Michael Morimoto (1,2), Lyn Powell (1,2), Rajalakshmi Santhakumar (1,3), Aaron Gowins (1,4), Joanne Arsenault (1,5), Carson Chow (1,4), Rukmini Kumar (1,3)
(1) HBGDki community, (2) Lynx Bioconsulting, USA, (3) Vantage Research, India, (4) NIH, USA (5) University of California at Davis, USA
Objectives: To develop a quantitative physiologic model that represents the major causal dependencies relating nutritional status and enteric pathogen exposure to macronutrient and energy availability in order to better understand and predict effective interventions for growth faltering children in low- to middle-income countries.
Methods: A thorough review of public literature guided the structural development of a 20-state nonlinear differential equation model representing the major mechanisms believed to causally connect nutrition and pathogen exposure to macronutrient and energy available for metabolism and growth. Published quantitative data and qualitative expectations were used for calibration, validation, refinement of the functional forms of the differential equations, and enforcement of local behavior around phenotypes (e.g., parameter values guaranteeing stability of healthy equilibria).
Results: Despite the wide range of biological domains and data sources combined into the model, it is able to exhibit larger-scale behaviors that result from mechanistic interactions of the smaller subsystems. Most notably, the model is able to confirm the prevailing hypothesis on the etiology of environmental enteropathy [1, 2], i.e., a) malnourishment leads to an increased susceptibility to infection, b) recovery time of intestinal damage after acute pathogen infection is increased because of malnutrition, and c) the increased duration of intestinal damage leads to a prolonged duration of malabsorption, causing a further deterioration of nutritional status. The model predicts that, with repeated exposure to enteric pathogens, even children with age-appropriate required gross intake may incur a cumulative energy deficit large enough to fall off a “normal” growth trajectory. Simulated reproduction of these behaviors confirms the “synergy”/super-additivity that is often reported between the effects of undernourishment and infection on growth faltering [1].
Conclusions: Model simulations suggest that reductions in macronutrient and energy availability for metabolism and growth are not just the result of deficient dietary intake, but may also arise due to repeated exposure to pathogens. Effective interventions should therefore be focused on increasing both nutritional quantity/quality and sanitation/water quality/hygiene.
Sponsored by the Bill & Melinda Gates Foundation, Healthy birth, growth and development initiative
References:
[1] Guerrant, R. L., Oriá, R. B., Moore, S. R., Oriá, M. O., & Lima, A. A. (2008). Malnutrition as an enteric infectious disease with long-term effects on child development. Nutrition reviews, 66(9), 487-505.
[2] Lunn, P. G. (2000). The impact of infection and nutrition on gut function and growth in childhood. Proceedings of the Nutrition Society, 59(01), 147-154.
Reference: PAGE 25 (2016) Abstr 5802 [www.page-meeting.org/?abstract=5802]
Poster: Methodology - Other topics