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Generation and robustness of Boolean networks to model Clostridium difficile infection

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Abstract

One of the more common healthcare associated infection is Chronic diarrhea. This disease is caused by the bacterium Clostridium difficile which alters the normal composition of the human gut flora. The most successful therapy against this infection is the fecal microbial transplant (FMT). They displace C. difficile and contribute to gut microbiome resilience, stability and prevent further episodes of diarrhea. The microorganisms in the FMT their interactions and inner dynamics reshape the gut microbiome to a healthy state. Even though microbial interactions play a key role in the development of the disease, currently, little is known about their dynamics and properties. In this context, a Boolean network model for C. difficile infection (CDI) describing one set of possible interactions was recently presented. To further explore the space of possible microbial interactions, we propose the construction of a neutral space conformed by a set of models that differ in their interactions, but share the final community states of the gut microbiome under antibiotic perturbation and CDI. To begin with the analysis, we use the previously described Boolean network model and we demonstrate that this model is in fact a threshold Boolean network (TBN). Once the TBN model is set, we generate and use an evolutionary algorithm to explore to identify alternative TBNs. We organize the resulting TBNs into clusters that share similar dynamic behaviors. For each cluster, the associated neutral graph is constructed and the most relevant interactions are identified. Finally, we discuss how these interactions can either affect or prevent CDI.

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Acknowledgements

This work was supported by Basal grant of the Center for Mathematical Modeling AFB170001 (UMI2807 UCHILE-CNRS), Center for Genome Regulation FONDAP 15090007 (D.T., M.C., M.L., A.M.), CONICYT PFCHA/Beca Doctorado Nacional 2015/FOLIO 21150895 (D.T.), FONDECYT 11150679 (M.L.), ECOS C16E01 (E.G.) and Internal Grant of the Universidad Adolfo Ibañez (E.G.). We also thank to the National Laboratory for High Performance Computing NLHPC (ECM-02).

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Authors and Affiliations

  1. Facultad de Ingeniería y Ciencias, Universidad Adolfo Ibáñez, Santiago, Chile

    Dante Travisany & Eric Goles

  2. Centro de Modelamiento Matemático, UMI-CNRS-2807, Universidad de Chile, Santiago, Chile

    Dante Travisany, Mauricio Latorre, María-Paz Cortés & Alejandro Maass

  3. Centro para la Regulación del Genoma, Universidad de Chile, Santiago, Chile

    Dante Travisany, Mauricio Latorre, María-Paz Cortés & Alejandro Maass

  4. Laboratorio de Bioinformática y Expresión Génica, INTA, Universidad de Chile, Santiago, Chile

    Mauricio Latorre

  5. Instituto de Ciencias de la Ingeniería, Universidad de O’Higgins, Rancagua, Chile

    Mauricio Latorre

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  1. Dante Travisany
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  2. Eric Goles
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  3. Mauricio Latorre
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  4. María-Paz Cortés
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  5. Alejandro Maass
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Correspondence to Dante Travisany.

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Travisany, D., Goles, E., Latorre, M. et al. Generation and robustness of Boolean networks to model Clostridium difficile infection. Nat Comput 19, 111–134 (2020). https://doi.org/10.1007/s11047-019-09730-0

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