The Gap Series · Essay 8 · Nutrigenomics · Biochemical Individuality
Calories are the least interesting thing about food. Every meal you eat is a set of biochemical instructions — signals that activate genes, regulate hormones, feed or starve microbial communities, and influence inflammation, detoxification, mood, and metabolism. The response to those instructions varies profoundly between individuals. Which is why the same diet produces such different results in different people.
This is part of The Gap — a series of clinical essays on what medicine misses. Earlier essays cover reference ranges, the gut as a system, stress physiology, and thyroid investigation.
There is a question I get asked, in one form or another, more than almost any other.
It goes like this: I've tried eating healthily. I follow the guidelines. I've done the Mediterranean diet, the low-carb diet, the plant-based diet, the elimination diet. Some things work for a while and then stop. Some things never work at all. Other people I know seem to thrive on exactly what makes me feel worse. Why is this so complicated?
The honest answer is that it's complicated because nutrition science has, for most of its history, asked the wrong question. It has asked what foods do to people in general — in populations, in averages, in statistical distributions — rather than what foods do to a specific person given their specific genetics, microbiome, metabolic state, gut function, stress load, and hormonal environment.
The field that is beginning to ask the right question is nutrigenomics — the study of how nutrients interact with genes, and how genetic variation shapes the response to diet. Combined with what we can now measure about the gut microbiome, the metabolic picture, and the functional status of key biochemical pathways, it is producing a clinical framework that makes the contradictions in conventional nutrition advice understandable — and actionable.
Food is not fuel. It is information. And the body's response to that information depends entirely on the receiver.
To understand why dietary individuality is so profound, it helps to understand what happens to a nutrient between the moment it enters the mouth and the moment it influences cellular function.
First, it has to be digested — broken down by stomach acid, pancreatic enzymes, and bile into forms that can be absorbed. Stomach acid insufficiency (extremely common, particularly in older adults and those on PPIs), pancreatic exocrine insufficiency (measured by elastase on the GI-MAP), and bile production or flow impairment all alter what gets absorbed before a nutrient even reaches the systemic circulation. Two people eating identical meals may absorb very different amounts of the same nutrients.
Then it has to cross the gut wall. The state of the gut barrier — whether tight junctions are intact, whether intestinal permeability is elevated — determines not just how much is absorbed but what else crosses alongside it. A permeable gut barrier changes the inflammatory context of every meal.
Then it enters the portal circulation and reaches the liver — where the majority of nutrient metabolism, detoxification, and conversion occurs. The liver's metabolic capacity is genetically variable. The cytochrome P450 enzyme family alone has hundreds of genetic variants that alter how individuals process everything from caffeine to alcohol to fat-soluble vitamins to pharmaceutical drugs.
And then, finally, the nutrient reaches target tissues — where its effects depend on receptor density, cellular metabolic state, competing substrates, and the hormonal environment at that moment.
At every one of these steps, individual variation exists. Significant, measurable, clinically consequential variation. The idea that a single dietary approach can be optimal for all of these variations simultaneously is not a position that survives scrutiny.
Every macronutrient and many micronutrients function as biochemical signals — not just as substrates for energy production, but as inputs to regulatory systems that govern gene expression, hormone production, immune function, and cellular metabolism.
Nutrigenomics has identified a growing number of genetic variants that meaningfully alter dietary requirements and responses. These are not rare mutations — they are common single nucleotide polymorphisms (SNPs) present in significant proportions of the population, many of which have direct nutritional implications.
Genetics sets the parameters. But within those parameters, the gut microbiome is perhaps the most powerful modifier of dietary response — and unlike genetics, it is substantially modifiable.
The Weizmann Institute's landmark 2015 study — the PREDICT-style research led by Eran Segal and Eran Elinav — demonstrated that glycaemic responses to identical foods varied enormously between individuals, and that gut microbiome composition was a better predictor of individual glycaemic response than any other measured variable, including the food itself. Two people eating white bread showed glycaemic responses that differed by as much as a person eating white bread versus a person eating ice cream. The food was the same. The microbiome was different.
This has profound implications for dietary advice. Population-level glycaemic index tables are averages of wildly variable individual responses. A food that is "low GI" for the average person may be high GI for an individual with a specific microbiome composition. And vice versa.
The microbiome also determines the bioavailability of polyphenols — plant compounds with significant health benefits whose absorption depends entirely on microbial transformation. Equol, the active metabolite of soy isoflavones with meaningful oestrogenic and anti-cancer activity, can only be produced by individuals who harbour the specific gut bacteria capable of the relevant transformation. Approximately half the population lack these bacteria entirely — meaning the much-discussed health benefits of soy are substantially inaccessible to them regardless of how much soy they consume.
Beyond genetics and microbiome, the metabolic state at the time of eating matters enormously for how food is processed.
Insulin resistance fundamentally alters the metabolic response to carbohydrate — a person with normal insulin sensitivity and a person with significant insulin resistance eating the same meal will have dramatically different blood glucose trajectories, different fat storage responses, and different inflammatory consequences. Insulin resistance is not binary — it exists on a spectrum that the OAT and blood chemistry can map functionally, and its presence changes the optimal dietary approach substantially.
Cortisol status at the time of eating alters nutrient partitioning — chronically elevated cortisol drives preferential fat storage around the viscera, impairs insulin sensitivity, and alters the balance between muscle protein synthesis and breakdown in response to dietary protein. The stressed person eating adequate protein may not be rebuilding muscle at the rate the intake would predict, because the hormonal environment is directing resources elsewhere.
Mitochondrial function determines how efficiently food is converted to ATP rather than stored or excreted. The OAT markers for the Krebs cycle — citric acid, isocitric acid, cis-aconitic acid, succinic acid — map mitochondrial efficiency. Poor mitochondrial function means food-derived energy is used less efficiently, with more substrate shunted toward fat storage or alternative metabolic pathways.
The conclusion from nutrigenomics, microbiome research, and functional metabolic assessment is not that diet doesn't matter — it is that diet matters enormously, and that the right diet is individual rather than universal.
This is why the diet wars — low-fat versus low-carb versus Mediterranean versus carnivore versus plant-based — are largely unresolvable. Each approach works well for some people and poorly for others, for reasons that are now increasingly understandable. The low-carb approach works particularly well for APOE4 carriers and those with significant insulin resistance. The plant-based approach works particularly well for certain microbiome compositions and those with high saturated fat sensitivity. The Mediterranean approach provides a useful middle ground for many — but "many" is not "everyone."
The question is never "what is the best diet?" The question is "what is the best diet for this specific person, given their genetics, microbiome, metabolic state, and clinical context?" These are different questions that require different investigations to answer.
In clinical practice, this means starting with assessment rather than prescription. The OAT gives functional micronutrient status — which nutritional gaps are actually limiting biochemical processes, regardless of what the dietary intake appears to be. The GI-MAP maps the microbiome and gut function that modifies dietary response. Blood chemistry maps insulin, glucose, and lipid metabolism. The DUTCH maps the hormonal and cortisol context that sits above dietary response.
From that picture, dietary recommendations become specific rather than generic. Not "eat more vegetables" — but "your folate metabolism is compromised by MTHFR variants and your OAT shows low functional B12 status, so the priority is leafy greens daily alongside active folate supplementation." Not "reduce carbohydrates" — but "your fasting insulin is elevated and your microbiome lacks the keystone species needed for efficient fibre fermentation, so reducing refined carbohydrates and supporting specific probiotic strains makes more sense than going broadly low-carb."
I trained early in my career under Bill Wolcott — the developer of Healthexcel Metabolic Typing — and the central principle of that system, whatever one thinks of its specific prescriptions, was correct: there is no universally healthy diet, only diets that are appropriate or inappropriate for a specific biochemical individuality.
Roger Williams coined the term "biochemical individuality" in the 1950s, documenting the extraordinary variation in human anatomy, biochemistry, and nutritional requirements that conventional nutrition science had systematically ignored in its pursuit of population averages. That variation is now being mapped with a precision that Williams could not have imagined — at the genetic level, the microbiome level, the metabolomic level.
The practical implication is the same as it was in Williams's time: food is not a generic input producing a predictable output. It is information entering a specific biological system — and the response to that information is as individual as the system receiving it.
Understanding your system — rather than following someone else's dietary prescription — is the beginning of actually eating for your health rather than for a population average that may not include you.
The DH Clinical Concierge can help map the connections between your symptoms, your diet, and what a proper functional investigation would reveal about your individual biochemistry.
Talk to the Concierge