to the intestinal tract by expressing the ALS3 protein, achieving the colonization of the engineered strain. Future iGEM may refer our design when considering colonization in guts for other diseases.

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fig 3 Tetrathionate Sensing Colonization System

Treatment for IBD


As we mentioned in Parts section, we utilize innovative pathways in Yeast, in order to secrete lactic acid in focuses of IBD. We are confident this treatment can not only contribute to future iGEM teams or iGEM community but also IBD patient community.

Current IBD treatments typically involve surgery or drug therapy. However, surgery does not address the root cause of the disease and may lead to numerous complications. Existing drug therapies, primarily anti-inflammatory drugs and immune system suppressors, can help alleviate IBD but carry risks, including an increased likelihood of cancer or immune system disorders within the intestinal tract.

Due to these concerns, Tsinghua iGEM 2024 introduces lactic acid into IBD treatment. Lactic acid secreted by lactic acid bacterial has been shown to limit autoimmunity and alleviate inflammatory conditions in the gut. As lactic acid is naturally present in the human gut and secreted by probiotics, using it as a treatment offers minimal side effects while providing significant relief for IBD symptoms.

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fig 4 Lactic Acid Treatment and Effects

In our project we combined the innovative Muscone molecular switch with lactic acid secretion pathway in yeast, with the combination, patients will no longer to take regular medication. All they need to do is turn on the Muscone Generator after having taken the Genetically modified yeast. And with our colonization system, the treatment will be high efficient and also have minimal influence on other healthy parts in gut

We hope this method can make a real contribution to the IBD patient community in the future, as we know they are currently burdened by painful treatments. For future iGEM teams focusing on IBD, we also hope our approach provides valuable insight and inspires the development of even better treatments.

References


[1] Chen, Y., Gao, H., Zhao, J., Ross, R.P., Stanton, C., Zhang, H., Chen, W., & Yang, B. (2023). Exploiting lactic acid bacteria for inflammatory bowel disease: A recent update. Trends in Food Science & Technology.

[2] Wu, Xin et al. (2024). AAV-delivered muscone-induced transgene system for treating chronic diseases in mice via inhalation. Nature communications.

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