Team:NTU-LIHPAO-Taiwan/Modeling/Conclusion

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Modeling Summary

Hypothesis

After orally ingested, certain amounts of modified probiotic L. casei can survive under acidic condition when passing through the stomach. Owning to gastric acid, bile acid and digestive enzymes, the presence of these bacteria in the intestinal tract only last for a limited time, and then are washed out in faeces.[1] During the process of transition and temporary colonization, CPP-PYY complexes are produced and exert the following effect.

1. Total oral ingestion of 10⁹ L. casei on the first day.
2. The varying ratio (%) of bacteria number to total ingested number attached on the intestine against time were according to the mouse experiment.
3. Incorporate suicide mechanism: 4 days for bacteria survival.
4. TAT penetrates through villi by an uncharacterized pinocytosis/endocytosis related mechanism, which is also receptor-independent.
5. CPP-PYY complex production rate per L. casei : 10^-10 μg/min.
6. One-fourth of the products secreted from L. casei penetrate through the small intestine epithelial cells, without being digested by the intestine fluid.
7. Effective permeability of TAT-insulin conjugates from literature as reference for TAT-PYY complex : P_eff = 1.62×10^-5 (cm/s).
8. Mean total mucosal surface of the small intestine interior averages 32 m².
9. L. casei cell size range = 0.7-1.1 x 2.0-4.0 μm. One-tenth of the bacteria height multiplied the mucosa surface area for the donor chamber volume.
10. Fick’s Law of Binary Diffusion applied for CPP-PYY complex adsorption into bloodstream. Interstitial fluid diffusion coefficient of bovine serum albumin in tissues was taken for reference : D_AB = 5.8 x 10^-7 cm²/s.
11. The distance from epithelial cells to capillaries is 4 μm.
12. The diffusion is rapid enough to adsorb all the products in every minute.
13. All the calculation was based on reaching steady-state condition in the interval of every minute discretely.
14. Thrombin cleavage efficiency of Arg-Ser(R-S) site in CPP-PYY complex was referred to Arg-Thr(R-T) site in salmon calcitonin.
15. Nearly 100 % of the complexes would be cleaved during 30 minutes due to the fluid motion in circulation.
16. PYY concentration of 100 pg/ml has the power of appetite suppression without drug resistance.
17. Average total blood volume of 5 liter in human body.

Conclusion

Ideally, the optimal concentration of PYY is 0.1 μg/L for appetite suppression, giving little side effect. Here we performed the simulation with 10⁹ of total L. casei intake, and 10^-10 μg/min of CPP-PYY complex production rate per L. casei. The results is shown below.

[Fig.1-1] Final concentration of PYY (μg/L) in the blood vessel

By building the model for simulation step by step, we summarized the general formula with varies parameters to determine the dose response :

[Final concentration of PYY in the blood (μg/L)] = 11745 × [Total L. casei intake] × [Distribution ratio of L. casei] × [CPP-PYY complex production rate per L. casei (μg/min)]

This general formula is based on one-dose response, and continuous drug intake should be further modified by successive accumulation for determining the appetite suppression effect.

Reference

Reference

[1] K.M. Tuohy and M. Pinart-Gilberga et al. Survivability of a probiotic Lactobacillus casei in the gastrointestinal tract of healthy human volunteers and its impact on the faecal microflora. J Appl Microbiol, ISSN 1364-5072. UK. (2006)

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