Multi-Scale Model of the Gastrointestinal Tract

Title: Multi-scale model of the gastrointestinal tract.

Authors: Marouen Ben Guebila and Ines Thiele.

Authors’ contact: Marouen.benguebila@uni.lu, ines.thiele@uni.lu

Authors’ affiliation: University of Luxembourg, campus Belval, Luxembourg Centre for Systems Biomedicine.

Background:

The gastrointestinal (GI) tract is the site of absorption and metabolism of nutrients and xenbotiotics. Several drug-diet interactions take place in the GI, thus reducing the drug efficacy, like levodopa and high protein diet (1). Levodopa is the gold standard treatment for Parkinson disease (PD) for almost 50 years. Despite its efficacy, levodopa leads to fluctuations in the motor response as a consequence of several factors, mainly diet. It has been proven that high protein diet leads to a decreased fraction of levodopa reaching the brain, with the consequence of worsening in the motor functions. Recently, the intestinal transporters of levodopa has been identified in vitro as a neutral and dibasic amino acids exchanger (2), which provided a molecular basis for the observed competition and suggested a basolateral trans-stimulation of levodopa secretion with amino acids. We aimed to translate the in vitro findings to human health through a combined physiologically based pharmacokinetic (PBPK) (3) and constraint-based reconstruction and analysis (COBRA) (4) approach.

Material and methods:

We present a multi-scale model of the GI, obtained through combining the ordinary differential equation based whole body model, in particular, the advanced compartmentalized absorption and transit model (ACAT) (5), with seven genome scale metabolic models of the small intestine epithelial cell (sIEC) (6) corresponding to the different anatomical parts of the gut wall. The fine grained depiction of intestinal processes aims to characterize the spatiotemporal relationship between levodopa and amino acids, taken as example. 

Results:

The parameters of the dynamic system were identified through curve fitting of plasma concentrations of levodopa on whole body PBPK model. The coupled PBPK-sIEC model allowed us to assess the impact of high protein diet on the bioavailability of levodopa. It also suggested that PD patients in stage 3 and 4 on Hoehn and Yahr scale needed dietary intervention. The comparison of routine dietary intervention showed that Protein Redistribution Diet (PRD) to the last meal performs better than Low Protein Diet (LPD) (7) as it increased the bioavailability of levodopa. The modeled mechanistic system suggested that serine rich diet augmented levodopa bioavailability by 22% in silico.

Conclusion:

The complex relationship between amino acids and levodopa varies between trans-stimulation to competition. A multi-scale systems approach allowed the optimization of diet in PD, which can lead to a better outcome of levodopa. Model analysis identified intestinal processes as the most influential to the plasma concentrations of levodopa and provide a rationale to bypass the stomach for drug administration as suggested by recent medical devices (8).

 

 

References:

 

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