The phrase "You are what you eat" is not only a well-known adage but also an accurate one and also indirectly reflecting the significant impact of diet on both acute and chronic health outcomes [1]. However, identifying the specific dietary molecules responsible for these effects is an extremely challenging task, as dietary habits are highly personalized along with host genetics and gut microbiome composition coordinating a person’s ability to metabolize food (Figure 1). This difficulty to map diet microbial metabolites arises from the vast diversity of diets and the wide range of molecules that are consumed, which can vary significantly depending on dietary sources [2]. At present, the scientific community has limited insight into the exact number and types of molecules ingested daily across the globe 3•, 4.

For example, consider the contrast between the diets of people living in the Brazilian Amazon forest, who rely on hunting and gathering, and those dining in a crepe restaurant along the Seine in Paris, rural villages in China, or a pizza shop in New York City. Each of these meals exposes individuals to vastly different sets of molecules, which leads to the speculation that there could be millions of distinct molecules consumed worldwide. Even for a single individual, the digestive system may be exposed to hundreds of thousands, or even millions, of different molecules throughout their lifetime — even if they maintain a relatively consistent diet. These molecules include those from foods and beverages, various forms of food preparation, as well as non-biological substances such as plastics, building materials, medications, insecticides, and pesticides, which can either be intentionally added to food or unknowingly enter the food supply [5].

Food molecules are digested and metabolized in hosts to form cellular building blocks, provide energy, serve as signals, and perform other functional roles. However, the human genome contains only about 20 000 protein-coding genes, and an even smaller number encodes enzymes that facilitate metabolic reactions. This creates a dilemma: how can such a limited number of proteins metabolize the vast array of food-derived metabolites? While human enzymes may exhibit some degree of promiscuity, carrying out similar biochemical transformations across related molecules, it is implausible that human enzymes alone can perform all the necessary biochemical reactions required to process the many different molecules we consume.

One possible solution to this metabolic challenge lies in the concept of proteoforms — where a single protein undergoes various post-translational modifications, potentially expanding its functional capabilities 6, 7. However, it remains unclear whether different proteoforms could significantly alter metabolic specificity on the scale required to process the enormous variety of metabolites we ingest. Additionally, while the human genome remains mostly stable over time — aside from mutations, antibody recombination, and insertion of endogenous retroviruses — it does not fully explain why some populations are better able to metabolize all the different molecules found in certain foods than others. An example is the ability of the Japanese population to digest seaweed more efficiently than individuals from the United States or Europe due to differences in their microbiomes [8]. The microbiome is a major metabolizer of the diets we consume.