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A PDMP model of the epithelial cell turn-over in the intestinal crypt including microbiota-derived regulations

Léo Darrigade 1, 2 Marie Haghebaert 1, 3 Claire Cherbuy 4 Simon Labarthe 5, 6, 1 Beatrice Laroche 1, 3 
2 BIGS - Biology, genetics and statistics
Inria Nancy - Grand Est, IECL - Institut Élie Cartan de Lorraine
3 MUSCA - Dynamiques de populations multi-échelles pour des systèmes physiologiques
Inria Saclay - Ile de France, PRC - Physiologie de la reproduction et des comportements [Nouzilly], MaIAGE - Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas]
5 PLEIADE - from patterns to models in computational biodiversity and biotechnology
LaBRI - Laboratoire Bordelais de Recherche en Informatique, Inria Bordeaux - Sud-Ouest, BioGeCo - Biodiversité, Gènes & Communautés
Abstract : Human health and physiology is strongly influenced by interactions between human cells and intestinal microbiota in the gut. In mammals, the host-microbiota crosstalk is mainly mediated by regulations at the intestinal crypt level: the epithelial cell turnover in crypts is directly influenced by metabolites produced by the microbiota. Conversely, enterocytes maintain hypoxia in the gut, favorable to anaerobic bacteria which dominate the gut microbiota. We constructed an individual-based model of epithelial cells interacting with the microbiota-derived chemicals diffusing in the crypt lumen. This model is formalized as a piecewise deterministic Markov process (PDMP). It accounts for local interactions due to cell contact (among which are mechanical interactions), for cell proliferation, differentiation and extrusion which are regulated spatially or by chemicals concentrations. It also includes chemicals diffusing and reacting with cells. A deterministic approximated model is also introduced for a large population of small cells, expressed as a system of porous media type equations. Both models are extensively studied through numerical exploration. Their biological relevance is thoroughly assessed by recovering bio-markers of an healthy crypt, such as cell population distribution along the crypt or population turn-over rates. Simulation results from the deterministic model are compared to the PMDP model and we take advantage of its lower computational cost to perform a sensitivity analysis by Morris method. We finally use the crypt model to explore butyrate supplementation to enhance recovery after infections by enteric pathogens.
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https://hal.inrae.fr/hal-03702825
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Submitted on : Thursday, June 23, 2022 - 1:37:33 PM
Last modification on : Tuesday, September 13, 2022 - 2:14:09 PM

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Léo Darrigade, Marie Haghebaert, Claire Cherbuy, Simon Labarthe, Beatrice Laroche. A PDMP model of the epithelial cell turn-over in the intestinal crypt including microbiota-derived regulations. Journal of Mathematical Biology, 2022, 84 (7), pp.1-67. ⟨10.1007/s00285-022-01766-8⟩. ⟨hal-03702825⟩

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