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Metabolism \u0026 Nutrition, Part 1: Crash Course Anatomy \u0026 Physiology #36

Energy metabolism and micronutrients -

Painter, D. Send all comments or additions to: Frankp chiro. FROM: J International Medical Research May ; 35 3 : � ~ FULL TEXT Huskisson E, Maggini S, Ruf M. King Edward VII Hospital, London, UK. Physicians are frequently confronted with patients complaining of fatigue, tiredness and low energy levels.

In the absence of underlying disease, these symptoms could be caused by a lack of vitamins and minerals. Certain risk groups like the elderly and pregnant women are well-recognized.

Our aim was, therefore, to find out if other, less well-established groups might also be at risk. Thus, the objectives of this review are: to describe the inter-relationship between micronutrients, energy metabolism and well-being; identify risk groups for inadequate micronutrient intake; and explore the role of micronutrient supplementation in these groups.

Micronutrient supplementation can alleviate deficiencies, but supplements must be taken for an adequate period of time. From the FULL TEXT Article: Introduction Every doctor is familior wi1b the patient who presents complaining of a lack of energy.

Food consumption between groups was compared using Mann—Whitney test. Analysis was done using GraphPad Prism software version 9 San Diego, CA, USA.

Data is represented as ±SEM unless otherwise indicated. We first determined whether the diet successfully induced micronutrient deficiency in the treated mice. Our results showed stark depletion of all five micronutrients in the LM mice compared to controls Figures 1A — F.

Mice on the low-micronutrient diet presented with anemia, indicated by several markers on the complete blood count panel. Reticulocyte to hemoglobin ratio, a strong indicator of bone marrow malfunction in reticulocyte production and aplastic anemia, was also reduced in the low-micronutrient group.

No difference was seen in red blood cell count and hemoglobin between the groups Figures 1G — M. Intriguingly, we also found copper, selenium, and molybdenum depletion and elevated manganese, although these nutrients were unaltered in our dietary formulation Supplementary Figure S1 in the LM group.

Taken together, we successfully created a co-occurring multiple micronutrient deficient mouse model with induced anemia.

Figure 1. Model design, micronutrient depletion and impact on host physiology. B—F Micronutrients [iron in liver tissues, serum folate and vitamin B12, retinal vitamin A ] and zinc in liver were markedly lower in LM mice.

Next, we examined the impact of postnatal micronutrient deficiency on growth and body composition. Figure 2. Impact of early life multiple micronutrient deficiencies on growth and body composition. Body composition assessed by DEXA scan Day 0 i. DEXA scan showed altered body composition in the LM group.

In summary, our model showed substantially altered growth and body composition in response to the low-micronutrient diet. Although aberrant glucose metabolism has been shown to be associated with some severe acute malnutrition survivors later in life, this link has not been explored in the case of multiple micronutrient deficiencies 19 , 20 , Thus, we investigated the impact of early-life micronutrient deficiency on glucose and insulin metabolism.

Since insulin and IGF-1 are major hormones that play roles in both linear growth and glycemic control 30 , we next measured insulin and IGF-1 concentrations. Further, no difference was found in serum insulin degrading enzyme, an enzyme involved in insulin clearance Supplementary Figure S2.

Figure 3. Glucose metabolism dysregulated in mice fed the low-micronutrient diet. A—F Fasting glucose, intraperitoneal glucose tolerance test IPGTT area under the curve AUC , intraperitoneal insulin tolerance test IPITT AUC. G—J IGF-1, serum insulin, liver glycogen storage periodic acid-Schiff stain, data not shown , glycogen assay and glucagon were assessed.

We further examined several pathways regulating glucose homeostasis, namely glycogenesis, and gluconeogenesis. Next, we examined glucagon, one of the key stimulators of hepatic glucose production Altered lipid phenotype in ten out of the thirty-one free fatty acids FFA measured was found.

Among the significant FFAs, polyunsaturated fatty acids PUFAs tended to be lower than monosaturated fatty acids MUFAs and saturated fatty acids in both groups. The complete list of results is provided Supplementary Table S1. Overall, we showed that energy metabolism was dysregulated in response to postnatal exposure to a multiple micronutrient-deficient diet.

Figure 4. Postnatal multiple micronutrient deficiencies alter non-esterified free fatty acids NEFA. Data represents 6 mice per group and the mean value represented as ± SEM. A paucity of data exists on the metabolic function of the maturing microbiome, especially within the context of undernutrition.

We performed shotgun metagenomics at the start Day 0 and end Day 28 of the experiment and investigated pathways related to glucose metabolism in the gut microbiome. Our results revealed a shift in the functional metabolism of the gut microbiome on Day 28 Figure 5A.

No difference was found in these sugars prior to dietary treatment at the Day 0 timepoint Supplementary Figure S3. Figure 5. Early life micronutrient deficiency alters gut microbiome functional pathways and SCFA profile. A Functional pathway bar plot.

B Glucose homeostasis, C Entner-Doudoroff, D monosaccharides utilization, E disaccharide utilization, F amino sugar utilization, G polysaccharide utilization, H Short-chain fatty acid analysis. I SCFA and fasting glucose correlation analysis.

Gut microbiome functional pathway analysis, central metabolism J , fatty acids K , protein metabolism L , branched-chain amino acid metabolism, isoleucine M , leucine N and valine O. All y axis values represent their percent abundance in the metagenomic functional dataset.

Wilcoxon tests were used to calculate all p values, which were then FDR corrected. SCFA analysis represented as q values.

SCFA, short-chain fatty acid. We found a significant difference in other functional metabolic pathways, including increased capacity in the central metabolism pathway i. We further examined whether the metagenomic findings could be observed in vitro.

For this end, we performed a carbohydrate fermentation assay on Day 28 fecal samples and examined the saccharolytic ability of the fecal microbiome exposed to several types of sugars, namely xylose, glucose, ribose, mannose, trehalose, maltose, lactose, and confirmed utilization indicated by pH change i.

Both groups consumed the sugars, producing organic acids which caused a reduction in pH changing the media from red to yellow data not shown. However, we observed differences in the gas-by product produced by the bacteria from the LM group consuming sugars compared to the controls.

Among the monosaccharides, mannose, and glucose were more greatly fermented, while maltose and lactose were more abundantly fermented among the disaccharides Table 2.

SCFAs are byproducts of carbohydrate fermentation and involved in energy metabolism which we further examined within our model. No difference was seen in other SCFAs Figure 5H. We saw no correlation between these two SCFA and fasting blood glucose in mice Figure 5I.

Taken together, we found that a low-micronutrient diet alters the energy metabolism and functional output of the developing microbiome and has a marginal effect on SCFA production. Zinc has been shown to play a role in stunting, glucose metabolism, and gut microbiota alteration 33 , Therefore we chose zinc as a likely candidate to examine the effect of a single micronutrient on these parameters.

Zinc deficiency did not result in growth faltering or in glucose metabolism Figures 6A — G. Figure 6. A Body weight comparison CON, LM, and ZND. B Intraperitoneal glucose tolerance test IPGTT, C IPGTT area under the curve bar plots. D Tail length CON and ZND, E Serum IGF1 CON and ZND, F Glucagon CON and ZND, G Pro-insulin CON and ZND.

Co-occurring micronutrient deficiencies are a global health problem that is vastly understudied. We developed a postnatal mouse model of multiple micronutrient deficiencies that addresses micronutrients of important public health concerns.

Our results suggest that multiple micronutrient deficiencies result in physical and metabolic changes in the host and gut microbiome that is consistent with other malnutrition models and human cohorts 7 , 23 , 33 , 35 , Surprisingly, we found simultaneous copper, selenium, and molybdenum deficiency and trapped manganese in the liver, yet all were not excluded from the diet.

The findings of copper deficiency associated with zinc depletion are of particular interest as previous literature shows that the only known relationship between these two micronutrients is that high, and not low, zinc is associated with low copper by preventing its absorption These intersecting relationships have not been previously described in an animal model or known in humans.

Our findings underscore the critical need to study multiple micronutrients and the interaction between host and gut microbiome metabolic function as these nutrients act in concert. Moreover, the lack of difference in our zinc-only experiment on growth, glucose, and insulin metabolism and behavior further supports the need to study co-occurring rather than single deficiencies within the context of global undernutrition.

A summary table of human studies and animal experiments with zinc deficiency and supplementation is provided in Supplementary Table S3. Micronutrients are critically involved in energy metabolism directly or indirectly by acting as cofactors or coenzymes, specifically in glucose metabolism through endocrine, biochemical, and microbial pathways 34 , However, much remains to be understood about their causal relationship.

Mice on the low-micronutrient diet consistently showed lower fasting glucose and lower circulating glucose levels within our model. While we hypothesized that impaired insulin clearance might play a role, we did not find evidence supporting this mechanism.

An interesting follow-up would be to examine whether postnatal exposure to multiple micronutrient deficiencies increases the risk of metabolic disease later in life, where the current model could be adapted to emulate the double burden of malnutrition, which is described as the cooccurrence of multiple forms of malnutrition within the same individual This model is currently under development.

Altered lipid metabolism, elevated or decreased levels, is frequently observed in malnourished children and animal models 23 , 39 , Moreover, both dyslipidemia and higher lipid serum concentration in adulthood are correlated with early-life undernutrition in children We did not alter lipids in our treatment group; thus, our findings suggest either malabsorption or dysfunction in the metabolism of lipids in mice fed a low-micronutrient diet.

Our findings were consistent with lower PUFA profiles frequently found among children with severe acute malnutrition SAM and moderate acute malnutrition MAM Interestingly, the PUFA profile in our model differed from SAM and MAM studies which are characteristic of lower arachidonic and docosahexaenoic acids as the main drivers in this model were γ-linoleic, dihimo γ-linoleic, eicosapentaenoic EPA , and docosapentaenoic clupanodonic acids DPA This, however, may be due to several factors, the most predominant being the form of malnutrition.

Severe acute and moderate acute malnutrition is caused by protein-energy deficiency, whereas our model focused on micronutrient deficiencies and was done in mice. Essential fatty acid deficiency EFAD is also common in children with severe acute malnutrition 41 , Given our fatty acid phenotype, our data suggest a potential onset of essential fatty acid disease within this mouse model, although this needs to be confirmed.

Moreover, low plasma NEFA is indicative of suppressed lipolysis, which induces increased fat storage. Given that our DEXA did not show an increased fat mass in the low-micronutrient mice, the altered fatty acid may have also contributed indirectly to our aberrant glucose phenotype.

Impaired fatty acid metabolism has also been shown to increase the risk of metabolic diseases, and our findings point to potential mechanisms of the developmental origins of disease in the undernourished In a cohort of undernourished infants with environmental enteric dysfunction EED in rural Pakistan, Narvaez-Rivas and colleagues found altered NEFA metabolism and EFAD correlated with impaired growth in EED children.

The infants also presented with EFAD linked to lower linoleic and n-6 PUFAs. Conversely, higher oleic acid was observed and suggested as a compensatory mechanism for dysregulated lipid metabolism Additional follow-up studies examining NEFA over multiple time points and growth would shed additional insights.

Furthermore, our model provides an excellent opportunity to elucidate the role of micronutrients in NEFA metabolism and EFAD in undernourished children. We conclude that different forms of malnutrition may select for different fatty acids, but the characteristic feature remains the same in the undernourished phenome, and our data complements findings in children.

Functional maturation of the microbiome is marked by its metabolic capacity, namely to utilize and degrade certain nutrients, like sugars or short-chain fatty acids, during different stages of development Derrien et al.

showed that the developing microbiome has a greater capacity for simple carbohydrate utilization, whereas functions to utilize and degrade complex carbohydrates e. Our data support an overall functional change in metabolism in the gut microbiome of the low-micronutrient-fed mice.

Although we did not see any differences between the groups in our SCFA analysis, we may have been underpowered to detect these differences. SCFAs have been shown to play a central role in host energy metabolism.

Propionate is the only SCFA substrate for gluconeogenesis in ruminants, where it is converted to glucose through the tricarboxylic acid TCA cycle, and studies have shown its role in glucose and insulin regulation 45 , We also found a strong trend toward lower isobutyric acid in the LM group.

Isobutyrate is a branched short-chain fatty acid BSCFA produced through fermentation of branched-chain amino acids BCAA , mainly by Bacteroides and Clostridium species However, BSCFAs are less studied, and their function insufficiently understood.

Nonetheless, BSCFA was recently investigated in energy metabolism and shown to modulate glucose and lipid metabolism in adipose tissue SCFAs can act on hormones such as glucagon-like peptide-1 GLP-1 and leptin to regulate host glucose SCFAs are substrates and regulators of lipid metabolism.

They, mainly butyrate and acetate, can activate fatty acid oxidation and inhibit lipolysis in adipose tissues, which impacts host energy 49 , Additional follow-up studies supplementing the diets with various SCFAs and examining adipose tissue and fatty acids via DEXA would be useful to examine their role in lipid and glucose metabolism in the micronutrient deficient host.

Our data also showed that micronutrient deficiency significantly impacts reshaping metabolism within the gut microbiome. How this differs between species and which can gain fitness in such an environment awaits further exploration. Early-life exposure to nutritional deficiencies has been linked to decreased neurocognitive function, including decreased verbal and motor skills, delayed learning, and spatial memory deficits in children We investigated the impact of early-life multiple and single micronutrient malnutrition on neurocognitive outcomes in mice.

Overall, we reported that mice in the LM group traveled less distance and alternated to different arms of the Y-maze than the CON and ZND mice; however, this was not significant after final adjustment calculations. It could be that the mice in the LM group had less exploration in general, which altered their final score.

We also reported no difference in brain weights. Our model has the following limitations; first, while insightful, mouse models have limited translations to humans. Nonetheless, they provide valuable biological information that can be further assessed using humanized mouse models and in vitro and ex vivo experiments e.

We only used male mice in this current model, and although the original plan was to include females, the COVID research disruption altered this course.

Future work would benefit from examining sex differences as micronutrients are metabolized and utilized differently in females.

We did, however, in our maternal model of micronutrient deficiency Holani et al. Other parameters remain to be explored. Multiple micronutrient deficiencies remain a grossly understudied area of research.

Global nutritional policies and interventions have been designed to address this condition, yet multiple micronutrient supplementation has only marginally delivered on its perceived promises 7 , 8 , 52 , In some cases, supplementation has improved micronutrient status but not growth.

In other situations, high doses of multiple supplements had less impact than single supplements 8. While in others, deficiency persisted despite supplementation, suggesting our understanding of the underlying biology is incomplete.

To our knowledge, animal models have not been used to guide many of these interventions or policies. Salameh et al. have also proposed the use of undernutrition animal models as a useful tool for nutritional assessment and devising therapeutic strategies Here, we both developed a model for postnatal multiple micronutrient deficiencies and simultaneously investigated mechanisms that may aid in our understanding of metabolic disease in host and microbiome.

Our model provides an exciting opportunity to study cooccurring micronutrient deficiencies that complement clinical trials to guide interventions that target both the host and gut microbiome and exploration of mechanisms underscoring the Developmental Origins of Health and Disease within a multiple micronutrient deficient perspective.

PL conceptualized and wrote manuscript, designed and executed experiment, and made figures. HB-Y edited manuscript and assisted with experiments. KE helped with experiments and edited manuscript. HL, CR-C, XH, PL, and KE performed all glucose measurements, analysis, and interpretation.

RH assisted with experiments and editing manuscript. AM-R performed bioinformatics, figures, and edited manuscript.

YF performed literature review. PL, YF, and TY performed the carbohydrate fermentation assay, assisted in writing the methods, imaging, and interpretation. NR performed the Y maze test, data analysis, and wrote methods. YF made zinc table. JJ helped draft the initial version and assisted with glucose metabolism interpretation.

PL, HB-Y, and BF reviewed and approved final version of the manuscript. All authors contributed to the article and approved the submitted version. This work was supported by research grants from the Canadian Institutes of Health Research CIHR BF [FDN] and grant from the Bill and Melinda Gates Foundation grant OPP The funder has no involvement or restrictions regarding publication.

BF is a University of British Columbia Peter Wall Distinguished Professor. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Biesalski Hans, K, and Jana, T.

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The term metabolims refers to vitamins and micronuttrients, which can be divided Ebergy macrominerals, trace minerals Calcium-rich foods water- and fat-soluble vitamins. An Sports diet plan amount metabolksm micronutrients often Energy metabolism and micronutrients aiming for a Energy metabolism and micronutrients diet. Micronutrients are one of the major groups of nutrients your body needs. They include vitamins and minerals. Vitamins are necessary for energy production, immune function, blood clotting and other functions. Meanwhile, minerals play an important role in growth, bone health, fluid balance and several other processes. This article provides a detailed overview of micronutrients, their functions and implications of excess consumption or deficiency. The micrpnutrients body requires micronutrients micrpnutrients trace amounts microonutrients normal growth and development. They are one of the major groups Senior sports nutrition tips nutrients in the body, including Senior sports nutrition tips and vitamins. Vitamins are crucial to perform various functions such as energy production, immune function, blood clotting, etc. At the same time, minerals have an essential role in growth and help in fluid balance and several different processes. There are different kinds of micronutrients that one should take into their diet.