Do you have patients who feel something is off but all their labs come back normal? Or wonder what they could do to optimize their health based on all the available data, from functional lab tests to genetics, epigenetics, microbiome, and more? How do we reap the benefits of such research and tests to improve our clinical outcomes? In this article, we will explain how metabolomic testing and AI can help with this problem.

Diagnostic Thinking vs Omics Thinking

Much of medicine, even integrative medicine, still follows the diagnostic model, where practitioners rely on history, symptoms, and diagnostic tests to diagnose disease. Then, they prescribe interventions to treat the diagnosed disease. However, this model tends to miss whether the entire person is healthy and if there are other opportunities to optimize health or catch diseases before they occur. 

In contrast, the omics model, such as metabolomics, uses the latest computational and testing powers to analyze all these together to derive the best health insights and decisions. In this article, we’ll explain metabolomic testing and how it can fix problems that arise from diagnostic thinking.

What Is Metabolomics?

Metabolomics is the omics of metabolites. It is a growing field that involves the measurement and analysis of all or a representative number of the metabolites and small molecules in a biological sample [1]. 

Metabolomics has two parts: 1) the lab-based measurements of metabolites and 2) the computational analyses in reference to pre-existing knowledge.

Metabolites are substances that are byproducts of all metabolic functions in the body. High-throughput mass spectrometry technologies make it possible to accurately measure far more metabolites than current lab techniques. 

The suffix “-omic” means the collective detection and analysis of all items that are present at a given time. Because you have well over 20,000 genes, up to 400,000 proteins, and over 220,000 identified metabolites, all omics generate huge amounts of data. To examine and derive useful actionable info from the big data, you will need powerful computers and artificial intelligence.

Image source: [2]

After the measurements, metabolomics also involves collective analysis of all data points together. Ideally, the algorithm should integrate background information about the person, such as disease states, symptoms, and health history. Some more sophisticated algorithms may also be able to take into account wearable data or daily measurements.  

In short, metabolomics offers a more complete picture of biological processes and metabolic pathways, making it a powerful tool in precision medicine.

What Does Metabolomics Tell You?

It’s easy to fall into the trap of diagnostic thinking, even with metabolomic tests. Most metabolomic tests on the market list out the metabolites, their levels, and perhaps your levels relative to the population. However, their interpretations tend to be diagnostic, such as identifying a Candida infection, mitochondrial dysfunction, or specific detoxification dysfunctions. Then, they recommend specific treatments based on the identified diagnosis.

This table provides a quick comparison of metabolomic tests on the market:

Theriome Aristotle	GenovaDX NutrEval	MosaicDX Organic Acids (OAT)
Dried blood spot	Blood draw, Urine sample	Urine sample
Analysis of 126 metabolites Organized into 12 key health domains Utilizes Digital twinning personal protocol for each domain. Recommendations include dietary, vitamin, mineral, herbal, supplement, lifestyle and pharmacological interventions Disease signatures with risk percentages Utilizes GC/MS, a technique reserved for metabolite analysis	Analysis of 119 metabolites Functional nutrition testing for individual metabolites  Organized into functional imbalance scores Provides nutrient recommendations based on a single metabolite or specific diagnosis  Utilizes ICP-MS, a technique typically reserved for elemental analysis and not metabolites	Measures 76 organic acids  Comprehensive nutritional and metabolic snapshot  Provide recommendations based on a single metabolite or specific diagnosis   Utilizes GC/MS, a technique typically utilized for metabolite analysis

Theriome, in contrast, not only uses state-of-the-art testing but also computational analyses that allows you to harness the following untapped benefits of metabolomics.

Health-related emergent properties

Beyond just the single test results or a list of metabolites, all the metabolites working together in your body create properties that are greater than the sum of their parts.These are called emergent properties. 

Examples of emergent properties:

1. Genetic readouts (expression) combined with environmental inputs can determine the eventual form and function of a cell [3]. 
2. Individual microbes in your gut flora are much more easily killed than your entire gut flora that inhabit your gut. Also, the more diverse and complex they are, the harder these microbes to change. After a dose of antibiotics, the more diverse and complex flora bounce back faster [4].
3. Complex conditions like cancers and cognitive dysfunction happen as a biological system reorganizes its constituting parts to generate different properties [5].

Health and disease states result from emergent properties, so it’s important to treat the whole person and not just specific numbers. Given the huge amount of data available, both from previous studies and your metabolomic measurements, the right metabolomic algorithms need to take into account these emergent properties. 

Emergent properties that metabolomic tests can measure

Here is a brief overview of each section to better understand the 12 key health domains and how they can be helpful. As you can see, many of them are interconnected with each other. 

1. Aging Index

Age isn’t just the number of years you’ve spent on earth. One can be 90 years old and yet biologically younger than a 70-year old. Several metabolites correlate with metabolic and biological age [6]. Biological aging also correlates with mitochondrial, metabolic health, inflammation, and gut flora. Therefore, this age index reflects metabolic age. 

Theriome Age Index Metabolites: sarcosine, niacinamide/nicotinamide, fumaric acid, palmitic acid, spermidine, stearic acid, and cadaverine 

Each metabolite comes from pathways that influence the aging process. For example, niacinamide is a metabolite of niacin (B3). Niacinamide is also a precursor for NAD+, which is involved in energy metabolism. Energy metabolism naturally decreases as we age. We can understand how we may be aging metabolically and our energy levels by measuring this specific metabolite.

1. Nutrition Index 

Nutrient deficiencies are becoming more common due to soil depletion and diets high in processed foods [7]. Nutrient status goes beyond intake, to absorption and metabolism, as some people may have genetic changes that require certain forms of the nutrients. The nutrition index based on metabolomics measures both nutrient levels and usage in the body. A high score on the nutrition index indicates that an individual is meeting their micronutrient needs in terms of dosage, form, and bioavailability. On the other hand, lower scores and the associated recommendations can suggest targeted supplements to correct the deficiencies. These targeted recommendations based on your current biochemical status are not possible with other kinds of tests like genetics or standard blood work.  

Metabolites: ferulic acid, glucose-6-phosphate, oleic and linoleic acid, taurine, niacinamide and adenine, guanine, and other nucleotide metabolites such as thiamine and uracil 

1. Inflammation Index

The inflammatory index measures an individual's overall inflammatory status. One can be inflamed without having any specific disease. However, high levels of inflammation can predict diseases like autoimmunity, cardiovascular diseases, and accelerated aging. This inflammatory score can help identify areas of concern to guide personalized interventions. 

Metabolites: taurine, spermine and spermidine, glutathione, guanosine, palmitic acid, gamma-aminobutyric acid (GABA)

1. Mitochondrial Health

The mitochondria are our cells' powerhouses. They are also responsible for detecting danger and initiating programmed cell deaths (apoptosis) if the cells are damaged [8]. The metabolic health score covers a range of overall metabolites for energy production, which also reflects overall health and danger perception. Suboptimal mitochondrial function can contribute to fatigue, brain fog, accelerated aging, chronic inflammation, and increased health risk. Most of our mitochondrial metabolites are important for the citric acid cycle (Krebs cycle), a key pathway for mitochondrial energy production.

Metabolites: citric acid, succinic acid, fumaric acid, malic acid, adenosine, oxoglutaric acid 

1. Cardiovascular Health

The cardiovascular health index measures pathways related to heart and blood vessel health. Inflammation, lipid metabolism and oxidative stress are all important cardiovascular markers. Monitoring these metabolites makes this index valuable for evaluating the risk of cardiovascular disease or deducing targeted actionable info to improve cardiovascular health. For example, adenosine is well known to have vasodilatory and cardioprotective effects.

Metabolites: adenosine, taurine, homocysteine, palmitic acid, oleic acid, linoleic and alpha-linolenic acid, niacinamide and nicotinic acid

1. Reproductive Health 

The reproductive health index refers to the overall health of the male or female reproductive system and its ability to function optimally. Various biochemical markers can assess reproductive health, and the potential for fertility and hormonal imbalances. For example, adenine is important for DNA and RNA production and plays a critical role in cell reproduction and division.

Metabolites: adenine, inosine, caffeine, palmitic acid, oleic acid, linoleic acid, alpha-linolenic acid, taurine, serotonin

1. Liver Health  

The liver is critical for biotransformation and elimination. It is responsible for filtering toxins and waste products from the blood, producing bile acids, and regulating metabolism. The liver health index measures biomarkers for liver function, including enzymes, to give an overview of liver health.

Metabolites: amino acids, urea cycle metabolites, and fatty acids 

The urea cycle metabolites are important to measure, as the liver plays a key role in detoxifying ammonia. By measuring ornithine and citrulline metabolites, we can get an overview of how the citric acid cycle works. 

1. Gut Health 

The gut health index provides an overall assessment of the digestive system, including key markers that indicate the health of your gut microbiome, inflammation, and nutrient absorption. 

Your gut microbiome is like a back pocket of about 2 million genes, which can adjust themselves to your environment and health status. So, your health is the result of both your own biochemistry and that of your gut microbes. Overall, metabolomic tests measure the sum of both your own and your gut microbes’ metabolites, whether in the blood or urine.

This index is vital as gut health and gut flora are major contributors to all aspects of health.

Metabolites: tryptophan metabolites, amino acids 

1. Neurocognitive Index 

The neurocognitive index measures markers of brain health and function. It measures amino acids, neurotransmitters, and other metabolites important for brain health and neurotransmitter production. These measurements can give insight into how the brain is functioning and indicate any concern for cognitive impairment or decline. 

Metabolites: GABA, serotonin, taurine, caffeine, adenine and adenosine, glutamate, homocarnosine, diaminopimelic acid, and myo-inositol

1. Integumentary Health 

The integumentary index measures the overall health of the skin, hair, and nails. The skin is the largest organ and protects the body and produces vitamin D. For example, glycerol is a humectant important for maintaining the skin's moisture barrier. Palmitic acid is a component of sebum, the oily substance produced by the sebaceous glands that provide moisture to the skin and hair.

Metabolites: taurine, palmitic acid, linoleic and alpha-linolenic, ethanolamine, caffeine, adenine and adenosine, glycerol

1. Environmental and Toxin Exposure Index 

The environmental and toxin exposure index measures the level of toxins and pollutants that can affect human health. This includes heavy metals, pesticides, and industrial chemicals. This index is important to assess the degree of toxic exposure, your detox capacity, and identify potential health risks associated with these harmful substances. The markers in this category also include several methylation markers.

Metabolites: taurine, glutathione, cysteine, cystathionine, methionine, adenine, adenosine, inosine and guanosine, uric acid, malic acid, fumaric acid, succinic acid, and citric acid 

1. Mutational Load 

Mutation load can contribute to biological age and cancer risk. The mutational load index measures the number of unrepaired mutations an individual has accumulated over their lifetime. Mutations can occur for many reasons, such as environmental toxins, aging, and inherited defects. This index is important for identifying people at higher risk for certain diseases and conditions.

Metabolites: adenine, guanosine, inosine, adenosine, taurine, and glutathione 

Artificial Intelligence Health and Metabolomics

Metabolomics and genetic testing generate a tsunami of data that most clinicians don’t know what to do with, especially when they’re not diagnostic. This is not just because of the number of metabolites tested, but also because the relationships between these metabolites have clinical significance. Due to the high volume of metabolites tested, you need solid analysis methodologies.

Omics research started in the early 90s and has boomed in recent years, making available numerous databases and analysis tools as basic research. Unfortunately, only a small fraction of these have been adopted for clinical use, such as in precision oncology and in predicting drug responses [9, 10]. Also, most metabolomic tests on the market do not include AI or even any computational analysis that takes into account the whole person.

Minimize human biases and error in diagnoses and treatments

Practicing medicine relies on knowledge, experience, and intuition. Medicine itself is an algorithm that takes into account a few data points. While doctors are absolutely essential in healthcare, humans are imperfect with biases, flaws, and errors. After all, our brains can only interpret so much data at any given time. Health AI tools like Theriome that take into account numerous data points, learning both from the patient and others, can eliminate several human factor problems. 

Identifying complex disease and disease signature

Numerous metabolomic studies have demonstrated some utilities of metabolomics for complex diseases, for which mainstream blood tests and workup can turn up negative. For example, the Robert Naviaux group at the University of California, San Diego, described a metabolic pattern called the Cell Danger Response. Naviaux posits that this metabolic pattern may explain chronic conditions like autism spectrum, chronic fatigue syndrome, ADHD, and several other chronic inflammatory diseases [11].

Currently, several individual metabolite tests are used for medical purposes such as newborn screening, and drug abuse and monitoring. However, no comprehensive metabolomic tests have been approved for diagnosis, treatment, or prevention for any disease, even though they test some of the diagnostic metabolites [12]. That means comprehensive metabolomic tests like Theriome and Genova Metabolomix+ are currently limited to wellness and health optimization. That said, we incorporate the most cutting-edge analysis algorithms to maximize the value for our patients and practitioners, including our disease signature report.

Our Disease Signature AI-based analysis uncovers potential disease states via metabolic footprints, which may explain some of the ambiguous symptoms and predict risks without being diagnostic [13]. We also base our recommendations and predictions on the latest clinical studies. 

Bypassing trial and error with digital health outcome simulations

Health optimization can involve the painstakingly slow process of making one change at a time to observe for outputs to identify the right changes, duration, dosages, etc. It’s common in functional medicine to prescribe 10 supplements at a time and a diet change, even though it’s difficult to identify what’s most effective or what to modify if the program is ineffective. Digital Twinning provides the very solution to help individualize client protocols in an objective manner.

The Digital Twinning algorithm takes into account your metabolome, health history, and presentation and models various scenarios to predict potential outcomes with different courses of actions. It helps find the best dietary supplements, lifestyle changes, and interventions to improve your overall health based on your metabolomic data and computational simulations. This feature can help you eliminate years of trial and error to optimize your health. 

Uncover the power of Theriome now

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2 Dai, X. and Shen, L. (2022) Advances and trends in omics technology development. Front. Med., Frontiers Media SA 9, 911861 https://doi.org/10.3389/fmed.2022.911861

3 Biological Complexity and Integrative Levels of Organization https://www.nature.com/scitable/topicpage/biological-complexity-and-integrative-levels-of-organization-468/

4 Muller, E., Algavi, Y. M. and Borenstein, E. (2021) A meta-analysis study of the robustness and universality of gut microbiome-metabolome associations. Microbiome, Springer Science and Business Media LLC 9, 203 https://doi.org/10.1186/s40168-021-01149-z

5 Finzer, P. (2017) How we become ill: Investigating emergent properties of biological systems could help to better understand the pathology of diseases. EMBO Rep. 18, 515–518 https://doi.org/10.15252/embr.201743948

6 Bortz, J., Guariglia, A., Klaric, L., Tang, D., Ward, P., Geer, M., et al. (2023) Biological age estimation using circulating blood biomarkers. Commun. Biol., Springer Science and Business Media LLC 6, 1089 https://doi.org/10.1038/s42003-023-05456-z

7 Bird, J. K., Murphy, R. A., Ciappio, E. D. and McBurney, M. I. (2017) Risk of deficiency in multiple concurrent micronutrients in children and adults in the United States. Nutrients 9 https://doi.org/10.3390/nu9070655

8 Naviaux, R. K. (2020) Perspective: Cell danger response Biology-The new science that connects environmental health with mitochondria and the rising tide of chronic illness. Mitochondrion, Elsevier BV 51, 40–45 https://doi.org/10.1016/j.mito.2019.12.005

9 Aldea, M., Friboulet, L., Apcher, S., Jaulin, F., Mosele, F., Sourisseau, T., et al. (2023) Precision medicine in the era of multi-omics: can the data tsunami guide rational treatment decision? ESMO Open, Elsevier BV 8, 101642 https://doi.org/10.1016/j.esmoop.2023.101642

10 Meyer, U. A., Zanger, U. M. and Schwab, M. (2013) Omics and drug response. Annu. Rev. Pharmacol. Toxicol., Annual Reviews 53, 475–502 https://doi.org/10.1146/annurev-pharmtox-010510-100502

11 Naviaux, R. K. (2014) Metabolic features of the cell danger response. Mitochondrion, Elsevier BV 16, 7–17 https://doi.org/10.1016/j.mito.2013.08.006

12 Cheng, S., Shah, S. H., Corwin, E. J., Fiehn, O., Fitzgerald, R. L., Gerszten, R. E., et al. (2017) Potential Impact and Study Considerations of Metabolomics in Cardiovascular Health and Disease: A Scientific Statement From the American Heart Association. Circ. Cardiovasc. Genet. 10 https://doi.org/10.1161/HCG.0000000000000032

13 Theriome Disease Signatures. Theriome https://therio.me/products/disease-signatures