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University of California, Davis

1. Overview

The University of California, Davis is one of the leading universities in the world in plant science and biological and agricultural sciences. For over 40 years, Mars has been conducting joint research with the university. The partnership began with research into animal nutrition and now covers cocoa flavanols, plant genomics, agricultural sustainability and other areas of food, health and nutrition. Some Mars scientists conduct research within the Department of Nutrition of the university itself. Mars and UC Davis continue to collaborate today on cocoa flavanol research, conducting dietary intervention trials, epidemiological studies, pharmacological research and more.

2. Partnership outcomes

Mars and the University of California, Davis have a long history of collaborative cocoa flavanol research dating back to the 1990s. Some examples of their recent partnership outcomes include papers published in the American Journal of Clinical Nutrition in 2015, Nature Scientific Reports in 2016 and again in Nature Scientific Reports in 2018.

Safety of 2000 mg of cocoa flavanols per day

The research published in the American Journal of Clinical Nutrition in 2015 was designed to look at the safety and efficacy of different intake amounts of cocoa flavanols. In a group of volunteers, we varied the intake amount from 1000 mg to 2000 mg cocoa flavanols per day and they found that all amounts were well tolerated. Some volunteers consumed 2000 mg of cocoa flavanols every day for 12 weeks. There was no significant difference in the type or severity of adverse effects that group experienced when compared to people that were taking a placebo and therefore no cocoa flavanols at all.

Previous research has shown that cocoa flavanols can improve blood pressure, cholesterol and various other metrics at doses far lower than 2000 mg. This study by researchers at Mars and the University of California, Davis has therefore underlined how safe it is to consume flavanols at these levels on a daily basis for research or for consumers wanting to maintain their cardiovascular health.

Read more about this study: Ottaviani, J.I., et al., Safety and efficacy of cocoa flavanol intake in healthy adults: a randomized, controlled, double-masked trial. Am J Clin Nutr, 2015.

A pharmacokinetic profile for (−)-epicatechin

In 2016, scientists from Mars, the University of California, Davis and the University of Reading in the UK published research in Nature Scientific Reports that established a pharmacokinetic profile for the flavanol compound found in cocoa called (−)-epicatechin. The compound is one of the most commonly consumed flavanols and is found naturally in tea, apples, pears, grapes, various berries and fresh cocoa beans.

We found that when the participants in the study were consuming (−)-epicatechin, none of it ended up in the blood. Instead, it was all metabolized inside the body into a series of over 20 different structurally related compounds. By measuring how long it took for these metabolites to appear in the bloodstream, we were also able to establish that much of this metabolism depended on processes specific to the bacteria in the gut.

Dietary intake of the compound (−)-epicatechin has been shown to improve the function of the blood vessels. The important outcome from this study, though, is that these improvements must be mediated by the 20+ metabolites that are absorbed into the bloodstream rather than by (−)-epicatechin itself. What is more, none of these metabolites act as anti-oxidants inside the body. We believe that any future in vitro cell-culture studies looking at the effects of (−)-epicatechin and other flavanols on the body should take into account how these compounds are metabolized by the body.

Image: the flavanol compounds found in the plants that we eat were shown in this study to be different to the compounds that enter the bloodstream. The compound (−)-epicatechin in metabolized into 20+ structurally related compounds that are then absorbed into the blood.

Another important finding in this study was that humans metabolized (−)-epicatechin differently to rats and mice. This is important because rodent models are often used to test the safety of specific compounds for human consumption. For the first time, we showed that rodents are not equivalent to humans in the metabolism of (−)-epicatechin — which could be the case for other polyphenolic compounds, as well.

Read more about this study: Ottaviani, J.I., et al., The metabolome of [2-(14)C](−)-epicatechin in humans: implications for the assessment of efficacy, safety, and mechanisms of action of polyphenolic bioactives. Sci Reports 2016

Gamma-valerolactone a reliable biomarker of flavanol intake

Another recent outcome from the relationship came from a study conducted by a team from Mars, the University of California, Davis, the University of Reading and the University of Cambridge in the UK. We managed to identify a nutritional biomarker that can be used to assess intake of flavan-3-ols, a type of commonly consumed flavanol found in food. A nutritional biomarker is, roughly speaking, a sort of test that scientists or medical professionals can perform to get an idea of what is going on inside the body. The biomarker discovered in this project is a compound present in the urine called gamma-valerolactone (gVL). Gamma-valerolactone only appears in the urine after people have consumed food or drink containing certain flavan-3-ols, including (−)-epicatechin. Using a urine test, scientists will now be able to assess whether people are consuming a diet high or low in these flavanols. They can use that information in scientific studies to determine whether the amount of flavanols in the diet affects study endpoints, such as the risk of developing cardiovascular disease. Previously, scientists would have to ask study participants to complete a food diary to determine the amount of flavanols in their diet, which can be unreliable.

Importantly, using urinary gamma-valerolactone concentration as a nutritional biomarker meets the criteria laid down by the International Agency for Research on Cancer (IARC) and the Institute of Medicine (IOM) for nutritional biomarkers. As part of the study, we found that the biomarker is specific for flavan-3-ols present in tea, fruits, wine and cocoa-derived products. There is no formation of gVL with other flavonoids or polyphenols. There is also a consistent relationship between the amount of flavan-3-ols consumed in the diet and the amount of gVL in the urine.

Image: Gamma-valerolactone is only formed when people consume certain flavan-3-ols, such as epicatechin gallate (ECG) and the epicatechin monomer (−)-epicatechin. Other polyphenolic compounds such as thearubigins do not result in gVL formation. This makes urinary gVL concentration a biomarker specific to the consumption of certain flavanol compounds.

Read more about this study: Ottaviani, J.I., et al., Evaluation at scale of microbiome-derived metabolites as biomarker of flavan-3-ol intake in epidemiological studies. Sci Reports 2018