Multiple micronutrient deficiencies alter energy metabolism in host and gut microbiome in an early-life murine model

Paula T Littlejohn; Haggai Bar-Yoseph; Karlie Edwards; Hong Li; Cynthia Y Ramirez-Contreras; Ravi Holani; Avril Metcalfe-Roach; Yiyun M Fan; Tom Min-Shih Yang; Nina Radisavljevic; Xiaoke Hu; James D Johnson; B Brett Finlay

doi:10.3389/fnut.2023.1151670

Multiple micronutrient deficiencies alter energy metabolism in host and gut microbiome in an early-life murine model

Front Nutr. 2023 Jul 10:10:1151670. doi: 10.3389/fnut.2023.1151670. eCollection 2023.

Authors

Paula T Littlejohn^{1

2}, Haggai Bar-Yoseph¹, Karlie Edwards³, Hong Li⁴, Cynthia Y Ramirez-Contreras⁵, Ravi Holani¹, Avril Metcalfe-Roach^{1

2}, Yiyun M Fan⁶, Tom Min-Shih Yang², Nina Radisavljevic^{1

7}, Xiaoke Hu⁴, James D Johnson⁴, B Brett Finlay^{1

2

7}

Affiliations

¹ Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.
² Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.
³ Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
⁴ Life Sciences Institute and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.
⁵ Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
⁶ Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.
⁷ Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.

Abstract

Introduction: Micronutrients perform a wide range of physiological functions essential for growth and development. However, most people still need to meet the estimated average requirement worldwide. Globally, 2 billion people suffer from micronutrient deficiency, most of which are co-occurring deficiencies in children under age five. Despite decades of research, animal models studying multiple micronutrient deficiencies within the early-life period are lacking, which hinders our complete understanding of the long-term health implications and may contribute to the inefficacy of some nutritional interventions. Evidence supporting the Developmental Origins of Health and Disease (DOHaD) theory demonstrates that early-life nutritional deficiencies carry life-long consequences mediated through various mechanisms such as abnormal metabolic programming, stunting, altered body composition, and the gut microbiome. However, this is largely unexplored in the multiple micronutrient deficient host.

Methods: we developed a preclinical model to examine undernutrition's metabolic and functional impact on the host and gut microbiome early in life. Three-week-old weanling C57BL/6N male mice were fed a low-micronutrient diet deficient in zinc, folate, iron, vitamin A, and vitamin B12 or a control diet for 4-weeks.

Results: Our results showed that early-life multiple micronutrient deficiencies induced stunting, altered body composition, impaired glucose and insulin tolerance, and altered the levels of other micronutrients not depleted in the diet within the host. In addition, functional metagenomics profiling and a carbohydrate fermentation assay showed an increased microbial preference for simple sugars rather than complex ones, suggestive of a less developed microbiome in the low-micronutrient-fed mice. Moreover, we found that a zinc-only deficient diet was not sufficient to induce these phenotypes, further supporting the importance of studying co-occurring deficiencies.

Discussion: Together, these findings highlight a previously unappreciated role of early-life multiple micronutrient deficiencies in shaping the metabolic phenome of the host and gut microbiome through altered glucose energy metabolism, which may have implications for metabolic disease later in life in micronutrient-deficient survivors.

Keywords: glucose dysregulation; gut microbiome; insulin dysregulation; multiple micronutrient deficiencies; stunting.