Metabolomics is the study of metabolites that a specific cellular process leave behind, also called a metabolic ‘fingerprint’. Metabolites are the intermediates and products of metabolism. Metabolites or patterns of metabolites that can be associated with specific diseases or impaired biochemical pathways, may be identified much earlier than frank disease. As research continues this systems biology approach may become more common in standard practice, including the development and acceptance of novel biomarkers that can serve to re-define personalized nutrition interventions. Specifically, Nutritional Metabolomics has noted nutrient metabolites such as, lipids, carbohydrates, and amino acids can be useful in evaluating nutrient status, the impact of diet, and the flow of biochemical pathways. Nutritional Metabolomics could help to facilitate the transition of nutritional sciences from population-based assessments to targeted individual-based nutritional assessment and management.
As I have noted in previous blog posts once all the assessment information has been gathered I use it to identify Core Nutrition Issues. My eight Core Issues are: Metabolomics, Mind-body, Immune, Inflammation, Nutrition, Nutrigenomics, Digestion and Dietoxification: MIND2. If I have laboratory values, such as fatty acids or amino acids, I will do a Nutritional Metabolomics review. I don’t always have a lot of lab values so this section is not vital, but it can help provide more personalized and targeted recommendations.
Metabolomics Study Examples:
Standard Metabolomics research generally takes two groups, one with a condition or disease and one without, and compares the metabolites. Nutritional Metabolomics works to find out what pathways those metabolites are associated with, how the pathways are impacted by diet or nutrient level, and if targeted substrates or nutrient co-factors can support the pathway. The identification of impaired pathways and how to support them may allow for the development of more precise nutritional therapies to prevent or manage chronic disease or conditions. If you’re unsure of the function of a metabolite or which pathway it is in, you can start by looking it up in the HMDB. The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about metabolites. Though be sure to check its references. http://www.hmdb.ca/
Metabolomics and IBD:
Researchers collected blood and urine samples from patients with IBD and healthy adults. Active IBD patients had increased serum levels of the amino acids, leucine, isoleucine, glycine, and phenylalanine, and the organic acids 3-hydroxybutyric acid and lactate. The urine levels of hippurate, succinate and taurine were lower, when compared to healthy controls. The urine metabolites were able to distinguish who had IBD from the healthy subjects. A nutritional metabolomics would then go further to research each of these metabolites, look at the pathways they are involved in, and work to make connections. [Serum and urine metabolomic fingerprinting in diagnostics of inflammatory bowel diseases, World J Gastroenterol. 2014 Jan 7;20(1):163-74. Dawiskiba T et. al.]
More is Better
Highlighting the importance of pathways, researchers of major depressive disorder utilized an analytical method of metabolomics and found that multi-biomarkers were better than single biomarkers at identifying those with major depression compared to healthy controls. Subjects with major depression had higher lipid and glucose levels. Specifically, those with major depression had higher levels of unsaturated fatty acids, adipic acid (adipate), lipids + N-acetyl signals, β- and α-glucose, and lower levels of pyruvate and formate. Adipate is involved in peroxisomal long-chain fatty acid breakdown, which may be impacted by inadequate carnitine, and pyruvate and formate at involved in the kreb cycle. [Zheng, et. al., Clin Chim Acta, 2017.]
Plasma Fatty Acids in T2DM
Researchers investigated fasting fatty acid levels and estimated desaturase and elongase activities as predictors of worsening glycemic control and incidence of type 2 diabetes in a 5.9 year follow-up, population-based study. Total saturated fatty acids, palmitoleic acid (16:1n-7), dihomo-γ-linolenic acid DGLA (20:3n-6) and estimated Δ(9)-desaturase (stearoyl-CoA desaturase1) and Δ(6)-desaturase (D6D) enzyme activities significantly predicted the worsening of glycemic control. Total polyunsaturated fatty acid, linoleic acid (18:2n-6) and elongase activity predicted a decrease. Estimated Δ(6)-desaturase activity and dihomo-γ-linolenic acid DGLA (20:3n-6) were also associated with an increased risk of incident type 2 diabetes. Desaturase enzymes remove hydrogen creating and increase in the carbon/carbon double bonds. Elongase enzymes add 2 carbons at time, elongating the fatty acid. Both desaturase and elongase enzymes have nutrient cofactors to function properly. Insulin is thought to decrease the function of Δ(9)-desaturase enzyme. Palmitoleic acid is biosynthesized from palmitic acid (a saturated fat) by the action of Δ(9)-desaturase. Overexpression of Δ(9)-desaturase has been associated with hypertriglyceridemia, atherosclerosis, and diabetes. [Lankinen MA., et. al. Diabetologia. 2015 Nov;58(11):2533-44]
Metabolomics and IR:
A study of almost 400 subjects, attempted to identify an early biomarker of insulin resistance (IR), a known risk factor for type 2 diabetes and cardiovascular disease, to identify those at risk. The researchers found that when the plasma metabolite alpha-hydroxybutyrate was elevated it correlated with insulin resistance. With an assessment of the metabolites the researchers were able to identify people with insulin resistance with 76% accuracy. Alpha-hydroxybutryate is a metabolite clinicians’ can order. It is involved in increased lipid peroxidation and oxidative stress, and has been proposed as identifying increased glutathione utilization. Low serum glycine was also found to be associated with a higher risk of insulin resistance. Glycine is one of the three components of glutathione. It may be that in the early stages of insulin resistance the physiologic response was to an increase demand for glutathione, due to oxidative stress. Clinicians can support with components of glutathione productions, such as glycine and NAC, as well as support for oxidative stress and inflammation. [a-Hydroxybutyrate Is an Early Biomarker of Insulin Resistance and Glucose Intolerance in a Nondiabetic Population, PLoS ONE. 2010 May 28;5(5).]
Amino Acids and GD
Circulating concentrations of essential amino acids, lysine, tyrosine, and valine were independently and positively associated with gestational diabetes. Research of >1,000 individuals found increased levels of leucine, arginine, valine, proline, phenylalanine, isoleucine and lysine were significantly associated with an increased risk of hypertriglyceridemia in a 7 year follow up. [J Endocrinol Invest. 2014 Apr;37(4):369-74.]
Pathways: From In-born Errors
The earliest use of evaluating metabolites was assessing in-born errors of metabolism. PKU, phenylkentunia, is an inability to breakdown the essential amino acid phenylalanine and it builds up in the blood, which is dangerous. Additionally, all those downstream metabolites that phenylalanine is used to make don’t get made. These include neurotransmitters like epinephrine, thyroid hormones, and melanin. This same theory is used in metabolomics when a pathway does not function well, leading to impairment of needed products and excess substrates. Researchers believe that sometimes enzymes aren’t working fully, and may require higher levels of nutrient co-factors to increase the enzyme’s function. Nutrient deficiencies and insufficiencies may cause a slow down or blockage of the pathway. Looking at the metabolites of a specific pathway may identify individuals that have partially impaired pathway that may not be identified under normal conditions. For example, if an enzyme that breaks down an amino acid needs more of a nutrient co-factor and the person goes on a high protein diet, getting more of the specific amino acid but not more of the nutrient co-factor, it could cause impairments or redirections in the pathway. Additionally, like a lot of things the issue may not show up until later in life, when you have fewer functional reserves to support it.