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

Abstract

IntroductionMicronutrients 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.Methodswe 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.ResultsOur 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.DiscussionTogether, 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.

A Murine Model of Maternal Micronutrient Deficiencies and Gut Inflammatory Host-microbe Interactions in the Offspring

“…Our model was based on a previous study from our lab, which characterized the role of micronutrients in host growth, metabolism, and gut microbiome in mice. 39 Micronutrients interact to influence absorption and bioavailability of each other, and hence, co-existing and increased deficiencies in minerals and vitamins are likely. 1 , 39 , 40 , 41 , 42 , 43 However, previous maternal animal models involving micronutrients are based on deficiency/supplementation of only 1 or 2 micronutrient(s) and are unable to interrogate the deleterious outcomes of multiple co-existing MNDs.…”

“… 39 Micronutrients interact to influence absorption and bioavailability of each other, and hence, co-existing and increased deficiencies in minerals and vitamins are likely. 1 , 39 , 40 , 41 , 42 , 43 However, previous maternal animal models involving micronutrients are based on deficiency/supplementation of only 1 or 2 micronutrient(s) and are unable to interrogate the deleterious outcomes of multiple co-existing MNDs. A recent maternal model of single MND shows that gestational vitamin C deficiency induces aberrant DNA methylation in fetal germ-cell development, resulting in lower oocyte numbers and reduced fecundity rate in the female offspring.…”

“…Furthermore, the LM pups did not exhibit any overt signs of stunting, such as reduced tail length and body weight, perhaps due to the specific time frame of the model and the absence of more severe forms of malnutrition. 39 , 46 …”

“…C57Bl/6J mice were acquired from the maximum barrier facility at Jax. Based on previous findings from our lab, 39 2 experimental approaches were undertaken to develop the early-life MMND model using C57Bl/6N mice: In model 1, mice were randomly assigned to either a CON or an LM diet deficient in vitamin A, vitamin B12, vitamin B9, zinc, and iron (#D18062501I and #D19041709I, respectively; Research Diets Inc) ( Table 7 ). Because gut resident bacteria can synthesize vitamin B12 and mice are coprophagic, pectin fiber was added to LM diet to prevent reabsorption of vitamin B12, whereas cellulose fiber was added to CON diet as a corresponding control.…”

Dietary micronutrients intake and its effect on haemoglobin levels of pregnant women for clinic visit in the Mount Cameroon health area: a cross-sectional study

“…Although required in small amounts, the impact of their deficiency is severe ( 3 ). Globally, more than 2 billion people suffer from micronutrient deficiencies, with the main being iron, zinc, iodine, vitamins A and B ( 4 , 5 ). During pregnancy, these deficiencies which results from; lack of consumption of nutrient-dense food groups, poor understanding of the importance of a diverse diet and inefficient utilisation of available micronutrients ( 6 , 7 ) can lead to a myriad of adverse maternal and perinatal outcomes including; anaemia, increased susceptibility to infectious diseases, low birth weight, preterm birth, increased risk of maternal and neonatal mortality as well as cognitive deficit in the baby later in life ( 2 , 8 ).…”