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Littlejohn, Paula T.

University of British Columbia

Worldwide, approximately 340 million children, 50% of children < 5 years old, suffer from multiple micronutrient deficiencies. Termed “hidden hunger,” micronutrient deficiencies are silent contributors to death and disease burden. While vulnerability to micronutrient deficiencies remains throughout life, considerable evidence shows that early-life nutritional insults increase disease risk later in life through various mechanisms, including the gut microbiome, epigenetic modulation, and metabolic programming. This is expected, as the first 1000 days (first 2 years of life) is a critical period of host development and coincides with the assembly and maturation of the gut microbiome. The global malnutrition literature lacks relevant biological models to investigate the impact of early life micronutrient deficiencies and methods to study the long-term effects. To address this gap, we created a novel multiple micronutrient deficient murine model to characterize the host phenome, set of phenotypes expressed by an organism, tissue, cell, or organ, and the gut microbiome. I further developed this model to investigate the long-term effects of postnatal micronutrient deficiency exposure in a condition known as the double burden of malnutrition. We used weanling C57Bl/6N mice fed an experimental control or a multiple low-micronutrient diet deficient in (vitamin A, B12, B9, zinc, and iron) for 4-weeks. In the second experiment, at the end of 4-weeks, mice were challenged with a high-fat diet for 12 weeks. Characterization of the host phenome within growth, metabolism, and methylome domains revealed significant stunting, altered body composition, and lipid profile and dysregulated glucose metabolism. Metagenomics sequencing of the microbiome showed significant dysbiosis driven by an expansion of relative and absolute (10¹⁰ CFU) abundance of Enterobacteriaceae, namely Klebsiella and Enterobacter. Despite the lack of antibiotic exposure, we observed significant expansion in antibiotic resistance mechanisms, namely efflux pumps, degradation enzymes, permeability, target site, and antibiotic resistance genes at 4-weeks. Moreover, postnatally micronutrient deficient mice later exposed to a high-fat diet had greater glucose intolerance and insulin resistance than control mice fed a high-fat diet. These findings highlight several unappreciated roles of postnatal multiple micronutrient deficiencies in the global threat of antibiotic resistance dissemination and the risk of non-communicable disease in low-to-mid-income countries.

Text; Moving Image

2024-03-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/82525

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/